Overview
An estimated 174,650 new cases of prostate cancer will be diagnosed in 2019, accounting for 20% of new cancer cases in men.1 The age-adjusted death rates from prostate cancer have declined 51% from 1993 to 2016.1 Researchers have estimated that prostate cancer will account for 9.8% of male cancer deaths in 2018.1 Over the past several years, the incidence of prostate cancer has declined, likely in part as a result of decreased detection attributed to decreased rates of prostate-specific antigen (PSA) screening.2–4 The decreasing and comparatively low death rate suggests that increased public awareness with earlier detection and treatment has affected mortality from this prevalent cancer.
Early detection can lead to overtreatment of prostate cancers that do not threaten life expectancy, which results in unnecessary side effects that impair quality of life (QOL) and increase health care expenditures. The U.S. Preventive Services Task Force (USPSTF) recommended against PSA testing in 2012.5 The incidence of metastatic disease has increased.4,6 The rate of prostate cancer mortality, which had been in decline for 2 decades, has stabilized.4 Prostate cancer incidence and deaths have increased in the past few years for the first time in recent history, with prostate cancer deaths increasing from an estimated 26,730 in 2017 to 31,620 in 2019.1,7 Increases in the incidence of metastases at presentation and in prostate cancer deaths may be influenced by declines in the rates of prostate cancer early detection, biopsies, diagnosis of localized prostate cancers, and radical prostatectomy that followed the 2012 USPSTF recommendations.8–18 The USPSTF released updated recommendations in 2018 that include individualized, informed decision-making regarding prostate cancer screening in men aged 55 to 69 years.19 These updated recommendations may allow for a more balanced approach to prostate cancer early detection. Better use of PSA for early detection of potentially fatal prostate cancer (see the NCCN Guidelines for Prostate Cancer Early Detection, available at NCCN.org) should decrease the risk of overdetection and overtreatment AND preserve the decrease in prostate cancer mortality.
Prostate Cancer Genetics
Family history of prostate cancer raises the risk of prostate cancer.20–22 In addition, prostate cancer has been associated with hereditary breast and ovarian cancer (HBOC) syndrome (due to germline mutations in homologous DNA repair genes) and Lynch syndrome (resulting from germline mutations in DNA mismatch repair [MMR] genes).23–27 In fact, approximately 11% of patients with prostate cancer and at least 1 additional primary cancer carry germline mutations associated with increased cancer risk.28 Therefore, the panel recommends a thorough review of personal and family history for all patients with prostate cancer.
The newfound appreciation of the frequency of germline DNA repair gene mutations (discussed in more detail subsequently) has implications for family genetic counseling, cancer risk syndromes, and assessment of personal risk for second cancers. Some patients with prostate cancer and their families may be at increased risk for breast and ovarian cancer, melanoma, and pancreatic cancer (HBOC), colorectal cancers (Lynch syndrome), and other cancer types. Data also suggest that patients with prostate cancer who have BRCA1/2 germline mutations have increased risk of progression on local therapy and decreased overall survival (OS).29–31 This information should be discussed with such men if they are considering active surveillance. Finally, there are possible treatment implications for patients with DNA repair defects (see “Treatment Implications for Patients with DNA Repair Gene Mutations,” page 497).
Prostate cancer is often associated with somatic mutations that occur in the tumor but not in the germline. An estimated 89% of metastatic castration-resistant prostate cancer (CRPC) tumors contain a potentially actionable mutation, with only about 9% of these occurring in the germline.32 Both germline and tumor mutations are discussed herein.
Homologous DNA Repair Genes
Somatic mutations in DNA repair pathway genes occur in a reported 19% of localized prostate tumors and 23% of metastatic CRPC tumors, with most mutations found in BRCA2 and ATM.32,33 These tumor mutations are often associated with germline mutations. For example, 42% of patients with metastatic CRPC and somatic mutations in BRCA2 were found to carry the mutation in their germlines.32 In localized prostate cancer, that number was 60%.33 In fact, recent data indicate that 11.8% of men with metastatic prostate cancer have germline mutations in 1 of 16 DNA repair genes: BRCA2 (5.3%), ATM (1.6%), CHEK2 (1.9%), BRCA1 (0.9%), RAD51D (0.4%), PALB2 (0.4%), ATR (0.3%), and NBN, PMS2, GEN1, MSH2, MSH6, RAD51C, MRE11A, BRIP1, or FAM175A.34 In patients with localized prostate cancer in the TCGA (Cancer Genome Atlas) cohort,33 the rates of germline DNA repair mutations were 6% in those with high-risk prostate cancer and 2% in low/intermediate risk.34 In another study, 16% of unselected patients with metastatic CRPC harbored germline mutations in BRCA2, ATM, and BRCA1.35
An additional study showed that 9 of 125 men with high-risk, very-high-risk, or metastatic prostate cancer (7.2%) had pathogenic germline mutations in MUTYH (4), ATM (2), BRCA1 (1), BRCA2 (1), and BRIP1 (1).36 In this study, the rate of mutation identification in men with metastatic disease was 28.6% (2 of 7 men). Although having a relative with breast cancer was associated with germline mutation identification (P=.035), only 45.5% of the mutation carriers in the study had mutations that were concordant with their personal and family history. Another study also found that a family history of breast cancer increased the chances of identifying a germline DNA repair gene mutation in men with prostate cancer (odds ratio [OR], 1.89; 95% CI, 1.33–2.68; P=.003).37 In a study of an unselected cohort of 3,607 patients with a personal history of prostate cancer who had germline genetic testing based on clinician referral, 11.5% had germline mutations in BRCA2, CHEK2, ATM, BRCA1, or PALB2.38
More than 2% of Ashkenazi Jews carry germline mutations in BRCA1 or BRCA2, and these carriers have a 16% chance (95% CI, 4%–30%) of developing prostate cancer by the age of 70.39 In a study of 251 unselected Ashkenazi Jewish patients with prostate cancer, 5.2% had germline mutations in BRCA1 and BRCA2, compared with 1.9% of control Ashkenazi Jewish men.40
Germline BRCA1 or BRCA2 mutations have been associated with an increased risk for prostate cancer in numerous reports.26,27,40–50 In particular, BRCA2 mutations have been associated with a 2- to 6-fold increase in the risk for prostate cancer, whereas the association of BRCA1 mutations and increased risks for prostate cancer are less consistent.26,27,40,42,44,49 In addition, limited data suggest that germline mutations in ATM, PALB2, and CHEK2 increase the risk of prostate cancer.51–54 Furthermore, prostate cancer in men with germline BRCA mutations appears to occur earlier, has a more aggressive phenotype, and is associated with significantly reduced survival times than in noncarrier patients.30,31,55–58
DNA MMR Genes
Tumor mutations in MLH1, MSH2, MSH6, and PMS2 may result in tumor microsatellite instability (MSI) and defective MMR (dMMR; detected by immunohistochemistry) and are sometimes associated with germline mutations and Lynch syndrome. In a study of >15,000 patients with cancer treated at Memorial Sloan Kettering Cancer Center who had their tumor and matched normal DNA sequenced and tumor MSI status assessed, approximately 5% of 1,048 patients with prostate cancer had MSI-high (MSI-H) or MSI-indeterminate tumors, 5.6% of whom were found to have Lynch syndrome (0.29% of patients with prostate cancer).23 In another prospective case series, the tumors of 3.1% of 1,033 patients with prostate cancer demonstrated MSI-H/dMMR status, and 21.9% of these patients had Lynch syndrome (0.68% of the total population).59 In a study of an unselected cohort of 3,607 patients with a personal history of prostate cancer who had germline genetic testing based on clinician referral, 1.7% had germline mutations in PMS2, MLH1, MSH2, or MSH6.38
Effect of Intraductal or Ductal Histology
Ductal prostate carcinomas are rare, accounting for approximately 1.3% of prostate carcinomas.60 Intraductal prostate cancer may be more common, especially in higher risk groups.61 It is important to note that there is significant overlap in diagnostic criteria and that intraductal, ductal, and invasive cribriform features may coexist in the same biopsy. By definition, intraductal carcinoma includes cribriform proliferation of malignant cells as long as they remain confined to a pre-existing gland that is surrounded by basal cells. These features are seen frequently with an adjacent invasive cribriform component and would be missed without the use of basal cell markers.
Limited data suggest that prostate tumors with ductal or intraductal histology have increased genomic instability.62–64 In particular, tumors with these histologies may be more likely to harbor somatic and/or germline MMR gene alterations than those with adenocarcinoma histology.65,66 In addition, limited data suggest that germline homologous DNA repair gene mutations may be more common in prostate tumors of ductal or intraductal origin67,68 and that intraductal histology is common in germline BRCA2 mutation carriers with prostate cancer.69 Overall, the panel believes that the data connecting histology and the presence of genomic alterations are stronger for intraductal than ductal histology at this time. Therefore, patients with the presence of intraductal carcinoma on biopsy should have germline testing as described subsequently.
Genetic Testing Recommendations
Germline Testing Based on Family History, Histology, and Risk Groups
The panel recommends inquiring about family and personal history of cancer at time of initial diagnosis. Based on the data discussed previously, the panel recommends germline genetic testing, with or without pretest genetic counseling, for patients with prostate cancer and any of the following:
A positive family history (see definition in the guidelines)
High-risk, very-high-risk, regional, or metastatic prostate cancer, regardless of family history
Ashkenazi Jewish ancestry
Intraductal histology
Somatic Tumor Testing Based on Risk Groups
Tumor testing recommendations are as follows:
Tumor testing for somatic homologous recombination gene mutations (eg, BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, and CHEK2) can be considered in patients with regional or metastatic prostate cancer.
Tumor testing for MSI or dMMR can be considered in patients with regional or metastatic prostate cancer.
Multigene molecular testing can be considered for patients with low- and favorable-intermediate risk prostate cancer and life expectancy ≥10 years (see “Tumor Multigene Molecular Testing,” page 488).
The Decipher molecular assay can be considered as part of counseling for risk stratification in patients with PSA resistance/recurrence after radical prostatectomy (category 2B; see “Tumor Multigene Molecular Testing,” page 488).
If MSI testing is performed, testing using an NGS assay validated for prostate cancer is preferred.72–74 If MSI-H or dMMR is found, the patient should be referred for genetic counseling to assess for the possibility of Lynch syndrome. MSI-H or dMMR indicate eligibility for pembrolizumab in second and subsequent lines of treatment of CRPC (see “Pembrolizumab,” page 496).
Patients should be informed that somatic tumor sequencing has the potential to uncover germline findings. However, virtually none of the NGS tests are designed or validated for germline assessment. Therefore, overinterpretation of germline findings should be avoided. If a germline mutation is suspected, the patient should be recommended for genetic counseling and follow-up dedicated germline testing.
Additional Testing
Tumors from most patients with metastatic CRPC harbor mutations in genes involved in the androgen receptor signaling pathway.32 AR-V7 testing in circulating tumor cells can be considered to help guide selection of therapy in the postabiraterone/enzalutamide metastatic CRPC setting (discussed in more detail in “Progression After Enzalutamide or Abiraterone,” available online, in these guidelines, at NCCN.org).
Risk Stratification For Clinically Localized Disease
Optimal treatment of prostate cancer requires assessment of risk: how likely is a given cancer to be confined to the prostate or spread to the regional lymph nodes? How likely is the cancer to progress or metastasize after treatment? How likely is adjuvant or salvage radiation to control cancer after an unsuccessful radical prostatectomy? Prostate cancers are best characterized by a digital rectal exam and radiographically determined clinical T stage, Gleason score and extent of cancer in the biopsy specimen, and serum PSA level. Imaging studies (ie, ultrasound, MRI) have been investigated intensively but have yet to be accepted as essential adjuncts to staging.
The NCCN Guidelines have, for many years, incorporated a risk stratification scheme that uses a minimum of stage, Gleason grade, and PSA to assign patients to risk groups. These risk groups are used to select the appropriate options that should be considered and to predict the probability of biochemical recurrence after definitive local therapy.75 Risk group stratification has been published widely and validated, and provides a better basis for treatment recommendations than clinical stage alone.76,77
A new prostate cancer grading system was developed during the 2014 International Society of Urological Pathology (ISUP) Consensus Conference.78 Several changes were made to the assignment of Gleason pattern based on pathology. The new system assigns Grade Groups from 1 to 5, derived from the Gleason score.
Grade Group 1: Gleason score ≤6; only individual discrete well-formed glands
Grade Group 2: Gleason score 3+4=7; predominantly well-formed glands with lesser component of poorly formed/fused/cribriform glands
Grade Group 3: Gleason score 4+3=7; predominantly poorly formed/fused/cribriform glands with lesser component of well-formed glands
For cases with >95% poorly formed/fused/cribriform glands or lack of glands on a core or at radical prostatectomy, the component of <5% well-formed glands is not factored into the grade.
