Androgen deprivation is the foundation for the systemic therapy of advanced prostate cancer. Multiple trials have tested combined androgen blockade versus androgen deprivation alone in patients with advanced disease. These studies suggest a slight advantage to the combined approaches that contain flutamide and bicalutamide, but the lack of dramatic differences in outcome makes monotherapy reasonable, especially in patients with more indolent disease. Intermittent androgen deprivation is an alternative that may allow patients to reduce the total time on androgen suppression as well as possibly delay the onset of androgen independence. A number of secondary hormonal therapies, including deferred and secondary antiandrogens, ketoconazole, and estrogens have shown modest response proportions. Patients with less advanced disease such as a rising prostate-specific antigen have varied outcomes, and no standard approach exists. In this group, noncastrating forms of hormonal therapy are being evaluated. Patients undergoing definitive local therapy who have high-risk features may benefit from early, as opposed to deferred, androgen deprivation. This review examines the evidence for the current state of the art in hormonal therapy in patients with prostate cancer and focuses, in particular, on treatment composition and timing as well as the rationale for the use of hormonal therapy in early stage disease.
Charles J. Ryan and Eric J. Small
Rahul Aggarwal, Tian Zhang, Eric J. Small and Andrew J. Armstrong
Neuroendocrine prostate cancer (NEPC) encompasses various clinical contexts, ranging from the de novo presentation of small cell prostatic carcinoma to a treatment-emergent transformed phenotype that arises from typical adenocarcinoma of the prostate. The development of resistance to potent androgen receptor signaling inhibition may be associated with the emergence of aggressive phenotype, advanced castration-resistant NEPC. Clinically, small cell prostate cancer and NEPC are often manifested by the presence of visceral or large soft tissue metastatic disease, a disproportionately low serum prostate-specific antigen level relative to the overall burden of disease, and a limited response to targeting of the androgen signaling axis. These tumors are often characterized by loss of androgen receptor expression, loss of retinoblastoma tumor suppressor copy number or expression, amplification of Aurora kinase A and N-Myc, and activation of the PI3K pathway. However, a consensus phenotype-genotype definition of NEPC has yet to emerge, and molecularly based biomarkers are needed to expand on traditional morphologic and immunohistochemical markers of NEPC to fully define the spectrum of this aggressive, androgen receptor-independent disease. Emerging studies implicate a shared clonal origin with prostatic adenocarcinoma in many cases, with the adaptive emergence of unique cellular programming and gene expression profiles. Ongoing clinical studies are focused on developing novel targeted therapeutic approaches for this high-risk, lethal subset of disease, to improve on the limited durations of response often observed with traditional platinum-based chemotherapy.
Heather H. Cheng, Alexandra O. Sokolova, Edward M. Schaeffer, Eric J. Small and Celestia S. Higano
It is increasingly important for clinicians involved in the management of prostate cancer to understand the relevance of heritable (germline) mutations that, for select patients, affect prostate cancer risk and cancer biology, and acquired (somatic) mutations that occur in prostate cancer cells. In the advanced disease setting, mutations in homologous recombination repair genes (eg, BRCA1, BRCA2, ATM, CHEK2, PALB2) suggest candidacy for platinum chemotherapy and PARP inhibitor trials. Similarly, microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest potential vulnerability to PD-1 inhibitors. Germline genetic testing has potential importance in the treatment and assessment of familial risk, and tumor-directed somatic sequencing may guide treatment decision-making. This review provides clinicians with knowledge of basic genetic terminology, awareness of the importance of family history of cancer (not limited to prostate cancer), contrasts between the different but potentially related objectives of germline versus somatic testing of tumor tissue, and indications for genetic counseling. Specific clinical scenarios, objectives of testing, and nature of the assays are reviewed. Germline and somatic mutations of known and potential relevance to prostate cancer are discussed in the context of treatment options, and algorithms to assist clinicians in approaching this area are proposed.
Eric Lu, George V. Thomas, Yiyi Chen, Alexander W. Wyatt, Paul Lloyd, Jack Youngren, David Quigley, Raymond Bergan, Shawna Bailey, Tomasz M. Beer, Felix Y. Feng, Eric J. Small and Joshi J. Alumkal
Background: PARP inhibition is a promising therapeutic strategy for the treatment of men with metastatic castration-resistant prostate cancer whose tumors harbor homologous recombination DNA repair gene alterations. However, questions remain for many practicing clinicians about which patients are ideally suited for PARP inhibitor treatment. This report details our institutional experience using PARP inhibitor therapy in patients whose tumors harbored specific DNA repair gene alterations. Patients and Methods: We performed a retrospective chart review to identify patients at Oregon Health & Science University who were treated with PARP inhibition. We identified 8 patients and determined the impact of the specific DNA repair gene alterations on tumor response and time on treatment with PARP inhibition. Results: A number of DNA repair gene alterations were identified. Three patients had pathogenic BRCA2 mutations and one had a BRCA2 mutation of uncertain significance. Conversely, the 4 other patients' tumors harbored alterations in other DNA repair genes, none of which were clearly pathogenic. A statistically significant difference in benefit was seen between patients whose tumors harbored BRCA2 gene alterations and those whose tumors did not, as measured by >50% decline in prostate-specific antigen levels (100% vs 0%; P=.03) and duration on therapy (31.4 vs 6.4 weeks; P=.03). Conclusions: Our results demonstrate that not all DNA repair alterations are equally predictive of PARP inhibitor response. Importantly, all responding patients had tumors harboring BRCA2 DNA repair alterations, including one without a known pathogenic mutation. Conversely, among the 4 nonresponders, several DNA repair alterations in genes other than BRCA2 were identified that were not clearly pathogenic. This demonstrates the need to carefully examine the functional relevance of the DNA repair alterations identified, especially in genes other than BRCA2, when considering patients for PARP inhibitor treatment.
