Impact of homologous recombination repair alterations ( <i>HRRalt</i> ) on survival outcomes of patients (Pts) with metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Chadi Hage Chehade, Ryon P Graf, Georges Gebrael, Zeynep Irem Ozay, Nicolas Sayegh, Gerald Li, Benjamin L. Maughan, Emmanuel S. Antonarakis, Rana R. McKay, Neeraj Agarwal, Umang Swami
Journal: Journal of Clinical Oncology (2025)

205 Background: Up to 30% of pts with advanced prostate cancer have HRRalt [PMID: 32343890]. The presence of tumor HRRalt has been associated with poor prognosis in the metastatic castration-resistant setting [PMID: 38417742]. However, the impact of HRRalt in patients with mHSPC is unknown. Herein, we sought to interrogate the effect of HRRalt on the survival outcomes of pts with mHSPC. Methods: This IRB-approved retrospective study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine prostate cancer clinico-genomic database (FH-FMI CGDB). The de-identified data originated from approximately 280 US cancer clinics (~800 sites of care). Inclusion criteria: de novo mHSPC, tissue biopsy within 90 days of diagnosis, and initiation of androgen deprivation therapy intensification (ADTi) with androgen receptor pathway inhibitor (ARPI) or taxane within 120 days of diagnosis. Survival outcomes were compared between pts with wild-type HRR ( wtHRR ) and those with HRRalt in 14 pre-specified genes per the olaparib FDA label. Time to castration-resistance (TTCR) was defined from the start of therapy for mHSPC to clinical, biochemical, or radiographic progression or death. Overall survival (OS) was defined from treatment initiation for mHSPC to death, or censored at the last follow-up. TTCR and OS indexed from metastatic diagnosis, were evaluated with Cox proportional hazards models adjusted for baseline prognostic factors. OS risk intervals were left truncated to date of comprehensive genomic profiling report to adjust for immortal time. Exploratory analyses were conducted to evaluate the association of individual HRR genes on survival outcomes in subgroups with sufficient events. Results: 637 pts were eligible and included (181 HRRalt , 28.4%), of whom 378 received an ARPI, and 259 received a taxane. The median age of the overall cohort was 68 (IQR 61 – 75). Results are summarized (Table). Conclusions: This is the largest real-world study to show significantly shorter TTCR in pts with mHSPC harboring HRRalt. No differences were observed in OS. However, CDK12m was enriched for less favorable TTCR and OS for both ARPI and taxane, highlighting an unmet need. These hypothesis-generating data may inform future clinical trial design and counseling of pts with mHSPC and HRRalt . Adjusted hazard ratio (aHR) for TTCR and OS. Genetic alteration Subgroup TTCR (aHR; 95% CI, p) OS (aHR; 95% CI, p) HRRalt vs. wtHRR ADT + ARPI 1.5; 1.1 – 2.0 1.1; 0.80 – 1.6 HRRalt vs. wtHRR ADT + Taxane 1.7; 1.2 – 2.3 1.2; 0.88 – 1.7 BRCA1/2 alt. vs. wtBRCA ADT + ARPI 1.7; 1.1 – 2.5 1.1; 0.67 – 1.8 BRCA1/2 alt. vs. wtBRCA ADT + Taxane 1.5; 0.92 – 2.3 1.1; 0.67 – 1.8 ATMm vs. wtATM ADT + ARPI 0.95; 0.50 – 1.8 0.82; 0.38 – 1.8 ATMm vs. wtATM ADT + Taxane 1.4; 0.65 – 2.9 1.3; 0.53 – 3.2 CDK12m vs. wtCDK12 ADT + ARPI 1.7; 1.1 – 2.8 1.7; 1.0 – 3.0 CDK12m vs. wtCDK12 ADT + Taxane 3.2; 2.0 – 5.3 1.7; 0.98 – 2.9