The landscape for first-line therapy (1L) of metastatic castration-resistant prostate cancer (mCRPC) is rapidly shifting. In the past 2 years, three phase 3 trials have examined the addition of a poly-ADP ribose polymerase inhibitor (PARPi) to an androgen receptor-signaling inhibitor (ARSI) in 1L. The FDA and the EMA recently considered whether one of these combinations should be approved for "all comers." Here, we review the trial designs, assays for homologous recombination repair mutations (HRRm) and BRCA mutations (BRCAm), and predictive capacity of mutational status on treatment efficacy to understand the basis for the FDA decision.
The phase 3 trials, PROpel, MAGNITUDE, and TALAPRO-2, each compared PARPi and ARSI to placebo (PBO) plus ARSI. PROpel and TALAPRO-2 (cohort 1) included all comers (i.e., no prospective biomarker selection), while MAGNITUDE prospectively assigned patients to HRRm and HRR nonmutated cohorts and TALAPRO-2 (cohort 2) included only those with HRRm. Radiographic progression-free survival (rPFS) was the primary endpoint, and overall survival (OS) was a key secondary endpoint in all trials. Although rPFS with a PARPi and ARSI was improved versus PBO with ARSI, major conclusions differed.
The nuances and interpretation of these trials provide an understanding of the rationale for the FDA's decision to restrict the approval of olaparib and abiraterone and prednisone (AAP) as 1L therapy to those with biomarker evidence of BRCAm.
Current opinion in urology. 2023 Jul 26 [Epub ahead of print]
Celestia S Higano, Heather H Cheng
Department of Urologic Sciences, University of British Columbia, Prostate Cancer Supportive Care Program, Vancouver Prostate Centre, Vancouver, British Columbia, Canada and Madrona Oncology, Seattle, Washington, USA., Department of Medicine, University of Washington, Fred Hutchinson Cancer Center, Seattle, Washington, USA.