Grade Group 4: Gleason score 4+4=8; 3+5=8; 5+3=8
Only poorly formed/fused/cribriform glands or
Predominantly well-formed glands and lesser component lacking glands (poorly formed/fused/cribriform glands can be a more minor component) or
Predominantly lacking glands and lesser component of well-formed glands (poorly formed/fused/cribriform glands can be a more minor component)
Grade Group 5: Gleason score 9–10; lack gland formation (or with necrosis) with or without poorly formed/fused/cribriform glands
For cases with >95% poorly formed/fused/cribriform glands or lack of glands on a core or at radical prostatectomy, the component of <5% well-formed glands is not factored into the grade.
Many experts believe that ISUP Grade Groups will enable patients to better understand their true risk level and thereby limit overtreatment. The new Grade Group system was validated in 2 separate cohorts, one of >26,000 men and one of 5,880 men, treated for prostate cancer with either radical prostatectomy or radiation.79,80 Both studies found that Grade Groups predicted the risk of recurrence after primary treatment. For instance, in the larger study, the 5-year biochemical recurrence-free progression probabilities after radical prostatectomy for Grade Groups 1 through 5 were 96% (95% CI, 95–96), 88% (95% CI, 85–89), 63% (95% CI, 61–65), 48% (95% CI, 44–52), and 26% (95% CI, 23–30), respectively. The separation between Grade Groups was less pronounced in the radiation therapy (RT) cohort, likely because of increased use of neoadjuvant/concurrent/adjuvant androgen deprivation therapy (ADT) in the higher risk groups. In another study of the new ISUP Grade Group system, all-cause mortality and prostate cancer-specific mortality were higher in men in Grade Group 5 than in those in Grade Group 4.81 Additional studies have supported the validity of this new system.82–86 The NCCN Panel has accepted the new Grade Group system to inform better treatment discussions compared with those using Gleason score. Patients remain divided into very low-, low-, intermediate-, high-, and very high-risk groups.
The NCCN Guidelines Panel recognized that heterogeneity exists within each risk group. For example, an analysis of 12,821 patients showed that men assigned to the intermediate-risk group by clinical stage (T2b–T2c) had a lower risk of recurrence than men categorized according to Gleason score (7) or PSA level (10–20 ng/mL).87 A similar trend of superior recurrence-free survival was observed in men placed in the high-risk group by clinical stage (T3a) compared with those assigned by Gleason score (8–10) or PSA level (>20 ng/mL), although it did not reach statistical significance. Other studies have reported differences in outcomes in the high-risk group depending on risk factors or primary Gleason pattern.88,89 Evidence also shows heterogeneity in the low-risk group, with PSA levels and percent positive cores affecting pathologic findings after radical prostatectomy.90,91
In a retrospective study, 1,024 patients with intermediate-risk prostate cancer were treated with radiation with or without neoadjuvant and concurrent ADT.92 Multivariate analysis revealed that primary Gleason pattern 4, number of positive biopsy cores ≥50%, and presence of >1 intermediate-risk factors (ie, T2b-c, PSA 10–20 ng/mL, Gleason score 7) were significant predictors of increased incidence of distant metastasis. The authors used these factors to separate the patients into unfavorable and favorable intermediate-risk groups and determined that the unfavorable intermediate-risk group had worse PSA recurrence-free survival and higher rates of distant metastasis and prostate cancer-specific mortality than the favorable intermediate-risk group. The use of active surveillance in men with favorable intermediate risk prostate cancer is discussed subsequently (see “Favorable Intermediate Risk,” available online, in these guidelines, at NCCN.org).
Nomograms
The more clinically relevant information that is used in the calculation of time to PSA recurrence, the more accurate the result. A nomogram is a predictive instrument that takes a set of input data (variables) and makes predictions about an outcome. Nomograms predict more accurately for the individual patient than risk groups, because they combine the relevant prognostic variables. The Partin tables were the first to achieve widespread use for counseling men with clinically localized prostate cancer.93–96 The tables give the probability (95% CI) that a patient with a certain clinical stage, Gleason score, and PSA will have a cancer of each pathologic stage. Nomograms can be used to inform treatment decision-making for men contemplating active surveillance,97–99 radical prostatectomy,100–103 neurovascular bundle preservation,104–106 or omission of pelvic lymph node dissection during radical prostatectomy,107–110 brachytherapy,100,111–113 or external beam RT (EBRT).100,114 Biochemical progression-free survival (PFS) can be reassessed postoperatively using age, diagnostic serum PSA, and pathologic grade and stage.100,115–117 Potential success of adjuvant or salvage RT after unsuccessful radical prostatectomy can be assessed using a nomogram.100,118
None of the current models predicts with perfect accuracy, and only some of these models predict metastasis99,100,115,119,120 and cancer-specific death.101,103,121–123 Given the competing causes of mortality, many men who sustain PSA recurrence will not live long enough to develop clinical evidence of distant metastases or to die of prostate cancer. Those with a short PSA doubling time (PSADT) are at greatest risk of death. Not all PSA recurrences are clinically relevant; thus, PSADT may be a more useful measure of risk of death.124 The NCCN Guidelines Panel recommends that NCCN risk groups be used to begin the discussion of options for the treatment of clinically localized prostate cancer and that nomograms be used to provide additional and more individualized information.
Tumor Multigene Molecular Testing
Personalized or precision medicine is a goal for many translational and clinical investigators. The National Academy of Medicine has described several lessons that should accelerate the development of useful biomarkers125 to inform men and their physicians about proper choices for treatment of clinically localized prostate cancer. Dr. Hayes has warned that a “bad tumor marker is as bad as a bad drug.”126,127 The NCCN Prostate Cancer Guidelines Panel strongly advocates for use of life expectancy estimation, use of nomograms, and active surveillance as the only option for men with low-risk prostate cancer and life expectancy less than 10 years or very low-risk prostate cancer and life expectancy less than 20 years. Although risk groups, life expectancy estimates, and nomograms help inform decisions, uncertainty about the risk of disease progression persists. American men continue to under-select active surveillance and their physicians may under-recommend it, likely as a result of this uncertainty.128 In 2013, <20% of men with low-risk prostate cancer were managed using active surveillance.16 However, active surveillance has become more common in some areas, such as Michigan, where its frequency has been measured and educational efforts have begun.129,130
Several tissue-based molecular assays have been developed in an effort to improve decision-making in newly diagnosed men considering active surveillance and in treated men considering adjuvant therapy or treatment of recurrence. Uncertainty about the risk of disease progression can be reduced if such molecular assays can provide accurate and reproducible prognostic or predictive information beyond NCCN risk group assignment and currently available life expectancy tables and nomograms. Retrospective case cohort studies have shown that these assays provide prognostic information independent of NCCN or CAPRA risk groups, which include likelihood of death with conservative management, likelihood of biochemical recurrence after radical prostatectomy or EBRT, likelihood of adverse pathologic features after radical prostatectomy, and likelihood of developing metastasis after operation or salvage EBRT.131–140 A prospective, clinical utility study of 3,966 patients newly diagnosed with localized prostate cancer found that the rates of active surveillance increased with use of a tissue-based gene expression classifier.141 Active surveillance rates were 46.2%, 75.9%, and 57.9% for those whose classifier results were above the specified threshold, below the threshold, and those who did not undergo genomic testing, respectively (P<.001). The authors estimate that 1 additional patient may chose active surveillance for every 9 men with favorable risk prostate cancer who undergo genomic testing.
No randomized controlled trials have studied the utility of these tests. Several of these assays are available, and 4 have received positive reviews by the Molecular Diagnostic Services Program (MolDX) and are likely to be covered by CMS (Centers for Medicare & Medicaid Services). Several other tests are under development, and the use of these assays is likely to increase in the coming years.
Table 1 lists these tests in alphabetical order and provides an overview of each test, populations in which each test independently predicts outcome, and supporting references. These molecular biomarker tests have been developed with extensive industry support, guidance, and involvement, and have been marketed under the less rigorous FDA regulatory pathway for biomarkers. The panel believes that men with low or favorable intermediate disease may consider the use of Decipher, Oncotype DX Prostate, Prolaris, or ProMark during initial risk stratification. In addition, Decipher may be considered during workup for radical prostatectomy PSA persistence or recurrence (category 2B). Future comparative effectiveness research may allow these tests and others like them to gain additional evidence regarding their utility for better risk stratification of men with prostate cancer.
Available Tissue-Based Tests for Prostate Cancer Risk Stratification/Prognosis
Androgen Deprivation Therapy
ADT is administered as primary systemic therapy for regional or advanced disease and as neoadjuvant/concomitant/adjuvant therapy in combination with radiation in localized or locally advanced prostate cancers.
In the community, ADT has been commonly used as primary therapy for early-stage, low-risk disease, especially in the elderly. This practice has been challenged by a large cohort study of 66,717 elderly men with T1–T2 tumors.142 No 15-year survival benefit was found in patients receiving ADT compared with observation alone. Similarly, another cohort study of 15,170 men diagnosed with clinically localized prostate cancer who were not treated with curative intent therapy reported no survival benefit from primary ADT after adjusting for demographic and clinical variables.143 Placing patients with early prostate cancer on ADT should not be routine practice.
Antiandrogen monotherapy (bicalutamide) after completion of primary treatment was investigated as an adjuvant therapy in patients with localized or locally advanced prostate cancer, but results did not support its use in this setting.144,145
Castrate levels of serum testosterone (<50 ng/dL; <1.7 nmol/L) should be achieved with ADT, because low nadir serum testosterone levels were shown to be associated with improved cause-specific survival in the PR-7 study.146
ADT for Castration-Naive Disease
The term “castration-naive” is used to define patients who are not on ADT at the time of progression. The NCCN Prostate Cancer Panel uses the term “castration-naive” even when patients have had neoadjuvant, concurrent, and/or adjuvant ADT as part of RT provided they have recovered testicular function.
ADT for castration-naïve prostate cancer can be accomplished using bilateral orchiectomy, a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist, or an LHRH agonist plus a first-generation antiandrogen. As discussed subsequently, abiraterone or docetaxel can be added to orchiectomy, LHRH agonist, or LHRH antagonist for M1 disease. For patients with M0 disease, observation is preferred over ADT.
LHRH agonists and LHRH antagonists appear equally effective in patients with advanced prostate cancer.147 Medical or surgical castration combined with an antiandrogen is known as combined androgen blockade. No prospective randomized studies have demonstrated a survival advantage with combined androgen blockade over the serial use of an LHRH agonist and an antiandrogen.148 Meta-analysis data suggest that bicalutamide may provide an incremental relative improvement in OS by 5%–20% over LHRH agonist monotherapy.149,150 However, others have concluded that more complete disruption of the androgen axis (with finasteride, dutasteride, or antiandrogen added to medical or surgical castration) provides little if any benefit over castration alone.151
Antiandrogen monotherapy appears to be less effective than medical or surgical castration and is not recommended for primary ADT. Furthermore, dutasteride plus bicalutamide showed no benefit over bicalutamide alone in patients with locally advanced or metastatic prostate cancer.152
Recent evidence suggests that orchiectomy may be safer than an LHRH agonist. Four hundred twenty-nine men with metastatic prostate cancer who underwent orchiectomy were compared with 2,866 men who received LHRH agonist between 1995 and 2009. Orchiectomy was associated with lower risk of fracture, peripheral arterial disease, and cardiac-related complications, although risk was similar for diabetes, deep vein thrombosis, pulmonary embolism, and cognitive disorders.153 Posthoc analysis of a randomized trial of LHRH antagonist versus LHRH agonist found lower risk of cardiac events in patients with existing cardiac disease treated with LHRH antagonist.154 The heart and T lymphocytes have receptors for LHRH. Therefore, LHRH agonists may affect cardiac contractility, vascular plaque stability, and inflammation.155
ADT for M0 Biochemical Recurrence
Controversy remains about the timing and duration of ADT when local therapy has failed. Many believe that early ADT is best, but cancer control must be balanced against side effects. Early ADT is associated with increased side effects and the potential development of the metabolic syndrome.
