Impact of BRCA Alterations on Androgen Receptor Pathway Inhibition Treatment Outcomes in Advanced Prostate Cancer

Androgen receptor pathway inhibitors (ARPI) are frequently used to treat advanced prostate cancer. 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 or abiraterone acetate) across prostate cancer 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; 95% confidence interval, 1.16-2.79; P value = 0.009) and mortality [HR = 1.6 (1.02-2.34); P value = 0.038] than those with BRCA wild type. HRR-altered patients had shorter rPFS than HRR wild-type patients [HR = 1.7 (1.2-2.3); P value = 0.001]. BRCA-altered patients had shorter OS compared with HRR wild-type 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] versus ADT alone. Although patients with HRR gene alterations benefit from the addition of ARPIs to ADT, they generally have worse outcomes with androgen receptor-directed therapy than HRR wild-type patients, with patients harboring BRCA alterations doing particularly poorly. These findings underline the unmet need for new and combination approaches for these patients.

ARPIs are standard-of-care treatment for advanced prostate cancer, but prostate cancer is a molecularly and clinically heterogeneous disease. HRR gene alterations are linked to more aggressive disease. We retrospectively analyzed pooled data from five randomized trials of next-generation ARPIs to assess the impact of HRR alterations on outcomes. Our study highlights an unmet need for improved therapies in patients with HRR-altered prostate cancer treated with ARPIs.