Rucaparib for the Treatment of Metastatic Castration-resistant Prostate Cancer Associated with a DNA Damage Repair Gene Alteration: Final Results from the Phase 2 TRITON2 Study.
[en] [en] BACKGROUND: Initial TRITON2 (NCT02952534) results demonstrated the efficacy of rucaparib 600 mg BID in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with a BRCA1 or BRCA2 (BRCA) or other DNA damage repair (DDR) gene alteration.
OBJECTIVE: To present the final data from TRITON2.
DESIGN, SETTING, AND PARTICIPANTS: TRITON2 enrolled patients with mCRPC who had progressed on one or two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was objective response rate (ORR; as per the modified Response Evaluation Criteria in Solid Tumor Version 1.1/Prostate Cancer Clinical Trials Working Group 3 criteria in patients with measurable disease by independent radiology review [IRR]); prostate-specific antigen (PSA) response rate (≥50% decrease from baseline [PSA50]) was a key secondary endpoint.
RESULTS AND LIMITATIONS: As of July 27, 2021 (study closure), TRITON2 had enrolled 277 patients, grouped by mutated gene: BRCA (n = 172), ATM (n = 59), CDK12 (n = 15), CHEK2 (n = 7), PALB2 (n = 11), or other DDR gene (Other; n = 13). ORR by IRR was 46% (37/81) in the BRCA subgroup (95% confidence interval [CI], 35-57%), 100% (4/4) in the PALB2 subgroup (95% CI, 40-100%), and 25% (3/12) in the Other subgroup (95% CI, 5.5-57%). No patients within the ATM, CDK12, or CHEK2 subgroups had an objective response by IRR. PSA50 response rates (95% CI) in the BRCA, PALB2, ATM, CDK12, CHEK2, and Other subgroups were 53% (46-61%), 55% (23-83%), 3.4% (0.4-12), 6.7% (0.2-32%), 14% (0.4-58%), and 23% (5.0-54%), respectively.
CONCLUSIONS: The final TRITON2 results confirm the clinical benefit and manageable safety profile of rucaparib in patients with mCRPC, including those with an alteration in BRCA or select non-BRCA DDR gene.
PATIENT SUMMARY: Almost half of TRITON2 patients with BRCA-mutated metastatic castration-resistant prostate cancer had a complete or partial tumor size reduction with rucaparib; clinical benefits were also observed with other DNA damage repair gene alterations.
Disciplines :
Oncology
Author, co-author :
Abida, Wassim ; Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: abidam@mskcc.org
Campbell, David; Barwon Health, University Hospital Geelong, Geelong, Victoria, Australia
Patnaik, Akash; University of Chicago Comprehensive Cancer Center, Chicago, IL, USA
Bryce, Alan H; Mayo Clinic, Phoenix, AZ, USA
Shapiro, Jeremy; Cabrini Hospital, Malvern, Victoria, Australia
Bambury, Richard M; Cork University Hospital, Wilton, Cork, Ireland
Zhang, Jingsong; H. Lee Moffitt Cancer Center, Tampa, FL, USA
Burke, John M; Rocky Mountain Cancer Centers and US Oncology Research, Denver, CO, USA
Castellano, Daniel; University Hospital 12 de Octubre, Madrid, Spain
Rucaparib for the Treatment of Metastatic Castration-resistant Prostate Cancer Associated with a DNA Damage Repair Gene Alteration: Final Results from the Phase 2 TRITON2 Study.
Teyssonneau, D., Margot, H., Cabart, M., et al. Prostate cancer and PARP inhibitors: progress and challenges. J Hematol Oncol, 14, 2021, 51.
Abida, W., Patnaik, A., Campbell, D., et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol 38 (2020), 3763–3772.
Merseburger, A.S., Waldron, N., Ribal, M.J., et al. Genomic testing in patients with metastatic castration-resistant prostate cancer: a pragmatic guide for clinicians. Eur Urol 79 (2021), 519–529.
Abida, W., Campbell, D., Patnaik, A., et al. Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: analysis from the phase II TRITON2 study. Clin Cancer Res 26 (2020), 2487–2496.
Clark, T.A., Chung, J.H., Kennedy, M., et al. Analytical validation of a hybrid capture-based next-generation sequencing clinical assay for genomic profiling of cell-free circulating tumor DNA. J Mol Diagn 20 (2018), 686–702.
Frampton, G.M., Fichtenholtz, A., Otto, G.A., et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 31 (2013), 1023–1031.
