Immune checkpoint inhibitors and BRAF-targeted therapies have redefined the management of malignant melanoma. Overall survival (OS) has increased significantly with immunotherapy, with >60 months reported.1 Stabilization of the survival curve in approximately one-third of patients is further suggestive of durable responses. Likewise, BRAF and MEK inhibitors targeting melanomas harboring BRAF V600E mutations have demonstrated excellent, although short-lived, responses.2–5 Despite these advances, a significant number of patients develop progressive disease, intolerable adverse side-effects, or become resistant to targeted therapies. There remains a need for viable alternative treatments for these patients with treatment-refractory melanoma.
PARP inhibitors (PARPi) have emerged as a promising treatment in cancers with alterations in homologous recombination repair (HRR) genes, one of the DNA damage repair genes (also termed HR-DDR).6 Cancer cells with homologous recombination deficiency (HRD) treated with PARPi are unable to repair double-strand breaks, leading to cell death by synthetic lethality. The prevalence of detected HRR mutations is common in melanoma, with frequencies ranging from 18.1% to upwards of 41%.7,8 In general, patients with metastatic melanoma without selection for PARPi sensitivity have only modest responses to rucaparib, with only 17.4% having a partial response and 17.4% having stable disease (34.8% disease control rate) when combined with chemotherapy.9 However, there are multiple reports of patients with HRR mutations responding to PARPi.10–12 Taken together, PARPi may be a promising treatment in immunotherapy-refractory melanoma, but patient selection will be critical.
PARPi response prediction necessitates an accurate assessment of HRD status. HRD score is not uniformly calculated but rather derived as a composite score from either a single or combination of the genomic findings that reflect genomic instability, genome-wide loss of heterozygosity (GW-LOH),13 telomeric allelic imbalance (TAI),14 and/or large-scale state transitions (LST).15 This composite HRD score derived from all 3 measures (GW-LOH, TAI, and LST) has been shown to correlate with response to PARPi in ovarian cancers.16 Direct gene testing may underappreciate secondary factors leading to genomic instability, such as epigenetic changes. Furthermore, various causes of genomic instability may have differential effects on response to treatment. A small but thorough study in high-grade ovarian cancer suggests that high HRD score through genetic alterations holds greater prognostic significance than high HRD score through epigenetic changes,17 but this finding has not been validated in other cancers. It remains unclear whether direct gene testing for common HRR-associated genes alone is sufficient to assess HRD status and potential treatment response to PARPi in melanoma.
Here, we examine the relationship between PARPi response and HRD scores derived from GW-LOH in 4 patients with metastatic melanoma, expanding on earlier reports, including our 2 prior reports as well as another study showing a profound and durable response in a patient with both HRR mutations and elevated HRD score.12,18,19 We next examined the prevalence of homologous recombination defects in 933 patients with melanoma derived from both GW-LOH and traditional direct gene testing to provide rationale for targeted therapy with a PARPi-based regimen based on HRD-LOH scoring.
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2019;381:1535–1546.
Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012;367:107–114.
Davies MA, Saiag P, Robert C, et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 2017;18:863–873.
Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol 2016;17:1248–1260.
Grossmann KF, Margolin K. Long-term survival as a treatment benchmark in melanoma: latest results and clinical implications. Ther Adv Med Oncol 2015;7:181–191.
Pilié PG, Gay CM, Byers LA, et al. PARP inhibitors: extending benefit beyond BRCA-mutant cancers. Clin Cancer Res 2019;25:3759–3771.
Heeke AL, Pishvaian MJ, Lynce F, et al. Prevalence of homologous recombination-related gene mutations across multiple cancer types. JCO Precis Oncol 2018;2:PO.17.00286.
Kim H, Ahn S, Kim H, et al. The prevalence of homologous recombination deficiency (HRD) in various solid tumors and the role of HRD as a single biomarker to immune checkpoint inhibitors. J Cancer Res Clin Oncol 2022;148:2427–2435.
Plummer R, Lorigan P, Steven N, et al. A phase II study of the potent PARP inhibitor, rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation. Cancer Chemother Pharmacol 2013;71:1191–1199.
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, Plummer R , Lorigan P , Steven N A phase II study of the potent PARP inhibitor, rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation. Cancer Chemother Pharmacol 2013; 71: 1191– 1199. 23423489
Chan WY, Brown LJ, Reid L, et al. PARP inhibitors in melanoma—an expanding therapeutic option? Cancers (Basel) 2021;13:4520.
Lau B, Menzies AM, Joshua AM. Ongoing partial response at 6 months to olaparib for metastatic melanoma with somatic PALB2 mutation after failure of immunotherapy: a case report. Ann Oncol 2021;32:280–282.
Kiel PJ, Radovich M, Schneider BP, Logan TF. Sustained exceptional response to poly (ADP-ribose) polymerase inhibition plus temozolomide in metastatic melanoma with DNA repair deficiency. JCO Precis Oncol 2018;2:1–7.
Abkevich V, Timms KM, Hennessy BT, et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 2012;107:1776–1782.
Birkbak NJ, Wang ZC, Kim JY, et al. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov 2012;2:366–375.
Popova T, Manié E, Rieunier G, et al. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res 2012;72:5454–5462.
Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016;375:2154–2164.
Takaya H, Nakai H, Takamatsu S, et al. Homologous recombination deficiency status-based classification of high-grade serous ovarian carcinoma. Sci Rep 2020;10:2757.