James L. Mohler, Philip W. Kantoff, Andrew J. Armstrong, Robert R. Bahnson, Michael Cohen, Anthony Victor D’Amico, James A. Eastham, Charles A. Enke, Thomas A. Farrington, Celestia S. Higano, Eric Mark Horwitz, Christopher J. Kane, Mark H. Kawachi, Michael Kuettel, Timothy M. Kuzel, Richard J. Lee, Arnold W. Malcolm, David Miller, Elizabeth R. Plimack, Julio M. Pow-Sang, David Raben, Sylvia Richey, Mack Roach III, Eric Rohren, Stan Rosenfeld, Edward Schaeffer, Eric J. Small, Guru Sonpavde, Sandy Srinivas, Cy Stein, Seth A. Strope, Jonathan Tward, Dorothy A. Shead and Maria Ho
Prostate cancer has surpassed lung cancer as the most common cancer in men in the United States. The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer based on clinical evidence and expert consensus. NCCN Panel guidance on treatment decisions for patients with localized disease is represented in this version. Significant updates for early disease include distinction between active surveillance and observation, a new section on principles of imaging, and revisions to radiation recommendations. The full version of these guidelines, including treatment of patients with advanced disease, can be found online at the NCCN website.
James L. Mohler, Philip W. Kantoff, Andrew J. Armstrong, Robert R. Bahnson, Michael Cohen, Anthony Victor D’Amico, James A. Eastham, Charles A. Enke, Thomas A. Farrington, Celestia S. Higano, Eric Mark Horwitz, Mark H. Kawachi, Michael Kuettel, Richard J. Lee, Gary R. MacVicar, Arnold W. Malcolm, David Miller, Elizabeth R. Plimack, Julio M. Pow-Sang, Sylvia Richey, Mack Roach III, Eric Rohren, Stan Rosenfeld, Eric J. Small, Sandy Srinivas, Cy Stein, Seth A. Strope, Jonathan Tward, Patrick C. Walsh, Dorothy A. Shead and Maria Ho
The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer. This report highlights notable recent updates. Radium-223 dichloride is a first-in-class radiopharmaceutical that recently received approval for the treatment of patients with symptomatic bone metastases and no known visceral disease. It received a category 1 recommendation as both a first-line and second-line option. The NCCN Prostate Cancer Panel also revised recommendations on the choice of intermittent or continuous androgen deprivation therapy based on recent phase III clinical data comparing the 2 strategies in the nonmetastatic and metastatic settings.
James E. Montie, Peter E. Clark, Mario A. Eisenberger, Rizk El-Galley, Richard E. Greenberg, Harry W. Herr, Gary R. Hudes, Deborah A. Kuban, Timothy M. Kuzel, Paul H. Lange, Subodh M. Lele, Jeffrey Michalski, Anthony Patterson, Kamal S. Pohar, Jerome P. Richie, Wade J. Sexton, William U. Shipley, Eric J. Small, Donald L. Trump, Phillip J. Walther and Timothy G. Wilson
Peter E. Clark, Neeraj Agarwal, Matthew C. Biagioli, Mario A. Eisenberger, Richard E. Greenberg, Harry W. Herr, Brant A. Inman, Deborah A. Kuban, Timothy M. Kuzel, Subodh M. Lele, Jeff Michalski, Lance C. Pagliaro, Sumanta K. Pal, Anthony Patterson, Elizabeth R. Plimack, Kamal S. Pohar, Michael P. Porter, Jerome P. Richie, Wade J. Sexton, William U. Shipley, Eric J. Small, Philippe E. Spiess, Donald L. Trump, Geoffrey Wile, Timothy G. Wilson, Mary Dwyer and Maria Ho
Bladder cancer is the fourth most common cancer in the United States. Urothelial carcinoma that originates from the urinary bladder is the most common subtype. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) provide recommendations on the diagnosis and management of non–muscle-invasive and muscle-invasive urothelial carcinoma of the bladder. This version of the guidelines provides extensive reorganization and updates on the principles of chemotherapy management.
Peter E. Clark, Philippe E. Spiess, Neeraj Agarwal, Matthew C. Biagioli, Mario A. Eisenberger, Richard E. Greenberg, Harry W. Herr, Brant A. Inman, Deborah A. Kuban, Timothy M. Kuzel, Subodh M. Lele, Jeff Michalski, Lance Pagliaro, Sumanta K. Pal, Anthony Patterson, Elizabeth R. Plimack, Kamal S. Pohar, Michael P. Porter, Jerome P. Richie, Wade J. Sexton, William U. Shipley, Eric J. Small, Donald L. Trump, Geoffrey Wile, Timothy G. Wilson, Mary Dwyer and Maria Ho
Squamous cell carcinoma of the penis represents approximately 0.5% of all cancers among men in the United States and other developed countries. Although rare, it is associated with significant disfigurement, and only half of the patients survive beyond 5 years. Proper evaluation of both the primary lesion and lymph nodes is critical, because nodal involvement is the most important factor of survival. The NCCN Clinical Practice Guidelines in Oncology for Penile Cancer provide recommendations on the diagnosis and management of this devastating disease based on evidence and expert consensus.