Dr Olmos on Evaluating HRR Alterations in mHSPC

“We found that the frequency of breakout two alteration and HRR, defined by 11 genes in the study, was almost the same the mCRPC.”

David Olmos, MD, PhD, head of the Prostate Cancer Clinical Research Unit at CNIO and a medical oncologist at Hospital Universitario 12 de Octubre, discussed findings from the prospective, multi-cohort CAPTURE study evaluating homologous recombination repair (HRR) alterations in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

Data were collected from 4 multicenter, observational studies: PROREPAIR-B (NCT03075735), PROSENZA (NCT02922218), PROSTAC (NCT02362620) and PROSABI (NCT02787837).

The study examined the prevalence of HRR mutations across 11 genes and their association with clinical outcomes, including radiographic progression-free survival (rPFS), time to castration resistance, and overall survival (OS).

During the analysis, investigators found that the frequency of BRCA2 and other HRR alterations in mHSPC was comparable with what has been observed in metastatic castration-resistant prostate cancer (mCRPC), Olmos said. This suggests that many of these genomic changes are present early in the disease course rather than being acquired during progression. The proportion of germline vs somatic mutations was also similar to mCRPC, although there was a slightly higher rate of germline BRCA2 alterations in the patients with mHSPC. This observation is consistent with prior reports linking germline BRCA2 mutations to an increased risk of metastatic spread at presentation, he noted.

From an efficacy perspective, the study reinforced the prognostic effect of BRCA1 and BRCA2 alterations, Olmos explained. Patients with either germline or somatic mutations in these genes demonstrated worse outcomes compared with patients without such alterations. Specifically, these patients had shorter rPFS durations, a reduced time to castration resistance, and poorer OS, with BRCA2 emerging as a particularly strong adverse prognostic biomarker.

Olmos emphasized that these results highlight the importance of early molecular profiling in metastatic disease. Identifying patients with BRCA1/2 or other HRR mutations at the time of diagnosis could enable earlier risk stratification and potentially inform treatment strategies beyond conventional androgen receptor–targeted therapy. The findings also support the rationale for integrating genetic testing in the hormone-sensitive setting, as the prevalence and effect of HRR mutations appear consistent across the disease continuum from mHSPC to mCRPC, he added.

He concluded that the CAPTURE study underscores the poor prognostic implications of BRCA2 mutations in prostate cancer and reinforces the role of HRR testing at diagnosis of metastatic disease to guide clinical decision-making and trial design.