BRCA1/2 and homologous recombination repair alterations in high- and low-volume metastatic hormone-sensitive prostate cancer: prevalence and impact on outcomes

Alterations in BRCA1/2 (BRCA) and other homologous recombination repair (HRR) genes have a negative impact on outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). Poly(adenosine diphosphate-ribose) polymerase inhibitors, the only treatment demonstrated to improve the prognosis of patients with mCRPC, are also being developed for the treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC). To fully assess their potential benefit in this setting, it is essential to understand how BRCA and HRR defects may influence the prognosis of conventionally treated patients with low and high disease volume. Eligible mHSPC patients diagnosed between January 2018 and December 2023 underwent paired somatic/germline DNA sequencing. Cases with alterations in one or more HRR genes were classified as BRCA, HRR non-BRCA, non-BRCA or non-HRR. Radiographic progression-free survival, time to castration resistance and overall survival were reported for all subgroups; associations between mutations and outcomes were assessed after controlling for treatment modality and baseline characteristics using inverse probability of treatment weighting models. Of 556 patients, 159 (28.6%) had HRR gene alterations: 69 (12.4%) with BRCA and 90 (16.2%) with HRR non-BRCA mutations. mHSPC was synchronous in 451 patients (81.1%) and was classified as high-volume (CHAARTED criteria) in 306 (55%) patients. Within the HRR subgroup, patients with BRCA mutations had significantly worse outcomes across all endpoints (P < 0.005 for all comparisons). Differences in prognosis by BRCA and HRR status were observed in both low- and high-volume subgroups and were independent of treatment with androgen receptor pathway inhibitors or taxanes. Presence of HRR mutations, particularly BRCA alterations, significantly worsened prognosis, regardless of disease volume or treatment regimen. These findings underscore the importance of integrating tumour biology for accurate risk stratification in mHSPC and the design of new treatment strategies and follow-up.