Patients with an increasing PSA level and with no symptomatic or clinical evidence of cancer after definitive treatment present a therapeutic dilemma regarding the role of ADT. Some of these patients will ultimately die of their cancer. Timing of ADT for patients whose only evidence of cancer is increasing PSA is influenced by PSA velocity (PSADT), patient and physician anxiety, the short-term and long-term side effects of ADT, and underlying comorbidities of the patient. Early ADT is acceptable, but an alternative is close observation until progression of cancer, at which time appropriate therapeutic options may be considered. Earlier ADT may be better than delayed therapy, although the definitions of early and late (ie, what level of PSA) remain controversial. The multicenter phase 3 TROG 03.06/VCOG PR 01-03 [TOAD] trial randomized 293 men with PSA relapse after operation or radiation (n=261) or who were not considered for curative treatment (n=32) to immediate ADT or ADT delayed by a recommended interval of ≥2 years.156 Five-year OS was improved in the immediate therapy arm compared with the delayed therapy arm (91.2% vs 86.4%; log-rank P=.047). No significant differences were seen in the secondary endpoint of global health-related QOL at 2 years.157 In addition, there were no differences over 5 years in global QOL, physical functioning, role or emotional functioning, insomnia, fatigue, dyspnea, or feeling less masculine. However, sexual activity was lower and the hormone-treatment-related symptoms score was higher in the immediate ADT group compared with the delayed ADT group. Most clinical trials in this patient population require PSA level ≥0.5 mg/dL (after radical prostatectomy) or “nadir + 2” (after radiation) for enrollment.
The panel believes that the benefit of early ADT is uncertain and must be balanced against the risk of ADT side effects. Patients with an elevated PSA and/or a shorter PSADT (rapid PSA velocity) and an otherwise long life expectancy should be encouraged to consider ADT earlier.
Primary ADT for M1 Castration-Naïve Prostate Cancer
ADT is the gold standard for initial treatment of patients with metastatic disease at presentation.148 A PSA value ≤4 ng/mL after 7 months of ADT is associated with improved survival of patients newly diagnosed with metastatic prostate cancer.158
ADT options for M1 castration-naïve disease are:
Orchiectomy ± docetaxel
LHRH agonist alone ± docetaxel
LHRH agonist plus first-generation antiandrogen ± docetaxel
LHRH antagonist ± docetaxel
Orchiectomy plus abiraterone
LHRH agonist plus abiraterone
LHRH antagonist plus abiraterone
The data supporting the addition of abiraterone or docetaxel to ADT in this setting are discussed subsequently. ADT with addition of EBRT to the primary tumor for low volume metastatic disease is discussed in “EBRT to the Primary Tumor in Low Volume M1 Disease” (available online, in these guidelines, at NCCN.org).
Abiraterone Acetate in Castration-Naïve Prostate Cancer
In February 2018, the FDA approved abiraterone in combination with prednisone for metastatic castration-naïve prostate cancer.161 This approval was based on 2 randomized phase 3 clinical trials of abiraterone and low-dose prednisone plus ADT that were reported in men with newly diagnosed metastatic prostate cancer or high-risk or node-positive disease (STAMPEDE and LATITUDE) that demonstrated improved OS over ADT alone.162 In LATITUDE, 1,199 men with high-risk, metastatic, castration-naïve prostate cancer were randomized to abiraterone with prednisone 5 mg once daily or matching placebos. High-risk disease was defined as at least 2 of the following: Gleason score 8–10, ≥3 bone metastases, and visceral metastases.162 Efficacy was demonstrated at the first interim analysis, and the trial was unblinded. The primary endpoint of OS was met and favored abiraterone (hazard ratio [HR], 0.62; 95% CI, 0.51–0.76; P<.0001). Estimated 3-year OS rates improved from 49% to 66% at 30 months follow-up. Secondary endpoints were improved and included delayed castration-resistant radiographic progression (from median 14.8–33.2 months), PSA progression (7.4–33.2 months), time to pain progression, and initiation of chemotherapy.
Adverse events were higher with abiraterone and prednisone but were generally mild in nature and largely related to mineralocorticoid excess (ie, hypertension, hypokalemia, edema), hormonal effects (ie, fatigue, hot flushes), and liver toxicity.162 Cardiac events, such as atrial fibrillation, were rare but slightly increased with abiraterone. The overall discontinuation rate due to side effects was 12%. Patient-reported outcomes were improved with the addition of abiraterone, with improvements in pain intensity progression, fatigue, functional decline, prostate cancer-related symptoms, and overall health-related QOL.163 A limitation of this trial is that only 27% of placebo-treated men received abiraterone or enzalutamide at progression, and only 52% of these men received any life-prolonging therapy.162
A second randomized trial (STAMPEDE) of 1,917 men with castration-naïve prostate cancer showed similar OS benefits.164 However, unlike LATITUDE, STAMPEDE eligibility permitted men with high-risk N0 M0 disease (2 of 3 high-risk factors: stage T3/4, PSA >40, or Gleason score 8–10; n=509), or N1 M0 disease (pelvic nodal metastases; n=369) in addition to patients with M1 disease, who made up the majority of patients (n=941). The majority of men were newly diagnosed, while a minority of men had recurrent, high-risk, or metastatic disease after local therapy (n=98). Thus, STAMPEDE was a heterogeneous mix of patients with high-risk, nonmetastatic, node-positive, or M1 disease. In M1 patients, treatment with abiraterone plus prednisone was continued until progression. In patients with N1 or M0 disease, 2 years of abiraterone plus prednisolone was used if curative-intent EBRT was used. OS was improved in the overall population (HR, 0.63; 95% CI, 0.5–0.76; P<.0001) and in the M1 and N1 subsets, without any heterogeneity of treatment effect by metastatic status. The survival benefit of abiraterone was larger in men <70 years of age than in older men (HR, 0.94 vs 0.51). Older men also experienced increased toxicities, which suggests heterogeneity in clinical benefits by age and comorbidity. The secondary endpoint of failure-free survival (FFS), which included PSA recurrence, was improved overall (HR, 0.29; P<.0001) and in all subgroups regardless of M1 (HR, 0.31), N1 (HR, 0.29), or M0 (HR, 0.21) status. No heterogeneity for FFS was observed based on subgroups or by age. In this trial, subsequent life-prolonging therapy was received by 58% of men in the control group, which included 22% who received abiraterone and 26% who received enzalutamide. Thus, these data reflect a survival advantage of initial abiraterone in newly diagnosed men compared with deferring therapy to the CRPC setting.
Adverse events in STAMPEDE were similar to that reported in LATITUDE, but were increased in older men, with higher incidences of grade 3–5 adverse events with abiraterone (47% vs 33%) and 9 versus 3 treatment-related deaths. Severe hypertension or cardiac disorders were noted in 10% of men and grade 3–5 liver toxicity in 7%, which illustrates the need for blood pressure and renal and hepatic function monitoring.
Taken together, these data led the panel to recommend abiraterone with 5-mg once-daily prednisone as a treatment option with ADT for men with newly diagnosed, M1, castration-naïve prostate cancer (category 1). Alternatively, the fine particle formulation of abiraterone can be used (category 2B; see “Abiraterone Acetate in M1 CRPC,” page 493). For men undergoing curative-intent treatment of N1 disease, abiraterone can be added to EBRT with 2 to 3 years of neoadjuvant/concurrent/adjuvant ADT or can be given with ADT for castration-naïve disease (without EBRT). The fine particle formulation of abiraterone is an option (category 2B; see “Abiraterone Acetate in M1 CRPC”). However, there was insufficient survival, FFS data, and follow-up available to recommend abiraterone for men with high-risk or very high-risk N0 M0 prostate cancer. Further follow-up and dedicated ongoing clinical trials are needed in this curative-intent RT population.
Abiraterone with prednisone can be given at 250 mg/day and administered following a low-fat breakfast, as an alternative to the dose of 1,000 mg/day after an overnight fast (see “Abiraterone Acetate in M1 CRPC,” page 493).165 The cost saving may reduce financial toxicity and improve compliance.
Secondary Hormone Therapy for CRPC
Most men with advanced disease eventually stop responding to traditional ADT and are categorized as castration-resistant (also known as “castration-recurrent”). Research has shown enhancement of autocrine and/or paracrine androgen synthesis in the tumor microenvironment of men receiving ADT.166,167 Androgen signaling consequent to nongonadal sources of androgen in CRPC refutes earlier beliefs that CRPC was resistant to further hormone therapies. The development of novel hormonal agents demonstrating efficacy in the metastatic CRPC setting dramatically changed the paradigm of CRPC treatment.
For men who develop CRPC, ADT with an LHRH agonist or antagonist should be continued to maintain castrate serum levels of testosterone (<50 ng/dL). Options for secondary hormone therapy include a first-generation antiandrogen, antiandrogen withdrawal, ketoconazole (adrenal enzyme inhibitor) with or without hydrocortisone, corticosteroid, diethylstilbestrol (DES), or other estrogen.168,169 However, none of these strategies has yet been shown to prolong survival in randomized clinical trials. New secondary hormone options include abiraterone (M1 only), enzalutamide (M0 or M1), and apalutamide (M0 only), as discussed subsequently.
DES can produce safe chemical castration in many men. Gynecomastia and cardiovascular side effects occur with increasing frequency with increasing dose. Side effects are rare, and survival appears equivalent to that of other means of ADT at a 1-mg daily dose. The mechanism of action of DES remains uncertain because a 1-mg dose does not render some men castrate, and DES produces responses when used in CRPC.170
Transdermal estradiol may provide similar cancer control with fewer side effects.171 The ongoing PATCH clinical trial demonstrated similar rates of castrate levels of testosterone, PSA response, and side effects in 85 men treated with LHRH agonist and 168 men treated with 100 mcg/24-hour estrogen patches twice weekly.172 QOL outcomes and the experience of vasomotor symptoms were better at 6 months in the transdermal group compared with the agonist group, but rates of significant gynecomastia were higher in the transdermal group (37% vs 5%).173 The PATCH trial continues enrollment to assess survival (ClinicalTrials.gov identifier: NCT00303784).
Abiraterone Acetate in M1 CRPC
In April 2011, the FDA approved the androgen synthesis inhibitor, abiraterone, in combination with low-dose prednisone, for the treatment of men with metastatic CRPC who have received prior chemotherapy containing docetaxel.
FDA approval in the postdocetaxel setting was based on the results of a phase 3, randomized, placebo-controlled trial (COU-AA-301) in men with metastatic CRPC previously treated with docetaxel-containing regimens.174,175 Patients were randomized to receive either abiraterone 1,000 mg orally once daily (n=797) or placebo once daily (n=398), and both arms received daily prednisone. In the final analysis, median survival was 15.8 vs 11.2 months in the abiraterone and placebo arm, respectively (HR, 0.74; 95% CI, 0.64–0.86; P<.0001).175 Time to radiographic progression, PSA decline, and pain palliation also were improved by abiraterone.175,176
FDA approval in the predocetaxel setting occurred on December 10, 2012, and was based on the randomized phase 3 COU-AA-302 trial of abiraterone and prednisone (n=546) versus prednisone alone (n=542) in men with asymptomatic or minimally symptomatic metastatic CRPC.177 Most men in this trial were not taking narcotics for cancer pain, and none had visceral metastatic disease or prior ketoconazole exposure. The coprimary endpoint of radiographic PFS was improved by treatment from 8.3 to 16.5 months (HR, 0.53; P<.001). OS was improved at final analysis with a median follow-up of 49.2 months (34.7 vs 30.3 months; HR, 0.81; 95% CI, 0.70–0.93; P=.003).178 Key secondary endpoints of time to symptomatic deterioration, time to chemotherapy initiation, time to pain progression, and PSA PFS improved significantly with abiraterone treatment, and PSA declines (62% vs 24% with >50% decline) and radiographic responses (36% vs 16% RECIST responses) were more common.
The most common adverse reactions with abiraterone/prednisone (>5%) were fatigue (39%); back or joint discomfort (28%–32%); peripheral edema (28%); diarrhea, nausea, or constipation (22%); hypokalemia (17%); hypophosphatemia (24%); atrial fibrillation (4%); muscle discomfort (14%); hot flushes (22%); urinary tract infection; cough; hypertension (22%, severe hypertension in 4%); urinary frequency and nocturia; dyspepsia; or upper respiratory tract infection. The most common adverse drug reactions that resulted in drug discontinuation were increased aspartate aminotransferase and/or alanine aminotransferase (11%–12%), or cardiac disorders (19%, serious in 6%).
