Impact of somatic/germline homologous recombination repair (HRR) alterations on metastatic hormone-sensitive prostate cancer (mHSPC) outcomes by disease volume.

5094 Background: The impact of HRR mutations in castration-resistant prostate cancer has previously been reported, but their role in mHSPC patients (pts) contemporaneously treated has not been established. Here we report the prevalence of somatic/germline HRR mutations, and their effect on the outcomes in mHSPC pts stratified by CHAARTED disease volume and BRCA/HRR alterations. Methods: Eligible mHPSC pts diagnosed between Jan. 2018 and Dec. 2023 underwent paired somatic/germline DNA sequencing. Cases with alterations in ≥1 HRR gene were hierarchically classified as BRCA, non-BRCA, HRR non-BRCA, or non-HRR. Radiographic progression free survival (rPFS), time to castration resistance (TTCR), and overall survival (OS) were reported for all subgroups; associations between mutations and outcomes were assessed using inverse probability of treatment weighting (IPTW) models, which were controlled for treatment modality and other baseline characteristics. Results: Of 556 pts, 69 (12.4%) harbored alterations in BRCA1 and/or BRCA2 genes (BRCA) and 90 (16%) had alterations in HRR non-BRCA genes. mHSPC was synchronous in 451 pts (81.1%) and was classified by conventional imaging as high-volume (HV) in 306 (55%) and low-volume (LV) in 250 (45%) pts as per CHAARTED criteria. Most pts (44.8%) were treated with androgen deprivation therapy (ADT)+androgen-receptor-pathway inhibitor (ARPi), 30.4% received docetaxel (Doc)+ADT, and 11.3% were treated with ADT+ARPi+Doc. Only 13.5% received ADT alone. Baseline pt characteristics and treatments administered were similar across all subgroups after adjustment. BRCA pts had significantly shorter rPFS, TTCR, and OS compared with non-BRCA in all groups (Table) using IPTW models. Similar significant differences were observed when BRCA pts were compared with HRR non-BRCA pts, but no clinically relevant differences were observed between HRR non-BRCA and non-HRR pts. Conclusions: Presence of BRCA mutations significantly worsened survival outcomes in HV and LV mHSPC treated with doublet or triplet therapy or ADT alone. Outcomes ALL BRCA (n=69) vsnon-BRCA (n=487) HVBRCA (n=42) vsnon-BRCA (n=264) LVBRCA (n=27) vsnon-BRCA (n=223) rPFSMedian (95% CI) a HR (95% CI) 14.6 (12.4–16.8) vs30.6 (27.8–36.6)2.4 (1.8–3.3) ** 13.0 (11.2–16.4) vs21.5 (19.0–28.6)2.1 (1.4–3.0) * 16.0 (12.5–28.8) vs43.0 (35.0–54.7)3.7 (2.3–5.8) ** TTCRMedian (95% CI) a HR (95% CI) 11.5 (10.1–14.6) vs22.9 (20.4–26.9)2.2 (1.7–3.0) ** 10.9 (9.6–12.4) vs17.0 (14.5–20.2)1.9 (1.3–2.7) * 13.8 (9.8–18) vs 35.9 (26.9–43.0)3.6 (2.3–5.5) ** OSMedian (95% CI) a HR (95% CI) 26.4 (24.0–34.6) vs55.2 (50.2–62.5)2.7 (2.0–3.6) ** 25.0 (17.8–33.1) vs41.4 (33.4–52.8)2.5 (1.7–3.5) ** 34.6 (24.0–50.0) vs71.6 (62.5–78.5)3.4 (1.8–6.5)* *p<0.05; ** p<0.0001. a Observed, in months. CI, confidence interval; HR, hazard ratio.