Differential activity of PARP inhibitors in BRCA1- versus BRCA2-altered metastatic castration-resistant prostate cancer (mCRPC).

• DOI: 10.1200/jco.2021.39.6_suppl.100
• Publication Date: 2021-03-02T17:06:00Z
• Authors: Fadi Taza; Albert E Holler; Nabil Adra; Ryan Ashkar; Alexandra Sokolova; Adam Kessel; Nellie Nafissi; Pedro C. Barata; Diogo Assed Bastos; Oren Smaletz; Rahul Raj Aggarwal; Jacob E Berchuck; Panagiotis J. Vla...; Christopher Su; Catherine Handy M...; Emmanuel S. Anton...
• Keywords: Olaparib; PARP inhibitor; Taxane; Veliparib; Enzalutamide; Clinical endpoint

100 Background: Two PARP inhibitors (olaparib, rucaparib) are now FDA approved for mCRPC patients with mutations in BRCA1/2, but the relative efficacy of inhibition BRCA1- vs BRCA2-altered is understudied. Methods: We conducted a multi-center retrospective analysis involving 11 academic sites. collected genomic and clinical data from 123 BRCA1/2-altered receiving inhibitor treatment. The primary endpoint was PSA50 response rate (≥50% decline PSA level). Secondary endpoints were PFS (clinical, radiographic or progression, whichever occurred first) overall survival (OS). also captured information on other concurrent alterations. compared characteristics outcomes among mCRPC. Results: A total (13 BRCA1, 110 BRCA2) included. used olaparib (n = 116), rucaparib 3), talazoparib 2) veliparib 2). All BRCA1 71% BRCA2 had Gleason 8-10 disease. Compared to patients, more likely have received prior taxane chemotherapy (77% 62%). Age, baseline PSA, enzalutamide/abiraterone treatment similar between groups. responses 38% 65% respectively ( P= 0.06). Median 3.0 mo (95%CI, 0.9–5.1) 8.0 5.3–10.6) (HR 0.42, 0.01). Similarly, median OS 11.0 9.9–12.1) 24.0 18.2–29.8) 0.33, 0.005). There roughly equal proportions germline (50% 45%) biallelic (31% 25%) groups, respectively. numerically TP53 group (40% 29%, 0.45), an number key genes PTEN, RB1 AR). Conclusions: activity diminished In our cohort, this differential not explained by mutation origin (germline somatic) allelic status (mono- biallelic). These findings warrant validation.