In May of 2018, the FDA approved a novel, fine-particle formulation of abiraterone, in combination with methylprednisolone, for the treatment of patients with metastatic CRPC.179 In studies of healthy men, this formulation at 500 mg was shown to be bioequivalent to 1,000 mg of the originator formulation.180,181 In a phase 2 therapeutic equivalence study, 53 men with metastatic CRPC who were not treated previously with abiraterone, enzalutamide, radium-223, or chemotherapy (docetaxel for metastatic CRPC completed ≥1 year prior to enrollment was allowed) were randomized to 500 mg daily of the new formulation plus 4 mg methylprednisolone orally twice daily or to 1,000 mg of the originator formulation daily plus 5 mg prednisone orally twice daily.182 Bioequivalence of these doses was confirmed based on serum testosterone levels, PSA response, and abiraterone pharmacokinetics. The rates of total and grade 3/4 adverse events were similar between the arms, with musculoskeletal and connective tissue disorders occurring more frequently in the originator-treated patients (37.9% vs 12.5%). The panel believes that the fine-particle formulation of abiraterone can be used instead of the original formulation of abiraterone in the treatment of men with metastatic CRPC (category 2A), but switching from one formulation to the other on disease progression should not be undertaken. Abiraterone with either steroid should not be given following progression on abiraterone with the other steroid.
Abiraterone should be given with concurrent steroid (either oral prednisone 5 mg twice daily or oral methylprednisolone 4 mg twice daily, depending on which formulation is given) to abrogate signs of mineralocorticoid excess that can result from treatment. These signs include hypertension, hypokalemia, and peripheral edema. Thus, monitoring of liver function, potassium and phosphate levels, and blood pressure readings on a monthly basis, at least initially, is warranted during abiraterone therapy. Some patients may be able to avoid steroids with abiraterone, but careful monitoring is warranted, and a mineralocorticoid receptor antagonist or steroid should be added to control side effects if necessary.183–185 Symptom-directed assessment for cardiac disease also is warranted, particularly in patients with pre-existing cardiovascular disease.
A randomized phase 2 noninferiority study of 75 patients with M1 CRPC compared 1,000 mg/day abiraterone with prednisone after an overnight fast with 250 mg/day after a low-fat breakfast.165 The primary endpoint was log change in PSA, with secondary endpoints of PSA response (≥ 50%) and PFS. The primary endpoint favored the low-dose arm (log change in PSA, −1.59 vs −1.19), as did the PSA response rate (58% vs 50%), with an equal PFS of 9 months in both arms. Noninferiority of the low dose was established according to the predefined criteria. Therefore, abiraterone with prednisone can be given at 250 mg/day administered after a low-fat breakfast, as an alternative to the dose of 1,000 mg/day after an overnight fast. The cost saving may reduce financial toxicity and improve compliance. Food impacts absorption unpredictably; side effects should be monitored and standard dosing (1,000 mg on empty stomach) used if excess toxicity is observed on modified dosing (250 mg with food).
Enzalutamide in M0 and M1 CRPC
On August 31, 2012, the FDA approved enzalutamide, a next-generation antiandrogen, for treatment of men with metastatic CRPC who had received prior docetaxel chemotherapy. Approval was based on the results of the randomized, phase 3, placebo-controlled trial (AFFIRM).186,187 AFFIRM randomized 1,199 men to enzalutamide or placebo in a 2:1 ratio, and the primary endpoint was OS. Median survival was improved with enzalutamide from 13.6 to 18.4 months (HR, 0.63; P<.001). Survival was improved in all subgroups analyzed. Secondary endpoints also were improved significantly, which included the proportion of men with >50% PSA decline (54% vs 2%), radiographic response (29% vs 4%), radiographic PFS (8.3 vs 2.9 months), and time to first skeletal related event (SRE) (16.7 vs 13.3 months). QOL measured using validated surveys was improved with enzalutamide compared with placebo. Adverse events were mild and included fatigue (34% vs 29%), diarrhea (21% vs 18%), hot flushes (20% vs 10%), headache (12% vs 6%), and seizures (0.6% vs 0%). The incidence of cardiac disorders did not differ between the arms. Enzalutamide is dosed at 160 mg daily. Patients in the AFFIRM study were maintained on GnRH agonist/antagonist therapy and could receive bone supportive care medications. The seizure risk in the enzalutamide FDA label was 0.9% versus 0.6% in the manuscript.186,188
Another phase 3 trial studied enzalutamide in the prechemotherapy setting. The PREVAIL study randomly assigned 1,717 patients with chemotherapy-naïve metastatic prostate cancer to daily enzalutamide or placebo.189,190 The study was stopped early due to benefits shown in the treatment arm. Compared with the placebo group, the enzalutamide group showed improved median PFS (20.0 vs 5.4 months) and median OS (35.3 vs 31.3 months). Improvements in all secondary endpoints also were observed (eg, the time until chemotherapy initiation or first SRE).
Two randomized clinical trials have reported that enzalutamide may be superior to bicalutamide for cancer control in metastatic CRPC. The TERRAIN study randomized 375 men with treatment-naïve, metastatic CRPC to 160 mg/day enzalutamide or 50 mg/day bicalutamide in a 1:1 manner.191 The enzalutamide group had significantly better PFS (defined as PSA progression, soft tissue progression, or development of additional bony metastases) compared with the bicalutamide group (median time to progression, 15.7 vs 5.8 months; HR, 0.44; 95% CI, 0.34–0.57).
The STRIVE trial randomized 396 men with M0 or M1 treatment-naïve CRPC to 160 mg/d enzalutamide or 50 mg/d bicalutamide in a 1:1 manner.192 The primary endpoint in this study was PFS, defined as either PSA progression, radiographic progression of disease, or death from any cause. Enzalutamide reduced the risk of progression or death by 76% compared with bicalutamide (HR, 0.24; 95% CI, 0.18–0.32). These studies demonstrated that enzalutamide extended PFS better than bicalutamide in men choosing an antiandrogen for secondary hormonal therapy treatment of CRPC. Bicalutamide can still be considered in some patients, given the different side-effect profiles of the agents and the increased cost of enzalutamide.
Thus, enzalutamide represents a treatment option for men in both the predocetaxel and postdocetaxel metastatic CRPC setting and is a reasonable choice for men who are not candidates for chemotherapy. Patients receiving enzalutamide have no restrictions for food intake, and concurrent prednisone is permitted but not required.186
The randomized, double-blind, placebo-controlled phase 3 PROSPER trial assessed the use of enzalutamide in 1,401 men with nonmetastatic CRPC.193 Men with PSADT ≤10 months were stratified according to PSADT (<6 vs ≥6 months) and use of bone-sparing agents and randomized 2:1 to enzalutamide (160 mg/day) plus ADT or placebo plus ADT. Enzalutamide improved the primary endpoint of metastasis-free survival over placebo (36.6 vs 14.7 months; HR for metastasis or death, 0.29; 95% CI, 0.24 to 0.35; P<.0001). No significant difference was seen in OS, although OS data were not mature at the time of final analysis for metastasis-free survival. Adverse events included fatigue (33% vs 14%), hypertension (12% vs 5%), major adverse cardiovascular events (5% vs 3%), and mental impairment disorders (5% vs 2%). Patient-reported outcomes from PROSPER indicate that enzalutamide delayed pain progression, symptom worsening, and decrease in functional status compared with placebo.194 The FDA expanded approval for enzalutamide to include men with nonmetastatic CRPC on July 13, 2018,188 and the panel believes that patients with M0 CRPC can be offered enzalutamide if PSADT is ≤10 months (category 1).
Apalutamide in M0 CRPC
The FDA approved apalutamide for treatment of patients with nonmetastatic CRPC on February 14, 2018.195 This approval was based on the phase 3 SPARTAN trial of 1,207 patients with M0 CRPC and PSADT ≤10 months.196 Participants were stratified according to PSADT (>6 vs ≤6 months), use of bone-sparing agents, and the presence of metastatic pelvic lymph nodes (N0 vs N1). After median follow-up of 20.3 months, apalutamide at 240 mg/day with ADT improved the primary endpoint of metastasis-free survival over placebo with ADT (40.5 vs 16.2 months; HR for metastasis or death, 0.28; 95% CI, 0.23 to 0.35; P<001). No significant difference was seen in OS, although OS data were not mature at the time of final analysis for metastasis-free survival. Adverse events included rash (24% vs 5.5%), fracture (11% vs 6.5%), and hypothyroidism (8% vs 2%). Patients with M0 CRPC can be offered apalutamide, if PSADT is ≤10 months (category 1). In a prespecified exploratory analysis of SPARTAN, health-related QOL was maintained in both the apalutamide and placebo groups.197
Chemotherapy and Immunotherapy
Recent research has expanded the therapeutic options for patients with metastatic CRPC depending on the presence or absence of symptoms.
Docetaxel
Two randomized phase 3 studies evaluated docetaxel-based regimens in symptomatic or rapidly progressive disease (TAX 327 and SWOG 9916).198–200 TAX 327 compared docetaxel (every 3 weeks or weekly) plus prednisone to mitoxantrone plus prednisone in 1,006 men.199 Every-3-week docetaxel resulted in higher median OS than mitoxantrone (18.9 vs 16.5 months; P=.009). This survival benefit was maintained at extended follow-up.200 The SWOG 9916 study also showed improved survival with docetaxel when combined with estramustine compared with mitoxantrone plus prednisone.198 Docetaxel is FDA-approved for metastatic CRPC. The standard regimen is every 3 weeks. An alternative to every-3-week docetaxel is a biweekly regimen of 50 mg/m2. This regimen is based on a large randomized phase 2 trial of 346 men with metastatic CRPC randomized to either every-2-week docetaxel or every-3-week docetaxel, each with maintenance of ADT and prednisone.201 Men treated with the every-2-week regimen survived an average of 19.5 months compared with 17.0 months with the every-3-week regimen (P=.015). Time-to-progression and PSA decline rate favored every-2-week therapy. Tolerability was improved with every-2-week docetaxel; febrile neutropenia rate was 4% versus 14%, and other toxicities and overall QOL were similar.
Docetaxel is included as an upfront option for men with castration-naïve prostate cancer and distant metastases based on results from 2 phase 3 trials (ECOG 3805/CHAARTED and STAMPEDE).202,203 CHAARTED randomized 790 men with metastatic, castration-naïve prostate cancer to docetaxel (75 mg/m2 intravenous every 3 weeks × 6 doses) plus ADT or ADT alone.203 After a median follow-up 53.7 months, the patients in the combination arm experienced a longer OS than those in the ADT arm (57.6 vs 47.2 months; HR, 0.72; 95% CI, 0.59–0.89; P=.002).204 Subgroup analysis showed that the survival benefit was more pronounced in the 65% of participants with high-volume disease (HR, 0.63; 95% CI, 0.50–0.79; P<.001). Men with low-volume disease in CHAARTED did not derive a survival benefit from the inclusion of docetaxel (HR, 1.04; 95% CI, 0.70–1.55; P=.86).
The STAMPEDE trial, a multiarm, multistage phase 3 trial, included patients with both M0 and M1 castration-naïve prostate cancer.202 The results in the M1 population essentially confirmed the survival advantage of adding docetaxel (75 mg/m2 intravenous every 3 weeks × 6 doses) to ADT seen in the CHAARTED trial. In STAMPEDE, extent of disease was not evaluated in the 1,087 men with metastatic disease, but the median OS for all patients with M1 disease was 5.4 years in the ADT-plus-docetaxel arm versus 3.6 years in the ADT-only arm (a difference of 1.8 years between groups compared with a 1.1-year difference in CHAARTED). The results of the STAMPEDE trial seem to confirm the results of the CHAARTED trial.
Some data suggest that the use of docetaxel in combination with ADT and EBRT may benefit fit men with high- and very-high-risk localized disease. The GETUG 12 trial, which randomized 413 men with high- or very-high risk prostate cancer to IMRT and ADT or ADT, docetaxel, and estramustine.205 After a median follow-up of 8.8 years, 8-year relapse-free survival was 62% in the combination therapy arm and 50% in the ADT-only arm (adjusted HR, 0.71; 95% CI, 0.54–0.94; P=.017). The multicenter, phase 3 NRG Oncology RTOG 0521 trial randomized 563 patients with high- or very-high-risk prostate cancer ADT plus EBRT with or without docetaxel.206 After median follow-up 5.7 years, 4-year OS was 89% (95% CI, 84%–92%) for ADT/EBRT and 93% (95% CI, 90%–96%) for ADT/EBRT/docetaxel (HR, 0.69; 90% CI, 0.49 to 0.97; one-sided P=.03). Improvements were also seen in disease-free survival and the rate of distant metastasis. The panel does not recommended the addition of docetaxel to ADT plus EBRT in patients with high and very-high risk prostate cancer, however, at this time. Longer follow-up is needed to determine the effects of early docetaxel on response to subsequent treatment. In addition, longer follow-up will show whether the long-term side effects of EBRT, which generally begin 4 to 5 years after EBRT, are increased with docetaxel.
