Impact of BRCA alterations on Androgen Receptor pathway inhibition treatment outcome in advanced prostate cancer.

Androgen Receptor Pathway Inhibitors (ARPIs) are frequently used to treat advanced prostate cancer (PCa). Understanding the impact of homologous recombination repair (HRR) alterations on ARPI treatment outcomes is critical for optimizing treatment. We conducted a retrospective analysis of pooled data from five randomized trials of ARPIs (apalutamide (Apa) or abiraterone acetate (Abi)) across PCa disease settings. Patients received ARPI-based regimens or androgen deprivation therapy (ADT) alone. HRR alterations were determined using targeted panel or whole-exome sequencing of diagnostic tissue or plasma samples. Radiographic progression-free survival (rPFS) and overall survival (OS) were compared between biomarker groups. Of 608 patients treated with ARPI-based regimens, BRCA-altered patients were at higher risk of progression (HR=1.8 (1.16-2.79), P-value=0.009) and mortality (HR=1.6 (1.02-2.34), P-value=0.038) than BRCA-wildtype. HRR-altered patients had shorter rPFS than HRR wildtype patients (HR=1.7 (1.2-2.3), P-value=0.001). BRCA-altered patients had shorter OS compared to HRR wildtype patients (HR=1.6 (1.03-2.36) P-value=0.036). The same results were observed in the full cohort of 878 patients treated with next-generation ARPI or ADT alone. In 115 HRR-altered patients, addition of ARPIs to ADT significantly prolonged rPFS (HR=0.42 (0.2-0.89), P-value=0.023) and OS (HR=0.45 (0.23-0.91), P-value=0.025) vs. ADT alone. While patients with HRR gene alterations benefit from the addition of ARPIs to ADT, they generally have worse outcomes with AR directed therapy than HRR wildtype patients, with patients harboring BRCA alterations doing particularly poorly. These findings underline the unmet need for new and combination approaches for these patients.