Crawford, B., Adams, S.B., Sittler, T., et al. Multi-gene panel testing for hereditary cancer predisposition in unsolved high-risk breast and ovarian cancer patients. Breast Cancer Res Treat 163 (2017), 383–390.
Neben, C.L., Zimmer, A.D., Stedden, W., et al. Multi-gene panel testing of 23,179 individuals for hereditary cancer risk identifies pathogenic variant carriers missed by current genetic testing guidelines. J Mol Diagn 21 (2019), 646–657.
de Bono, J., Mateo, J., Fizazi, K., et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med 382 (2020), 2091–2102.
de Bono, J.S., Mehra, N., Scagliotti, G.V., et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol 22 (2021), 1250–1264.
Smith, M.R., Scher, H.I., Sandhu, S., et al. Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial. Lancet Oncol 23 (2022), 362–373.
Chi, K.N., Rathkopf, D.E., Smith, M.R., et al. Phase 3 MAGNITUDE study: first results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations. J Clin Oncol, 40(6_suppl), 2022, 12.
Saad, F., Armstrong, A.J., Thiery-Vuillemin, A., et al. PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol, 40(6_suppl), 2022, 11.
Ashworth, A., A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol 26 (2008), 3785–3790.
Abida, W., Cyrta, J., Heller, G., et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci U S A 116 (2019), 11428–11436.
Hamid, A.A., Gray, K.P., Shaw, G., et al. Compound genomic alterations of TP53, PTEN, and RB1 tumor suppressors in localized and metastatic prostate cancer. Eur Urol 76 (2019), 89–97.
Ferraldeschi, R., Nava Rodrigues, D., Riisnaes, R., et al. PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate. Eur Urol 67 (2015), 795–802.
Aparicio, A.M., Shen, L., Tapia, E.L., et al. Combined tumor suppressor defects characterize clinically defined aggressive variant prostate cancers. Clin Cancer Res 22 (2016), 1520–1530.
Reiss, K.A., Mick, R., O'Hara, M.H., et al. Phase II study of maintenance rucaparib in patients with platinum-sensitive advanced pancreatic cancer and a pathogenic germline or somatic variant in BRCA1, BRCA2, or PALB2. J Clin Oncol 39 (2021), 2497–2505.
Gruber, J.J., Afghahi, A., Timms, K., et al. A phase II study of talazoparib monotherapy in patients with wild-type BRCA1 and BRCA2 with a mutation in other homologous recombination genes. Nat Cancer 3 (2022), 1181–1191.
Sautois, B., Loehr, A., Watkins, S.P., Schroeder, H., Abida, W., A case study of clinical response to rucaparib in a patient with metastatic castration-resistant prostate cancer and a RAD51B alteration. Curr Oncol 29 (2022), 4178–4184.
Lynparza® (olaparib) tablets [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2022.
Mota, J.M., Barnett, E., Nauseef, J.T., et al. Platinum-based chemotherapy in metastatic prostate cancer with DNA repair gene alterations. JCO Precis Oncol 4 (2020), 355–366.
Kristeleit, R., Shapiro, G.I., Burris, H.A., et al. A phase I-II study of the oral PARP inhibitor rucaparib in patients with germline BRCA1/2-mutated ovarian carcinoma or other solid tumors. Clin Cancer Res 23 (2017), 4095–4106.
Grivas, P., Loriot, Y., Morales-Barrera, R., et al. Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS). BMC Cancer, 21, 2021, 593.
McCormick, A., Swaisland, H., In vitro assessment of the roles of drug transporters in the disposition and drug-drug interaction potential of olaparib. Xenobiotica 47 (2017), 903–915.
Kikuchi, R., Lao, Y., Bow, D.A., et al. Prediction of clinical drug-drug interactions of veliparib (ABT-888) with human renal transporters (OAT1, OAT3, OCT2, MATE1, and MATE2K). J Pharm Sci 102 (2013), 4426–4432.
Zibetti Dal Molin, G., Westin, S.N., Msaouel, P., Gomes, L.M., Dickens, A., Coleman, R.L., Discrepancy in calculated and measured glomerular filtration rates in patients treated with PARP inhibitors. Int J Gynecol Cancer 30 (2020), 89–93.
Fizazi, K., Piulats, J.M., Reaume, M.N., et al. Rucaparib or physician's choice in metastatic prostate cancer. N Engl J Med 388 (2023), 719–732.