Cabazitaxel
In June 2010, the FDA approved cabazitaxel, a semisynthetic taxane derivative, for men with metastatic CRPC previously treated with a docetaxel-containing regimen. An international randomized phase 3 trial (TROPIC) randomized 755 men with progressive metastatic CRPC to receive cabazitaxel 25 mg/m2 or mitoxantrone 12 mg/m2, each with daily prednisone.207 A 2.4-month improvement in OS was demonstrated with cabazitaxel compared with mitoxantrone (HR, 0.72; P<.0001). The improvement in survival was balanced against a higher toxic death rate with cabazitaxel (4.9% vs 1.9%), which was due, in large part, to differences in rates of sepsis and renal failure. Febrile neutropenia was observed in 7.5% of cabazitaxel-treated men vs 1.3% of mitoxantrone-treated men. The incidences of severe diarrhea (6%), fatigue (5%), nausea/vomiting (2%), anemia (11%), and thrombocytopenia (4%) also were higher in cabazitaxel-treated men, which indicated the need for vigilance and treatment or prophylaxis in this setting to prevent febrile neutropenia. The survival benefit was sustained at an updated analysis with a median follow-up of 25.5 months.208 Furthermore, results of a posthoc analysis of this trial suggested that the occurrence of grade ≥3 neutropenia after cabazitaxel treatment was associated with improvements in both progression-free survival and OS.209
The phase 3 open-label, multinational, noninferiority PROSELICA study compared 20 mg/m2 cabazitaxel with 25 mg/m2 cabazitaxel in 1,200 patients with metastatic CRPC who progressed on docetaxel.210 The lower dose was found to be noninferior to the higher dose for median OS (13.4 months [95% CI, 12.19–14.88] vs 14.5 months [95% CI, 13.47–15.28]), and grade 3/4 adverse events were decreased (39.7% vs 54.5%). In particular, grade ≥3 neutropenia rates were 41.8% and 73.3% for the lower and higher dose groups, respectively. Cabazitaxel at 20 mg/m2 every 3 weeks, with or without growth factor support, is now standard of care for fit patients. Cabazitaxel at 25 mg/m2 may be considered for healthy men who wish to be more aggressive.
Recent results from the phase 3 FIRSTANA study suggested that cabazitaxel has clinical activity in patients with chemotherapy-naïve metastatic CRPC.211 Median OS, the primary endpoint, was similar between 20 mg/m2 cabazitaxel, 25 mg/m2 cabazitaxel, and 75 mg/m2 docetaxel (24.5, 25.2, and 24.3 months, respectively). Cabazitaxel was associated with lower rates of peripheral sensory neuropathy than docetaxel, particularly at 20 mg/m2 (12% vs 25%). Therefore, patients who are not candidates for docetaxel, who cannot tolerate docetaxel, or who have pre-existing mild peripheral neuropathy should be considered for cabazitaxel.211
Cabazitaxel should be given with concurrent steroids (daily prednisone or dexamethasone on the day of chemotherapy). Physicians should follow current guidelines for prophylactic white blood cell growth factor use, particularly in this heavily pretreated, high-risk population. In addition, supportive care should include antiemetics (prophylactic antihistamines, H2 antagonists, and corticosteroids prophylaxis), and symptom-directed antidiarrheal agents. Cabazitaxel was tested in patients with hepatic dysfunction in a small, phase I, dose-escalation study.212 Cabazitaxel was tolerated in patients with mild to moderate hepatic impairment. However, cabazitaxel should not be used in patients with severe hepatic dysfunction. Cabazitaxel should be stopped on clinical disease progression or intolerance.
Sipuleucel-T
In April 2010, sipuleucel-T became the first in a new class of cancer immunotherapeutic agents to be approved by the FDA. This autologous cancer “vaccine” involves collection of the white blood cell fraction containing antigen-presenting cells from each patient, exposure of the cells to the prostatic acid phosphatase-granulocyte macrophage colony-stimulating factor (PAP-GM-CSF recombinant fusion protein), and subsequent reinfusion of the cells. The pivotal study was a phase 3, multicenter, randomized, double-blind trial (D9902B),213 in which 512 patients with minimally symptomatic or asymptomatic metastatic CRPC were randomized 2:1 to receive sipuleucel-T or placebo. Median survival in the vaccine arm was 25.8 months compared with 21.7 months in the control arm. Sipuleucel-T treatment resulted in a 22% reduction in mortality risk (HR, 0.78; 95% CI, 0.61–0.98; P=.03). Common complications included mild to moderate chills (54.1%), pyrexia (29.3%), and headache (16.0%), which usually were transient.
The panel prefers that sipuleucel-T be used as initial therapy for asymptomatic or minimally symptomatic patients with metastatic CRPC, so that disease burden is lower and immune function potentially more intact. Clinicians and patients should be aware that the usual markers of benefit (decline in PSA and improvement in bone or CT scans) are not seen. Therefore, benefit to the individual patient cannot be ascertained using currently available testing.
Pembrolizumab
The FDA approved the use of pembrolizumab, an anti-PD1 antibody, for treatment of patients with “unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair (MMR)-deficient solid tumors who have progressed on prior treatment and who have no satisfactory alternative treatment options” on May 23, 2017.214 The indication has since been expanded to include several cancer types, but not prostate cancer specifically.215 The recommended adult dose of pembrolizumab for this indication is 200 mg intravenously once every 3 weeks.
FDA accelerated approval was based on the treatment of 149 patients across 5 clinical studies involving MSI-H or MMR-deficient (dMMR) colorectal (n=90) or noncolorectal (n=59) cancer for an objective response rate of 40% (59/149).214 All patients received ≥1 prior regimen. Among the noncolorectal cohorts, 2 patients had metastatic CRPC: one attained a partial objective response, and the other attained stable disease for >9 months.
A limited number of additional patients with metastatic CRPC treated with pembrolizumab have been reported.59,216–218 In 1 study, only 1 patient had prostate cancer.217 He had treatment-refractory, progressive, metastatic, dMMR disease and experienced a complete response; his prior therapy was not reported. In the other study, 10 patients with CRPC and nonvisceral metastases (bone, 7; lymph nodes, 2; bone and liver, 1) who had disease progression on enzalutamide were treated with pembrolizumab and enzalutamide.216 Some of the patients also had experienced disease progression on additional therapies (docetaxel for castration-naïve disease, abiraterone, and/or sipuleucel-T). Three of the 10 patients showed a near complete PSA response. Two of these 3 patients had radiographically measurable disease and showed a partial radiographic response (including a response in liver metastases). Of the remaining patients, 3 showed stable disease and 4 displayed no evidence of clinical benefit. Genetic analysis of biopsy tissue from 2 PSA responders and 2 PSA nonresponders revealed that one responder had an MSI-H tumor, whereas the other responder and the nonresponders did not. The nonrandomized phase Ib KEYNOTE-028 trial included 23 patients with advanced, progressive prostate cancer, of whom 74% had received ≥2 previous therapies for metastatic disease.218 The objective response rate by investigator review was of 17.4% (95% CI, 5.0%–38.8%), with 4 confirmed partial responses. Eight patients (34.8%) had stable disease. Treatment-related adverse events occurred in 61% of patients after median follow-up 7.9 months; 17% of the cohort experienced grade 3/4 events (ie, grade 4 lipase increase, grade 3 peripheral neuropathy, grade 3 asthenia, grade 3 fatigue).
The most common adverse events from pembrolizumab are fatigue, pruritus, diarrhea, anorexia, constipation, nausea, rash, fever, cough, dyspnea, and musculoskeletal pain. Pembrolizumab also may be associated with immune-mediated side effects, which include colitis, hepatitis, endocrinopathies, pneumonitis, or nephritis.
Based on the available data, the panel supports the use of pembrolizumab in patients with MSI-H or dMMR metastatic CRPC whose disease has progressed through at least 1 line of systemic therapy for M1 CRPC (category 2B). The prevalence of MMR deficiency in metastatic CPRC is estimated at 2%–5%,32,217, and testing for MSI-H or dMMR can be performed using DNA testing or immunohistochemistry. If tumor MSI-H or dMMR is identified, the panel recommends referral to genetic counseling for consideration of germline testing for Lynch syndrome.
Treatment Implications for Patients With DNA Repair Gene Mutations
Early studies suggest germline and somatic mutations in homologous recombination repair genes (eg, BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2) may be predictive of the clinical benefit of poly-ADP ribose polymerase (PARP) inhibitors.219–221 In particular, phase 2 data suggest that one PARP inhibitor, olaparib, has clinical activity in such patients, and trials of this agent and other PARP inhibitors are ongoing to assess the overall net clinical benefit of such therapy in men with CRPC, particularly in those men with either germline or somatically acquired DNA repair enzyme mutations.220,221 One of these trials was randomized, double-blind, and placebo-controlled, and the primary endpoint of median radiographic PFS was met (13.8 months in the olaparib/abiraterone arm vs 8.2 months in the placebo/abiraterone arm; HR, 0.65; 95% CI, 0.44-0.97; P=.034).221 The 142 patients in this trial were not selected based on mutational status. At present, no PARP inhibitor is approved for use in prostate cancer.
DNA repair defects have been reported to be predictive for sensitivity to platinum agents in CRPC and other cancers.222–224 Platinum agents have shown some activity in patients with CRPC without molecular selection.225 Studies of platinum agents in patients with CRPC that have DNA repair gene mutations are needed.
In addition, a recent study suggested that patients with metastatic CRPC and germline mutations in DNA repair genes may have better outcomes if treated with abiraterone or enzalutamide than with taxanes.35 However, it should be noted that the response of patients with metastatic CRPC and homologous recombination repair gene mutations respond to standard therapies is similar to the response of patients without mutations.226,227
The panel recommends clinical trial enrollment for men with prostate cancer and DNA repair gene mutations.
Agents Related to Bone Health in CRPC
In a multicenter study, 643 men with CRPC and asymptomatic or minimally symptomatic bone metastases were randomized to intravenous zoledronic acid every 3 weeks or placebo.228 At 15 months, fewer men in the zoledronic acid 4-mg group than men in the placebo group had SREs (33% vs 44%; P=.02). An update at 24 months also revealed an increase in the median time to first SRE (488 days vs 321 days; P=.01).229 No significant differences were found in OS. Other bisphosphonates have not been shown to be effective for prevention of disease-related skeletal complications. Earlier use of zoledronic acid in men with castration-naïve prostate cancer and bone metastases is not associated with lower risk for SREs, and in general should not be used for SRE prevention until the development of metastatic CRPC.230
The randomized TRAPEZE trial used a 2×2 factorial design to compare clinical PFS (pain progression, SREs, or death) as the primary outcome in 757 men with bone metastatic CRPC treated with docetaxel alone or with zoledronic acid, 89Sr, or both.231 The bone-directed therapies had no statistically significant effect on the primary outcome or on OS in unadjusted analysis. However, adjusted analysis revealed a small effect for 89Sr on clinical PFS (HR, 0.85; 95% CI, 0.73-0.99; P=.03). For secondary outcomes, zoledronic acid improved the SRE-free interval (HR, 0.78; 95% CI, 0.65–0.95; P=.01) and decreased the total SREs (424 vs 605) compared with docetaxel alone.
Denosumab was compared with zoledronic acid in a randomized, double-blind, placebo-controlled study in men with CRPC.232 The absolute incidence of SREs was similar in the 2 groups; however, the median time to first SRE was delayed by 3.6 months by denosumab compared with zoledronic acid (20.7 vs 17.1 months; P=.0002 for noninferiority, P=.008 for superiority). The rates of important SREs with denosumab were similar to zoledronic acid and included spinal cord compression (3% vs 4%), need for radiation (19% vs 21%), and pathologic fracture (14% vs 15%).
Treatment-related toxicities reported for zoledronic acid and denosumab were similar and included hypocalcemia (more common with denosumab 13% vs 6%), arthralgias, and osteonecrosis of the jaw (1%–2% incidence). Most, but not all, patients who develop osteonecrosis of the jaw have preexisting dental problems.233
References
- 2.↑
Herget KA, Patel DP, Hanson HA, et al.. Recent decline in prostate cancer incidence in the United States, by age, stage, and Gleason score. Cancer Med 2016;5:136–141.
- 3.↑
Kohler BA, Sherman RL, Howlader N, et al.. Annual report to the nation on the status of cancer, 1975-2011, featuring incidence of breast cancer subtypes by race/ethnicity, poverty, and state. J Natl Cancer Inst 2015;107:djv048.
- 4.↑
Negoita S, Feuer EJ, Mariotto A, et al.. Annual report to the nation on the status of cancer, part II: recent changes in prostate cancer trends and disease characteristics. Cancer 2018;124:2801–2814.