Khaddour K, Ansstas M, Visconti J, et al. Mutation clearance and complete radiologic resolution of immunotherapy relapsed metastatic melanoma after treatment with nivolumab and olaparib in a patient with homologous recombinant deficiency: any role for PARP inhibitors and checkpoint blockade? Ann Oncol 2021;32:279–280.
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, Khaddour K , Ansstas M , Visconti J Mutation clearance and complete radiologic resolution of immunotherapy relapsed metastatic melanoma after treatment with nivolumab and olaparib in a patient with homologous recombinant deficiency: any role for PARP inhibitors and checkpoint blockade?Ann Oncol 2021; 32: 279– 280.
Khaddour K, Ansstas M, Ansstas G. Clinical outcomes and longitudinal circulating tumor DNA changes after treatment with nivolumab and olaparib in immunotherapy relapsed melanoma with detected homologous recombination deficiency. Cold Spring Harb Mol Case Stud 2021;7:a006129.
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, Khaddour K , Ansstas M Ansstas G Clinical outcomes and longitudinal circulating tumor DNA changes after treatment with nivolumab and olaparib in immunotherapy relapsed melanoma with detected homologous recombination deficiency. Cold Spring Harb Mol Case Stud 2021; 7: a006129. 34667064
Leibowitz BD, Dougherty BV, Bell JSK, et al. Validation of genomic and transcriptomic models of homologous recombination deficiency in a real-world pan-cancer cohort. BMC Cancer 2022;22:587.
Bell JSK, Venkat A, Parsons J, et al. An integrative molecular framework to predict homologous recombination deficiency. J Clin Oncol 2020;38(Suppl):Abstract e15664.
Tempus. Genetic profiling. Accessed October 29, 2022. Available at: https://www.tempus.com/oncology/genomic-profiling/
Beaubier N, Tell R, Lau D, et al. Clinical validation of the tempus xT next-generation targeted oncology sequencing assay. Oncotarget 2019;10:2384–2396.
Beaubier N, Bontrager M, Huether R, et al. Integrated genomic profiling expands clinical options for patients with cancer. Nat Biotechnol 2019;37:1351–1360.
Fernandes LE, Epstein CG, Bobe AM, et al. Real-world evidence of diagnostic testing and treatment patterns in US patients with breast cancer with implications for treatment biomarkers from RNA sequencing data. Clin Breast Cancer 2021;21:e340–361.
Kim KB, Soroceanu L, de Semir D, et al. Prevalence of homologous recombination pathway gene mutations in melanoma: rationale for a new targeted therapeutic approach. J Invest Dermatol 2021;141:2028–2036.e2.
van Wijk LM, Nilas AB, Vrieling H, et al. RAD51 as a functional biomarker for homologous recombination deficiency in cancer: a promising addition to the HRD toolbox? Expert Rev Mol Diagn 2022;22:185–199.
Makino E, Fröhlich LM, Sinnberg T, et al. Targeting Rad51 as a strategy for the treatment of melanoma cells resistant to MAPK pathway inhibition. Cell Death Dis 2020;11:581.
Moschetta M, George A, Kaye SB, et al. BRCA somatic mutations and epigenetic BRCA modifications in serous ovarian cancer. Ann Oncol 2016;27:1449–1455.
Sahnane N, Carnevali I, Formenti G, et al. BRCA methylation testing identifies a subset of ovarian carcinomas without germline variants that can benefit from PARP inhibitor. Int J Mol Sci 2020;21:9708.
Smeby J, Kryeziu K, Berg KCG, et al. Molecular correlates of sensitivity to PARP inhibition beyond homologous recombination deficiency in pre-clinical models of colorectal cancer point to wild-type TP53 activity. EBioMedicine 2020;59:102923.
Chabanon RM, Muirhead G, Krastev DB, et al. PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer. J Clin Invest 2019;129:1211–1228.
Nolan E, Savas P, Policheni AN, et al. Combined immune checkpoint blockade as a therapeutic strategy for BRCA1-mutated breast cancer. Sci Transl Med 2017;9:eaal4922.
Connor AA, Denroche RE, Jang GH, et al. Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma. JAMA Oncol 2017;3:774–783.
Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014;371:2189–2199.
Jiao S, Xia W, Yamaguchi H, et al. PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res 2017;23:3711–3720.
Teo MY, Seier K, Ostrovnaya I, et al. Alterations in DNA damage response and repair genes as potential marker of clinical benefit from PD-1/PD-L1 blockade in advanced urothelial cancers. J Clin Oncol 2018;36:1685–1694.
Drew Y, Penson RT, O’Malley DM, et al. Phase II study of olaparib plus durvalumab and bevacizumab (MEDIOLA): initial results in patients with non-germline BRCA-mutated platinum sensitive relapsed ovarian cancer. Ann Oncol 2020;31(Suppl 4):S551–589. Abstract 814MO.
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, Drew Y , Penson RT , O’Malley DM Phase II study of olaparib plus durvalumab and bevacizumab (MEDIOLA): initial results in patients with non-germline BRCA-mutated platinum sensitive relapsed ovarian cancer. Ann Oncol 2020; 31( Suppl 4): S551– 589. Abstract 814MO.
Vikas P, Borcherding N, Chennamadhavuni A, et al. Therapeutic potential of combining PARP inhibitor and immunotherapy in solid tumors. Front Oncol 2020;10:570.