Effective therapy was still needed for patients with severely pretreated mCRPC. Therefore, Pembrolizumab (P) + olaparib (O) vs. abi or enza for molecularly unselected patients with mCRPC following a next-generation hormonal agent (NHA) and docetaxel was compared for effectiveness and safety in KEYLYNK-010.
Patients were required to be more or around 18 years, have mCRPC that progressed on or after abi or enza (but not both), and docetaxel, and have an ECOG PS of less or around 1. Patients were randomly assigned 2:1 to receive either NHA: 1,000 mg abi orally QD (if preceding enza) or 160 mg enza orally QD, or 200 mg P IV Q3W for about less or around 35 cycles (if prior abi). The PCWG-modified RECIST 1.1’s radiographic PFS (rPFS) by blinded independent central review (BICR) (final testing at first intermediate analysis [IA1]) and OS were the 2 main objectives (final testing at IA2). Safety/AEs, ORR by BICR per PCWG-modified RECIST 1.1, and other endpoints were considered secondary.
Between May 30, 2019, and July 16, 2021, 793 points were randomly assigned to P + O (n=529) or NHA (n=264). The KEYLYNK-010 research came to an end due to its futility. As of January 18, 2022, IA2 follow-up has a median (range) of 11.9 months (0.9–31.0). The arms had equal baseline characteristics. The key outcomes for rPFS (median 4.4 mo with P + O vs 4.2 mo with NHA; HR 1.02, 95% CI 0.82–1.25; P=0.55) and OS (15.8 mo vs 14.6 mo; HR 0.94, 95% CI 0.77–1.14; P=0.26) were not achieved. The ORR with P + O was 17% compared to 6% with NHA (nominal P=0.002). The results of an exploratory analysis of subgroups by tissue-based homologous recombination repair gene alteration (HRRm) at IA2 revealed a possible difference in rPFS (HRRm [P + O n=81, NHA n=37]: HR 0.53, 95% CI 0.33-0.86; non-HRRm [P + O n=246, NHA n=118]: HR 1.19, 95% CI 0.90-1.58) but not in OS (HRRm: HR 0.91, 95% CI 0.53–1.56; non-HRRm: HR 1.03, 95% CI 0.77–1.38). Gr ≥3 immune-mediated AEs affected 5% and 1% of patients, respectively, while gr 3 TRAEs occurred in 35% of patients with P + O and 9% of patients with NHA.
Despite a higher ORR, pembrolizumab + olaparib did not enhance rPFS or OS in the unselected group. In patients with previously treated mCRPC, pembrolizumab + olaparib caused a higher grade ≥3 TRAEs than NHA, but no new safety signals materialized.