- 5.↑
Moyer VA, U.S. Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012;157:120–134.
- 6.↑
Kelly SP, Anderson WF, Rosenberg PS, et al.. Past, current, and future incidence rates and burden of metastatic prostate cancer in the United States. Eur Urol Focus 2017;71:195–201.
- 8.↑
Barocas DA, Mallin K, Graves AJ, et al.. Effect of the USPSTF grade D recommendation against screening for prostate cancer on incident prostate cancer diagnoses in the United States. J Urol 2015;194:1587–1593.
- 9.↑
Drazer MW, Huo D, Eggener SE. National prostate cancer screening rates after the 2012 US Preventive Services Task Force recommendation discouraging prostate-specific antigen-based screening. J Clin Oncol 2015;33:2416–2423.
- 10.↑
Etzioni R, Gulati R. Recent trends in PSA testing and prostate cancer incidence: a look at context. JAMA Oncol 2016;2:955–956.
- 11.↑
Fedewa SA, Ward EM, Brawley O, et al.. Recent patterns of prostate-specific antigen testing for prostate cancer screening in the United States. JAMA Intern Med 2017;177:1040–1042.
- 12.↑
Halpern JA, Shoag JE, Artis AS, et al.. National trends in prostate biopsy and radical prostatectomy volumes following the US Preventive Services Task Force guidelines against prostate-specific antigen screening. JAMA Surg 2017;152:192–198.
- 13.↑
Houston KA, King J, Li J, et al.. Trends in prostate cancer incidence rates and prevalence of prostate-specific antigen screening by socioeconomic status and regions in the US, 2004-2013. J Urol 2018;199:676–682.
- 14.↑
Kearns JT, Holt SK, Wright JL, et al.. PSA screening, prostate biopsy, and treatment of prostate cancer in the years surrounding the USPSTF recommendation against prostate cancer screening. Cancer 2018;124:2733–2739.
- 15.↑
Jemal A, Fedewa SA, Ma J, et al.. Prostate cancer incidence and PSA testing patterns in relation to USPSTF screening recommendations. JAMA 2015;314:2054–2061.
- 16.↑
Maurice MJ, Kim SP, Abouassaly R. Current status of prostate cancer diagnosis and management in the United States. JAMA Oncol 2016;2:1505–1507.
- 17.↑
Sammon JD, Abdollah F, Choueiri TK, et al.. Prostate-specific antigen screening after 2012 US Preventive Services Task Force recommendations. JAMA 2015;314:2077–2079.
- 18.↑
Zavaski ME, Meyer CP, Sammon JD, et al.. Differences in prostate-specific antigen testing among urologists and primary care physicians following the 2012 USPSTF recommendations. JAMA Intern Med 2016;176:546–547.
- 19.↑
Prostate cancer: Screening. The US Preventive Services Task Force (USPSTF); 2018. Available at: https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/prostate-cancer-screening1?ds=1&s=prostate. Accessed March 15, 2019.
- 20.↑
Albright F, Stephenson RA, Agarwal N, et al.. Prostate cancer risk prediction based on complete prostate cancer family history. Prostate 2015;75:390–398.
- 21.↑
Bratt O, Drevin L, Akre O, et al.. Family history and probability of prostate cancer, differentiated by risk category: a nationwide population-based study. J Natl Cancer Inst 2016;108.
- 22.↑
Jansson F, Drevin L, Frisell T, et al.. Concordance of non-low-risk disease among pairs of brothers with prostate cancer. J Clin Oncol 2018;36:1847–1852.
- 23.↑
Latham A, Srinivasan P, Kemel Y, et al.. Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer. J Clin Oncol 2019;37:286–295. JCO1800283.
- 24.↑
Haraldsdottir S, Hampel H, Wei L, et al.. Prostate cancer incidence in males with Lynch syndrome. Genet Med 2014;16:553–557.
- 25.↑
Ryan S, Jenkins MA, Win AK. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev 2014;23:437–449.
- 26.↑
Moran A, O’Hara C, Khan S, et al.. Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations. Fam Cancer 2012;11:235–242.
- 27.↑
Mersch J, Jackson MA, Park M, et al.. Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer 2015;121:269–275.
- 28.↑
Pilié PG, Johnson AM, Hanson KL, et al.. Germline genetic variants in men with prostate cancer and one or more additional cancers. Cancer 2017;123:3925–3932.
- 29.↑
Castro E, Goh C, Leongamornlert D, et al.. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment of localised prostate cancer. Eur Urol 2015;68:186–193.
- 30.↑
Castro E, Goh C, Olmos D, et al.. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol 2013;31:1748–1757.
- 31.↑
Na R, Zheng SL, Han M, et al.. Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death. Eur Urol 2017;71:740–747.
- 32.↑
Robinson D, Van Allen EM, Wu YM, et al.. Integrative clinical genomics of advanced prostate cancer. Cell 2015;161:1215–1228.
- 33.↑
Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 2015;163:1011–1025.
- 34.↑
Pritchard CC, Mateo J, Walsh MF, et al.. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med 2016;375:443–453.
- 35.↑
Castro E, Romero-Laorden N, Del Pozo A, et al.. PROREPAIR-B: a prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration-resistant prostate cancer. J Clin Oncol 2019;37:490–503.
- 36.↑
Giri VN, Obeid E, Gross L, et al.. Inherited mutations in men undergoing multigene panel testing for prostate cancer: emerging implications for personalized prostate cancer genetic evaluation [published online May 4, 2017]. JCO Precision Oncol. doi: 10.1200/PO.16.00039
- 37.↑
Giri VN, Hegarty SE, Hyatt C, et al.. Germline genetic testing for inherited prostate cancer in practice: implications for genetic testing, precision therapy, and cascade testing. Prostate 2019;79:333–339.
- 38.↑
Nicolosi P, Ledet E, Yang S, et al.. Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines [published online February 7, 2019]. JAMA Oncol. doi: 10.1001/jamaoncol.2018.6760
- 39.↑
Struewing JP, Hartge P, Wacholder S, et al.. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 1997;336:1401–1408.
- 40.↑
Kirchhoff T, Kauff ND, Mitra N, et al.. BRCA mutations and risk of prostate cancer in Ashkenazi Jews. Clin Cancer Res 2004;10:2918–2921.
- 41.↑
Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 1999;91:1310–1316.
- 42.↑
Agalliu I, Gern R, Leanza S, et al.. Associations of high-grade prostate cancer with BRCA1 and BRCA2 founder mutations. Clin Cancer Res 2009;15:1112–1120.
- 43.↑
Ford D, Easton DF, Bishop DT, et al..; Breast Cancer Linkage Consortium Risks of cancer in BRCA1-mutation carriers. Lancet 1994;343:692–695.
- 44.↑
Gallagher DJ, Gaudet MM, Pal P, et al.. Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res 2010;16:2115–2121.
- 45.↑
Leongamornlert D, Mahmud N, Tymrakiewicz M, et al..; UKGPCS Collaborators Germline BRCA1 mutations increase prostate cancer risk. Br J Cancer 2012;106:1697–1701.
- 46.↑
Liede A, Karlan BY, Narod SA. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol 2004;22:735–742.
- 47.↑
Thompson D, Easton DF.; Breast Cancer Linkage Consortium Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 2002;94:1358–1365.
- 48.↑
Tulinius H, Olafsdottir GH, Sigvaldason H, et al.. The effect of a single BRCA2 mutation on cancer in Iceland. J Med Genet 2002;39:457–462.
- 49.↑
van Asperen CJ, Brohet RM, Meijers-Heijboer EJ, et al..; Netherlands Collaborative Group on Hereditary Breast Cancer (HEBON) Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet 2005;42:711–719.
- 50.↑
Lecarpentier J, Silvestri V, Kuchenbaecker KB, et al..; EMBRACE; GEMO Study Collaborators; HEBON; KConFab Investigators Prediction of breast and prostate cancer risks in male BRCA1 and BRCA2 mutation carriers using polygenic risk scores. J Clin Oncol 2017;35:2240–2250.
- 51.↑
Helgason H, Rafnar T, Olafsdottir HS, et al.. Loss-of-function variants in ATM confer risk of gastric cancer. Nat Genet 2015;47:906–910.
- 52.↑
Erkko H, Xia B, Nikkilä J, et al.. A recurrent mutation in PALB2 in Finnish cancer families. Nature 2007;446:316–319.
- 53.↑
Näslund-Koch C, Nordestgaard BG, Bojesen SE. Increased risk for other cancers in addition to breast cancer for CHEK2*1100delC heterozygotes estimated from the Copenhagen General Population Study. J Clin Oncol 2016;34:1208–1216.
- 54.↑
Wu Y, Yu H, Zheng SL, et al.. A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer. Prostate 2018;78:607–615.
- 55.↑
Mitra A, Fisher C, Foster CS, et al..; IMPACT and EMBRACE Collaborators Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype. Br J Cancer 2008;98:502–507.
- 56.↑
Narod SA, Neuhausen S, Vichodez G, et al..; Hereditary Breast Cancer Study Group Rapid progression of prostate cancer in men with a BRCA2 mutation. Br J Cancer 2008;99:371–374.
- 57.↑
Thorne H, Willems AJ, Niedermayr E, et al..; Kathleen Cunningham Consortium for Research in Familial Breast Cancer Consortium Decreased prostate cancer-specific survival of men with BRCA2 mutations from multiple breast cancer families. Cancer Prev Res (Phila) 2011;4:1002–1010.
- 58.↑
Tryggvadóttir L, Vidarsdóttir L, Thorgeirsson T, et al.. Prostate cancer progression and survival in BRCA2 mutation carriers. J Natl Cancer Inst 2007;99:929–935.
- 59.↑
Abida W, Cheng ML, Armenia J, et al.. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade [published online December 27, 2018]. JAMA Oncol. doi: 10.1001/jamaoncol.2018.5801
- 60.↑
Zhou M High-grade prostatic intraepithelial neoplasia, PIN-like carcinoma, ductal carcinoma, and intraductal carcinoma of the prostate. Mod Pathol 2018;31(S1):S71–S79.
- 61.↑
Porter LH, Lawrence MG, Ilic D, et al.. Systematic review links the prevalence of intraductal carcinoma of the prostate to prostate cancer risk categories. Eur Urol 2017;72:492–495.
- 62.↑
Chua MLK, Lo W, Pintilie M, et al.. A prostate cancer “nimbosus”: genomic instability and SChLAP1 dysregulation underpin aggression of intraductal and cribriform subpathologies. Eur Urol 2017;72:665–674.
- 63.↑
Seipel AH, Whitington T, Delahunt B, et al.. Genetic profile of ductal adenocarcinoma of the prostate. Hum Pathol 2017;69:1–7.
- 64.↑
Böttcher R, Kweldam CF, Livingstone J, et al.. Cribriform and intraductal prostate cancer are associated with increased genomic instability and distinct genomic alterations. BMC Cancer 2018;18:8.
- 65.↑
Antonarakis ES, Shaukat F, Isaacsson Velho P, et al.. Clinical features and therapeutic outcomes in men with advanced prostate cancer and DNA mismatch repair gene mutations. Eur Urol 2019;75:378–382.
- 66.↑
Schweizer MT, Cheng HH, Tretiakova MS, et al.. Mismatch repair deficiency may be common in ductal adenocarcinoma of the prostate. Oncotarget 2016;7:82504–82510.
- 67.↑
Isaacsson Velho P, Silberstein JL, Markowski MC, et al.. Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer. Prostate 2018;78:401–407.
- 68.↑
Taylor RA, Fraser M, Livingstone J, et al.. Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories. Nat Commun 2017;8:13671.
- 69.↑
Risbridger GP, Taylor RA, Clouston D, et al.. Patient-derived xenografts reveal that intraductal carcinoma of the prostate is a prominent pathology in BRCA2 mutation carriers with prostate cancer and correlates with poor prognosis. Eur Urol 2015;67:496–503.
- 70.↑
Ewing CM, Ray AM, Lange EM, et al.. Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med 2012;366:141–149.
- 71.↑
Kote-Jarai Z, Mikropoulos C, Leongamornlert DA, et al..; UK Genetic Prostate Cancer Study Collaborators, and ProtecT Study Group Prevalence of the HOXB13 G84E germline mutation in British men and correlation with prostate cancer risk, tumour characteristics and clinical outcomes. Ann Oncol 2015;26:756–761.
- 72.↑
Middha S, Zhang L, Nafa K, et al.. Reliable pan-cancer microsatellite instability assessment by using targeted next-generation sequencing data [published online October 3, 2017]. JCO Precis Oncol. doi: 10.1200/PO.17.00084
- 73.↑
Guedes LB, Antonarakis ES, Schweizer MT, et al.. MSH2 loss in primary prostate cancer. Clin Cancer Res 2017;23:6863–6874.
