Table 1.
Summary of Phase II and III Clinical Trials in mCRPC Patients with PARPi Monotherapy. Table summarizing results from 7 landmark PARPi monotherapy trials. All trials led one common inference that patients with BRCA loss yielded highest measurable response
| Clinical Trials | Study Design | PARPi | Patient Selection | Total Patients Enrolled | DDR Gene Alterations | Clinical Outcome | Reported Grade 3 Adverse Events |
|---|---|---|---|---|---|---|---|
| TOPARP-A (2015)39 | Phase-II, Open label | Olaparib | Molecularly unselected mCRPC; prior exposure to ARSI/chemotherapy. | n=50 | 33% with DDR gene alterations (DDR+); BRCA2 (14%), ATM (10%) | rPFS: DDR (+) vs DDR (−): median 9.8 mo vs 2.7 mo; p<0.001. OS: DDR (+) vs DDR(–): median (13.8 mo vs 7.5 mo; p=0.05. 6% DDR (–) attained objective response. | Anemia: 20%. Fatigue: 12%. Leucopenia: 6%. Thrombocytopenia: 4%. Neutropenia (4%) |
| TOPARP-B (2020)38 | Phase-II, open-label, RCT | Olaparib | mCRPC, DDR gene alterations$; taxane-treatment history (+); ARSI exposure agnostic | N=98 (2 treatment groups. Group 1: n=49 Olaparib 300 mg twice daily; Group 2, n=49, Olaparib 400 mg twice daily). | BRCA1/2 (33%) ATM (21%), CDK12 (21%), PALB2 (7%) | ORR- 400 mg treatment arm: 54%; 300 mg treatment arm; 39%. ORR- BRCA1/2 mutant: 83%, 57% PALB2 mutant: 57% and ATM mutant: 37%. | 300 mg cohort Anemia: 31%. 400 mg cohort Anemia: 37% |
| PROfound (2020)40 | Phase III, RCT | Olaparib | Predefined DDR gene altered mCRPC#; Progressed on ARSI; chemo naïve | Cohort A n=245, Cohort B n=142 | Cohort A (n=245) with BRCA1/2 or ATM alterations. Cohort B (n=142) with at least one of the other 12 prespecified DDR gene alterations | Cohort A- Median rPFS 7.4 vs 3.6 mo, P<0.001. Overall population (Cohorts A & B) median rPFS 5.8 vs 3.5 mo, P<0.001 | Olaparib arm Anemia: 21%. Placebo arm Anemia: 5% |
| TRITON3 (2023)42 | Phase-III, RCT | Rucaparib | mCRPC with BRCA1/2 and ATM alterations. Prior ARSI exposure | Rucaparib arm n=270, Control arm n=135 | BRCA1/2 (n=302). ATM (n=103) | BRCA subgroup- median PFS of 11.2 mo (rucaparib arm) vs 6.4 mo (control arm), p<0.001 by long-rank test. ORR of 45% vs 17% | Anemia (24%). Neutropenia (7%) |
| TRITON2 (2020)41 | Phase-II, open level | Rucaparib | mCRPC Prior ARSI exposure. | n=115 | BRCA1 (n=13) BRCA2 (n=102) | ORR -Cohort with measurable disease: 44%. Entire cohort PSA response: 55% | Anemia: 25% |
| GALAHAD (2022)43 | Phase-II, open label | Niraparib | mCRPC with prespecified DDR gene alterations^ | n=223; DDR mutants. BRCA1/2 cohort (n=142). Non-BRCA cohort (n=81) | BRCA1/2 mutants with measurable disease (n=76). BRCA intact with measurable disease (n=47) | ORR- BRCA mutant cohort: 34%. BRCA intact cohort: 11% | Anemia: 33%. Thrombocytopenia: 16%. Neutropenia: 10% |
| TALAPRO-1 (2021)44 | Phase II, open label | Talazoparib | mCRPC, 11 predefined DDR gene alterations## | n=104 | BRCA2 mutants (50%), BRCA1 mutants (4%), ATM mutants (14%) or PALB2 mutants (4%) | ORR-Overall cohort: 30%. BRCA1/2 cohort: 46% | Anemia: 31%. Thrombocytopenia: 9% Neutropenia: 8% |
Notes: #BRCA1/2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54; $BRCA1/2, ATM, PALB2, CDK12 and any other DDR gene. ##BRCA1/2, ATM, ATR, CHEK2, FANCA, MLH1, MRE11A, RAD51C, PALB2, and NBN. ^ATM, BRCA1/2, BRIP1, CHEK2, FANCA, HDAC2, PALB2.
Abbreviations: ARSIs, Androgen receptor signaling inhibitors; DDR, DNA damage response; mCRPC, Metastatic castration-resistant prostate cancer; mo, Month; ORR, Objective response rate; OS, Overall survival; RCT, Randomized controlled trial; rPFS, radiographic progression free survival.