Association of Homologous Recombination Repair Alterations with Outcomes in Patients with Metastatic Hormone-Sensitive Prostate Cancer

Purpose: Homologous recombination/DNA damage repair (HRR) alterations (HRRalt) are found in around 30% of patients with advanced prostate cancer and have been associated with worse prognosis in the metastatic castrate-resistant setting. However, there are limited data with regard to their association with outcomes of patients with metastatic hormone-sensitive prostate cancer (mHSPC). Experimental Design: This study used a de-identified nationwide (U.S.-based) prostate cancer clinico-genomic database. Patients with de novo mHSPC treated with androgen deprivation therapy intensification with either an androgen receptor pathway inhibitor (ARPI) or a taxane who underwent tissue biopsy within 90 days of mHSPC diagnosis were included. Time to castrate resistance (TTCR) and overall survival (OS) were compared between patients with non-altered HRR and those with HRRalt in any of 14 prespecified genes per the olaparib monotherapy FDA label. TTCR and OS indexed from mHSPC diagnosis were evaluated with Cox proportional hazard models adjusted for baseline prognostic factors. Results: Of 637 eligible patients included in our analysis, 181 harbored HRRalt (28.4%). Compared with patients with non-altered HRR, those with HRRalt had less favorable TTCR when treated with an ARPI [adjusted HR (aHR) = 1.58; 95% confidence interval (CI), 1.17–2.14] or a taxane (aHR = 1.77; 95% CI, 1.3–2.4). Additionally, OS was directionally less favorable in patients with HRRalt (ARPI: aHR = 1.12; 95% CI, 0.80–1.57 and taxane: aHR = 1.23; 95% CI, 0.88–1.72). Conclusions: To date, this is the largest real-world natural history study evaluating the association of HRRalt with outcomes in the mHSPC setting. These data may inform future clinical trial design and counseling of these patients. See related commentary by Graham and Yu, p. 4001.