- 74.↑
Hempelmann JA, Lockwood CM, Konnick EQ, et al.. Microsatellite instability in prostate cancer by PCR or next-generation sequencing. J Immunother Cancer 2018;6:29.
- 75.↑
D’Amico AV, Whittington R, Malkowicz SB, et al.. Pretreatment nomogram for prostate-specific antigen recurrence after radical prostatectomy or external-beam radiation therapy for clinically localized prostate cancer. J Clin Oncol 1999;17:168–172.
- 76.↑
D’Amico AV, Whittington R, Malkowicz SB, et al.. Biochemical outcome after radical prostatectomy or external beam radiation therapy for patients with clinically localized prostate carcinoma in the prostate specific antigen era. Cancer 2002;95:281–286.
- 77.↑
D’Amico AV, Whittington R, Malkowicz SB, et al.. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969–974.
- 78.↑
Epstein JI, Egevad L, Amin MB, et al..; Grading Committee The 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. Am J Surg Pathol 2016;40:244–252.
- 79.↑
Epstein JI, Zelefsky MJ, Sjoberg DD, et al.. A contemporary prostate cancer grading system: a validated alternative to the Gleason score. Eur Urol 2016;69:428–435.
- 80.↑
Loeb S, Folkvaljon Y, Robinson D, et al.. Evaluation of the 2015 Gleason grade groups in a nationwide population-based cohort. Eur Urol 2016;69:1135–1141.
- 81.↑
Ham WS, Chalfin HJ, Feng Z, et al.. New prostate cancer grading system predicts long-term survival following surgery for Gleason score 8-10 prostate cancer. Eur Urol 2017;71:907–912.
- 82.↑
Delahunt B, Egevad L, Srigley JR, et al.. Validation of International Society of Urological Pathology (ISUP) grading for prostatic adenocarcinoma in thin core biopsies using TROG 03.04 ‘RADAR’ trial clinical data. Pathology 2015;47:520–525.
- 83.↑
Mathieu R, Moschini M, Beyer B, et al.. Prognostic value of the new Grade Groups in Prostate Cancer: a multi-institutional European validation study. Prostate Cancer Prostatic Dis 2017;20:197–202.
- 84.↑
Leapman MS, Cowan JE, Simko J, et al.. Application of a prognostic Gleason grade grouping system to assess distant prostate cancer outcomes. Eur Urol 2017;71:750–759.
- 85.↑
He J, Albertsen PC, Moore D, et al.. Validation of a contemporary five-tiered Gleason grade grouping using population-based data. Eur Urol 2017;71:760–763.
- 86.↑
Pompe RS, Davis-Bondarenko H, Zaffuto E, et al.. Population-based validation of the 2014 ISUP Gleason grade groups in patients treated with radical prostatectomy, brachytherapy, external beam radiation, or no local treatment. Prostate 2017;77:686–693.
- 87.↑
Reese AC, Pierorazio PM, Han M, et al.. Contemporary evaluation of the National Comprehensive Cancer Network prostate cancer risk classification system. Urology 2012;80:1075–1079.
- 88.↑
Muralidhar V, Chen MH, Reznor G, et al.. Definition and validation of “favorable high-risk prostate cancer”: implications for personalizing treatment of radiation-managed patients. Int J Radiat Oncol Biol Phys 2015;93:828–835.
- 89.↑
Gandaglia G, Karnes RJ, Sivaraman A, et al.. Are all grade group 4 prostate cancers created equal? Implications for the applicability of the novel grade grouping. Urol Oncol 2017;35:461.e7–461.e14.
- 90.↑
Dinh KT, Muralidhar V, Mahal BA, et al.. Occult high-risk disease in clinically low-risk prostate cancer with ≥50% positive biopsy cores: should national guidelines stop calling them low-risk? Urology 2016;87:125–132.
- 91.↑
Dinh KT, Mahal BA, Ziehr DR, et al.. Incidence and predictors of upgrading and up staging among 10,000 contemporary patients with low risk prostate cancer. J Urol 2015;194:343–349.
- 92.↑
Zumsteg ZS, Spratt DE, Pei I, et al.. A new risk classification system for therapeutic decision making with intermediate-risk prostate cancer patients undergoing dose-escalated external-beam radiation therapy. Eur Urol 2013;64:895–902.
- 93.↑
Johns Hopkins Medicine. The Partin Tables. Available at: https://www.hopkinsmedicine.org/brady-urology-institute/specialties/conditions-and-treatments/prostate-cancer/fighting-prostate-cancer/partin-table.html Accessed April 11, 2019.
- 94.↑
Makarov DV, Trock BJ, Humphreys EB, et al.. Updated nomogram to predict pathologic stage of prostate cancer given prostate-specific antigen level, clinical stage, and biopsy Gleason score (Partin tables) based on cases from 2000 to 2005. Urology 2007;69:1095–1101.
- 95.↑
Borque Á, Rubio-Briones J, Esteban LM, et al.. Implementing the use of nomograms by choosing threshold points in predictive models: 2012 updated Partin Tables vs a European predictive nomogram for organ-confined disease in prostate cancer. BJU Int 2014;113:878–886.
- 96.↑
Tosoian JJ, Chappidi M, Feng Z, et al.. Prediction of pathological stage based on clinical stage, serum prostate-specific antigen, and biopsy Gleason score: Partin tables in the contemporary era. BJU Int 2017;119:676–683.
- 97.↑
Kattan MW, Eastham JA, Wheeler TM, et al.. Counseling men with prostate cancer: a nomogram for predicting the presence of small, moderately differentiated, confined tumors. J Urol 2003;170:1792–1797.
- 98.↑
Leyh-Bannurah SR, Dell’Oglio P, Tian Z, et al.. A proposal of a new nomogram for predicting upstaging in contemporary D’Amico low-risk prostate cancer patients. World J Urol 2017;35:189–197.
- 99.↑
Wong LM, Neal DE, Finelli A, et al.. Evaluation of models predicting insignificant prostate cancer to select men for active surveillance of prostate cancer. Prostate Cancer Prostatic Dis 2015;18:137–143.
- 100.↑
Memorial Sloan-Kettering Cancer Center Prostate Cancer Nomograms. Available at: http://www.mskcc.org/mskcc/html/10088.cfm. Accessed June 11, 2018.
- 101.↑
Punnen S, Freedland SJ, Presti JC, Jr., et al.. Multi-institutional validation of the CAPRA-S score to predict disease recurrence and mortality after radical prostatectomy. Eur Urol 2014;65:1171–1177.
- 102.↑
Stephenson AJ, Scardino PT, Eastham JA, et al.. Preoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Natl Cancer Inst 2006;98:715–717.
- 103.↑
Stephenson AJ, Kattan MW, Eastham JA, et al.. Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era. J Clin Oncol 2009;27:4300–4305.
- 104.↑
Graefen M, Haese A, Pichlmeier U, et al.. A validated strategy for side specific prediction of organ confined prostate cancer: a tool to select for nerve sparing radical prostatectomy. J Urol 2001;165:857–863.
- 105.↑
Ohori M, Kattan MW, Koh H, et al.. Predicting the presence and side of extracapsular extension: a nomogram for staging prostate cancer. J Urol 2004;171:1844–1849., discussion 1849.
- 106.↑
Steuber T, Graefen M, Haese A, et al.. Validation of a nomogram for prediction of side specific extracapsular extension at radical prostatectomy. J Urol 2006;175:939–944., discussion 944.
- 107.↑
Briganti A, Chun FK, Salonia A, et al.. A nomogram for staging of exclusive nonobturator lymph node metastases in men with localized prostate cancer. Eur Urol 2007;51:112–119; discussion 119–120.
- 108.↑
Cagiannos I, Karakiewicz P, Eastham JA, et al.. A preoperative nomogram identifying decreased risk of positive pelvic lymph nodes in patients with prostate cancer. J Urol 2003;170:1798–1803.
- 109.↑
Gandaglia G, Fossati N, Zaffuto E, et al.. Development and internal validation of a novel model to identify the candidates for extended pelvic lymph node dissection in prostate cancer. Eur Urol 2017;72:632–640.
- 110.↑
Gandaglia G, Ploussard G, Valerio M, et al.. A novel nomogram to identify candidates for extended pelvic lymph node dissection among patients with clinically localized prostate cancer diagnosed with magnetic resonance imaging-targeted and systematic biopsies. Eur Urol 2019;75:506–514.
- 111.↑
Kattan MW, Potters L, Blasko JC, et al.. Pretreatment nomogram for predicting freedom from recurrence after permanent prostate brachytherapy in prostate cancer. Urology 2001;58:393–399.
- 112.↑
Potters L, Morgenstern C, Calugaru E, et al.. 12-year outcomes following permanent prostate brachytherapy in patients with clinically localized prostate cancer. J Urol 2008; 179(5, Suppl)S20–S24.
- 113.↑
Potters L, Roach M III, Davis BJ, et al.. Postoperative nomogram predicting the 9-year probability of prostate cancer recurrence after permanent prostate brachytherapy using radiation dose as a prognostic variable. Int J Radiat Oncol Biol Phys 2010;76:1061–1065.
- 114.↑
Zelefsky MJ, Kattan MW, Fearn P, et al.. Pretreatment nomogram predicting ten-year biochemical outcome of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for prostate cancer. Urology 2007;70:283–287.
- 115.↑
Lee SJ, Lindquist K, Segal MR, et al.. Development and validation of a prognostic index for 4-year mortality in older adults. JAMA 2006;295:801–808.
- 116.↑
Kattan MW, Wheeler TM, Scardino PT. Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer. J Clin Oncol 1999;17:1499–1507.
- 117.↑
Ondracek RP, Kattan MW, Murekeyisoni C, et al.. Validation of the Kattan nomogram for prostate cancer recurrence after radical prostatectomy. J Natl Compr Canc Netw 2016;14:1395–1401.
- 118.↑
Tendulkar RD, Agrawal S, Gao T, et al.. Contemporary update of a multi-institutional predictive nomogram for salvage radiotherapy after radical prostatectomy. J Clin Oncol 2016;34:3648–3654.
- 119.↑
Dearnaley DP, Khoo VS, Norman AR, et al.. Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial. Lancet 1999;353:267–272.
- 120.↑
Khoo VS. Radiotherapeutic techniques for prostate cancer, dose escalation and brachytherapy. Clin Oncol (R Coll Radiol) 2005;17:560–571.
- 121.↑
D’Amico AV, Cote K, Loffredo M, et al.. Determinants of prostate cancer-specific survival after radiation therapy for patients with clinically localized prostate cancer. J Clin Oncol 2002;20:4567–4573.
- 122.↑
Dell’Oglio P, Suardi N, Boorjian SA, et al.. Predicting survival of men with recurrent prostate cancer after radical prostatectomy. Eur J Cancer 2016;54:27–34.
- 123.↑
Abdollah F, Karnes RJ, Suardi N, et al.. Predicting survival of patients with node-positive prostate cancer following multimodal treatment. Eur Urol 2014;65:554–562.
- 124.↑
D’Amico AV, Moul JW, Carroll PR, et al.. Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J Natl Cancer Inst 2003;95:1376–1383.
- 125.↑
Committee on the Review of Omics-based Tests for Predicting Patient Outcomes in Clinical Trials, Institute of Medicine Evolution of translational omics, lessons learned and the path forward. 2012. Available at: https://www.ncbi.nlm.nih.gov/books/NBK202165/. Accessed June 11, 2018.
- 127.↑
Hayes DF. OMICS-based personalized oncology: if it is worth doing, it is worth doing well! BMC Med 2013;11:221.
- 128.↑
Maurice MJ, Abouassaly R, Kim SP, et al.. Contemporary nationwide patterns of active surveillance use for prostate cancer. JAMA Intern Med 2015;175:1569–1571.
- 129.↑
Womble PR, Montie JE, Ye Z, et al..; Michigan Urological Surgery Improvement Collaborative Contemporary use of initial active surveillance among men in Michigan with low-risk prostate cancer. Eur Urol 2015;67:44–50.
- 130.↑
Cher ML, Dhir A, Auffenberg GB, et al..; Michigan Urological Surgery Improvement Collaborative Appropriateness criteria for active surveillance of prostate cancer. J Urol 2017;197:67–74.
- 131.↑
Bishoff JT, Freedland SJ, Gerber L, et al.. Prognostic utility of the cell cycle progression score generated from biopsy in men treated with prostatectomy. J Urol 2014;192:409–414.
- 132.↑
Cuzick J, Swanson GP, Fisher G, et al..; Transatlantic Prostate Group Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study. Lancet Oncol 2011;12:245–255.
- 133.↑
Cuzick J, Berney DM, Fisher G, et al..; Transatlantic Prostate Group Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort. Br J Cancer 2012;106:1095–1099.
- 134.↑
Freedland SJ, Gerber L, Reid J, et al.. Prognostic utility of cell cycle progression score in men with prostate cancer after primary external beam radiation therapy. Int J Radiat Oncol Biol Phys 2013;86:848–853.
- 135.↑
Klein EA, Cooperberg MR, Carroll PR. Reply to Yuri Tolkach, Markus Kuczyk, Florian Imkamp’s letter to the editor re: Eric A. Klein, Matthew R. Cooperberg, Cristina Magi-Galluzzi, et al. A 17-gene assay to predict prostate cancer aggressiveness in the context of gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. Eur urol 2014;66:550-60. Eur Urol 2014;66:e117–e118.
- 136.↑
Zhao SG, Chang SL, Spratt DE, et al.. Development and validation of a 24-gene predictor of response to postoperative radiotherapy in prostate cancer: a matched, retrospective analysis. Lancet Oncol 2016;17:1612–1620.
- 137.↑
Sinnott JA, Peisch SF, Tyekucheva S, et al.. Prognostic utility of a new mRNA expression signature of Gleason score. Clin Cancer Res 2017;23:81–87.
- 138.↑
Van Den Eeden SK, Lu R, Zhang N, et al.. A biopsy-based 17-gene genomic prostate score as a predictor of metastases and prostate cancer death in surgically treated men with clinically localized disease. Eur Urol 2018;73:129–138.
- 139.↑
Kim HL, Li P, Huang HC, et al.. Validation of the Decipher Test for predicting adverse pathology in candidates for prostate cancer active surveillance [published online December 12, 2018]. Prostate Cancer Prostatic Dis. doi: 10.1038/s41391-018-0101-6
- 140.↑
Spratt DE, Zhang J, Santiago-Jiménez M, et al.. Development and validation of a novel integrated clinical-genomic risk group classification for localized prostate cancer. J Clin Oncol 2018;36:581–590.
- 141.↑
Hu JC, Tosoian JJ, Qi J, et al.. Clinical utility of gene expression classifiers in men with newly diagnosed prostate cancer [published online, October 19, 2018]. JCO Precis Oncol. doi: 10.1200/PO.18.00163
- 142.↑
Lu-Yao GL, Albertsen PC, Moore DF, et al.. Fifteen-year survival outcomes following primary androgen-deprivation therapy for localized prostate cancer. JAMA Intern Med 2014;174:1460–1467.
- 143.↑
Potosky AL, Haque R, Cassidy-Bushrow AE, et al.. Effectiveness of primary androgen-deprivation therapy for clinically localized prostate cancer. J Clin Oncol 2014;32:1324–1330.
- 144.↑
McLeod DG, Iversen P, See WA, et al..; Casodex Early Prostate Cancer Trialists’ Group Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int 2006;97:247–254.
- 145.↑
McLeod DG, See WA, Klimberg I, et al.. The bicalutamide 150 mg early prostate cancer program: findings of the North American trial at 7.7-year median followup. J Urol 2006;176:75–80.
- 146.↑
Klotz L, O’Callaghan C, Ding K, et al.. Nadir testosterone within first year of androgen-deprivation therapy (ADT) predicts for time to castration-resistant progression: a secondary analysis of the PR-7 trial of intermittent versus continuous ADT. J Clin Oncol 2015;33:1151–1156.
- 147.↑
Trachtenberg J, Gittleman M, Steidle C, et al..; Abarelix Study Group A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. J Urol 2002;167:1670–1674.
- 148.↑
Loblaw DA, Virgo KS, Nam R, et al..; American Society of Clinical Oncology Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol 2007;25:1596–1605.
- 149.↑
Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists’ Collaborative Group. Lancet 2000;355:1491–1498.
- 150.↑
Samson DJ, Seidenfeld J, Schmitt B, et al.. Systematic review and meta-analysis of monotherapy compared with combined androgen blockade for patients with advanced prostate carcinoma. Cancer 2002;95:361–376.
- 151.↑
Laufer M, Denmeade SR, Sinibaldi VJ, et al.. Complete androgen blockade for prostate cancer: what went wrong? J Urol 2000;164:3–9.
- 152.↑
Dijkstra S, Witjes WP, Roos EP, et al.. The AVOCAT study: bicalutamide monotherapy versus combined bicalutamide plus dutasteride therapy for patients with locally advanced or metastatic carcinoma of the prostate-a long-term follow-up comparison and quality of life analysis. Springerplus 2016;5:653.
- 153.↑
Kolinsky M, de Bono JS. The ongoing challenges of targeting the androgen receptor. Eur Urol 2016;69:841–843.
- 154.↑
Albertsen PC, Klotz L, Tombal B, et al.. Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. Eur Urol 2014;65:565–573.
- 155.↑
Sun M, Choueiri TK, Hamnvik OP, et al.. Comparison of gonadotropin-releasing hormone agonists and orchiectomy: effects of androgen-deprivation therapy. JAMA Oncol 2016;2:500–507.
- 156.↑
Duchesne GM, Woo HH, Bassett JK, et al.. Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. Lancet Oncol 2016;17:727–737.
- 157.↑
Duchesne GM, Woo HH, King M, et al.. Health-related quality of life for immediate versus delayed androgen-deprivation therapy in patients with asymptomatic, non-curable prostate cancer (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. Lancet Oncol 2017;18:1192–1201.
- 158.↑
Hussain M, Tangen CM, Higano C, et al..; Southwest Oncology Group Trial 9346 (INT-0162) Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol 2006;24:3984–3990.
- 159.↑
Labrie F, Dupont A, Belanger A, et al.. Flutamide eliminates the risk of disease flare in prostatic cancer patients treated with a luteinizing hormone-releasing hormone agonist. J Urol 1987;138:804–806.
- 160.↑
Schulze H, Senge T. Influence of different types of antiandrogens on luteinizing hormone-releasing hormone analogue-induced testosterone surge in patients with metastatic carcinoma of the prostate. J Urol 1990;144:934–941.
- 161.↑
ZYTIGA® (abiraterone acetate) tablets. Janssen Biotech, Inc., Horsham, PA. 2018. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202379s025lbl.pdf, Accessed March 15, 2019
- 162.↑
Fizazi K, Tran N, Fein L, et al..; LATITUDE Investigators Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 2017;377:352–360.
- 163.↑
Chi KN, Protheroe A, Rodríguez-Antolín A, et al.. Patient-reported outcomes following abiraterone acetate plus prednisone added to androgen deprivation therapy in patients with newly diagnosed metastatic castration-naive prostate cancer (LATITUDE): an international, randomised phase 3 trial. Lancet Oncol 2018;19:194–206.
- 164.↑
James ND, de Bono JS, Spears MR, et al..; STAMPEDE Investigators Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med 2017;377:338–351.
- 165.↑
Szmulewitz RZ, Peer CJ, Ibraheem A, et al.. Prospective international randomized phase II study of low-dose abiraterone with food versus standard dose abiraterone in castration-resistant prostate cancer. J Clin Oncol 2018;36:1389–1395.
- 166.↑
Holzbeierlein J, Lal P, LaTulippe E, et al.. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol 2004;164:217–227.
- 167.↑
Mohler JL, Gregory CW, Ford OH III, et al.. The androgen axis in recurrent prostate cancer. Clin Cancer Res 2004;10:440–448.
- 168.↑
Small EJ, Halabi S, Dawson NA, et al.. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol 2004;22:1025–1033.
- 169.↑
Oh WK, Kantoff PW, Weinberg V, et al.. Prospective, multicenter, randomized phase II trial of the herbal supplement, PC-SPES, and diethylstilbestrol in patients with androgen-independent prostate cancer. J Clin Oncol 2004;22:3705–3712.
- 170.↑
Turo R, Smolski M, Esler R, et al.. Diethylstilboestrol for the treatment of prostate cancer: past, present and future. Scand J Urol 2014;48:4–14.
- 171.↑
Ockrim JL, Lalani EN, Laniado ME, et al.. Transdermal estradiol therapy for advanced prostate cancer--forward to the past? J Urol 2003;169:1735–1737.
- 172.↑
Langley RE, Cafferty FH, Alhasso AA, et al.. Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09). Lancet Oncol 2013;14:306–316.
- 173.↑
Gilbert DC, Duong T, Kynaston HG, et al.. Quality-of-life outcomes from the Prostate Adenocarcinoma: TransCutaneous Hormones (PATCH) trial evaluating luteinising hormone-releasing hormone agonists versus transdermal oestradiol for androgen suppression in advanced prostate cancer. BJU Int 2017;119:667–675.
- 174.↑
de Bono JS, Logothetis CJ, Molina A, et al..; COU-AA-301 Investigators Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995–2005.
- 175.↑
Fizazi K, Scher HI, Molina A, et al..; COU-AA-301 Investigators Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012;13:983–992.
- 176.↑
Logothetis CJ, Basch E, Molina A, et al.. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol 2012;13:1210–1217.
- 177.↑
Ryan CJ, Smith MR, de Bono JS, et al..; COU-AA-302 Investigators Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013;368:138–148.
- 178.↑
Ryan CJ, Smith MR, Fizazi K, et al..; COU-AA-302 Investigators Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015;16:152–160.
- 179.↑
YONSA® (abiraterone acetate) tablets, for oral use. Sun Pharmaceutical Industries, Inc., Cranbury, NJ. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210308s000lbl.pdf. Accessed March 15, 2019
- 180.↑
Hussaini A, Olszanski AJ, Stein CA, et al.. Impact of an alternative steroid on the relative bioavailability and bioequivalence of a novel versus the originator formulation of abiraterone acetate. Cancer Chemother Pharmacol 2017;80:479–486.
- 181.↑
Goldwater R, Hussaini A, Bosch B, et al.. Comparison of a novel formulation of abiraterone acetate vs The originator formulation in healthy male subjects: two randomized, open-label, crossover studies. Clin Pharmacokinet 2017;56:803–813.
- 182.↑
Stein CA, Levin R, Given R, et al.. Randomized phase 2 therapeutic equivalence study of abiraterone acetate fine particle formulation vs originator abiraterone acetate in patients with metastatic castration-resistant prostate cancer: the STAAR study. Urol Oncol 2018;36:81.e9–81.e16.
- 183.↑
Attard G, Reid AH, A’Hern R, et al.. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol 2009;27:3742–3748.
- 184.↑
Attard G, Reid AH, de Bono JS. Abiraterone acetate is well tolerated without concomitant use of corticosteroids. J Clin Oncol 2010;28:e560–e561, author reply e562.
- 185.↑
Reid AH, Attard G, Danila DC, et al.. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol 2010;28:1489–1495.
- 186.↑
Scher HI, Fizazi K, Saad F, et al..; AFFIRM Investigators Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:1187–1197.
- 187.↑
Fizazi K, Scher HI, Miller K, et al.. Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial. Lancet Oncol 2014;15:1147–1156.
- 188.↑
XTANDI® (enzalutamide) capsules, for oral use. Astellas Pharma US, Inc., Northbrook, IL. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/203415Orig1s014lbl.pdf. Accessed March 15, 2019.
- 189.↑
Beer TM, Armstrong AJ, Rathkopf DE, et al..; PREVAIL Investigators Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371:424–433.
- 190.↑
Beer TM, Armstrong AJ, Rathkopf D, et al.. Enzalutamide in men with chemotherapy-naive metastatic castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL study. Eur Urol 2017;71:151–154.
- 191.↑
Shore ND, Chowdhury S, Villers A, et al.. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol 2016;17:153–163.
- 192.↑
Penson DF, Armstrong AJ, Concepcion R, et al.. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE trial. J Clin Oncol 2016;34:2098–2106.
- 193.↑
Hussain M, Fizazi K, Saad F, et al.. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med 2018;378:2465–2474.
- 194.↑
Tombal B, Saad F, Penson D, et al.. Patient-reported outcomes following enzalutamide or placebo in men with non-metastatic, castration-resistant prostate cancer (PROSPER): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2019;20:556–569.
- 195.↑
ERLEADATM (apalutamide) tablets, for oral use. Horsham, PA: Janssen Products, LP; 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210951s000lbl.pdf. Accessed March 15, 2019.
- 196.↑
Smith MR, Saad F, Chowdhury S, et al..; SPARTAN Investigators Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018;378:1408–1418.
- 197.↑
Saad F, Cella D, Basch E, et al.. Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2018;19:1404–1416.
- 198.↑
Petrylak DP, Tangen CM, Hussain MH, et al.. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513–1520.