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Evaluating the prognostic implications of homologous recombination repair (HRR) gene alterations, including BRCA1/2 mutations, in patients with metastatic hormone-sensitive prostate cancer (mHSPC) helps build on prior evidence demonstrating the negative impact of these mutations in later disease settings, according to David Olmos, MD, PhD.
In the prospective, multi-cohort CAPTURE study, findings presented at the 2025 ASCO Annual Meeting showed that patients with mHSPC harboring BRCA mutations experienced a median radiographic progression-free survival (rPFS) of 13.6 months compared with 30.4 months for those without BRCA mutations (HR, 2.4; 95% CI, 1.8-3.3; P < .001).1 The median overall survival (OS) was 26.2 months vs. 55.1 months, respectively (HR, 2.7; 95% CI, 2.0-3.6; P < .001).
For patients harboring HRR alterations, the median rPFS was 20.5 months compared with 30.6 months for those lacking HRR alterations (HR, 1.6; 95% CI, 1.3-2.0; P < .001). The respective median OS were 39.0 months and 55.7 months (HR, 1.5; 95% CI, 1.1-2.0; P = .003).
Earlier findings from the observational CAPTURE study in metastatic castration-resistant prostate cancer (mCRPC) showed that BRCA and other HRR mutations correlated with worse outcomes across standard therapies compared with wild-type disease.2
In an interview with OncLive®, Olmos discussed the clinical rationale for assessing HRR alterations in mHSPC, described the design and eligibility criteria of the CAPTURE cohort, and addressed how evolving treatment standards may influence outcomes in this biomarker-defined population.
OncLive: What is the rationale for evaluating the impact of homologous recombination repair (HRR) gene mutations, such as BRCA, on outcomes in patients with metastatic hormone-sensitive prostate cancer?
Olmos: This is the second cohort that we have reported on [from] the CAPTURE study. The CAPTURE study is a multi-cohort study in which we are analyzing the prevalence and impact of HRR DNA deficiency in multiple settings. Two years ago at [the 2023] ASCO [Annual Meeting], the impact in[metastatic castration-resistant prostate cancer [mCRPC], and we demonstrated that BRCA and [other] HRR gene mutations were associated with worse outcomes than those patients [who did not harbor HRR alterations], with any standard treatment.
In this [analysis presented at ASCO 2025], we reported on the cohort [of patients with] mHSPC. Here, the rationale was to look at whether [HRR alterations have] the same impact from the beginning of disease, with respect to treatment effect, and at the same time whether the biology associated with these alterations is more or less important than traditional prognostic factors that we use on a daily basis in our clinic, such as disease volume, when deciding treatment.
What were the key elements of the study design, including eligibility criteria and methodology, that should be considered when interpreting the results of this cohort study?
First, it is important to say that this is a prospective study [and] contemporaneous, because recruitment started in January 2018, and the last patient enrolled in December 2023, for a total of 556 patients. All [patients were] metastatic by conventional imaging. [Fifty-five percent of patients had] high-volume [disease], and [45%] were low volume. [The rate of] metachronous disease was also low, at [18.9%]. The majority of patients, reflecting the practice that we usually see in Spain, Italy, and Portugal—the three countries participating in the study—had de novo disease [81.1%].
Outside [those criteria], all standard treatment options were allowed. What we can see [from] the trial recruitment is a reflection of how the standard has changed. We have very little exposure to [only] androgen deprivation therapy [ADT] at less than 13.5%, which was higher at the beginning of the trial. Then we saw a lot of docetaxel plus ADT in the first 2 years, but since the COVID-19 pandemic, we saw a rise in the prescription of androgen receptor pathway inhibitors along with ADT, such as abiraterone acetate [Zytiga], apalutamide [Erleada], and more recently, darolutamide [Nubeqa]. Triplet therapy [use] was very low at the beginning of the study, [with much] higher exposure during the last years of recruitment.
What were the key efficacy findings observed in patients with BRCA mutations compared with those harboring other HRR mutations or non-HRR alterations, and how consistent were these outcomes across subgroups?
The first thing to highlight before discussing outcomes: we found the frequency of BRCA2 alterations and HRR mutations, defined by 11 genes in the study, was almost the same as in mHSPC [as we observed in patients with mCRPC]. This is an important finding and builds on the fact that many of these mutations are already present at the beginning of the disease. The percentage of germline vs somatic mutations was again very similar to mCRPC, with a slightly higher proportion of germline BRCA2 mutations. This is consistent with previous reports in the literature associating germline BRCA2 mutations with a higher rate of metastasis.
From an efficacy perspective, we demonstrated again that BRCA mutations are a poor prognostic factor. Patients with either germline or somatic mutations in BRCA1 and BRCA2 had shorter rPFS, shorter time to castration resistance, and worse overall survival. This was independent of disease volume.
Patients with BRCA2 or BRCA1 mutations and high-volume disease had a median rPFS of 12.8 months compared with 21.8 months in [patients without BRCA mutations]. For low-volume disease, the median rPFS was 16.8 months in the BRCA-mutated population vs 43.0 months in the non-[mutated] population, reflecting the significant prognostic impact of BRCA mutations, even when patients are diagnosed with low-volume disease.
Similar results were observed for patients with other HRR mutations, although the effect was not as pronounced as with BRCA. Within the HRR gene set—as we already knew from the mCRPC cohort—these genes are not all equal from a prognostic standpoint.
Finally, an important analysis we conducted, since there were enough patients, examined whether patients with BRCA or HRRalterations had different outcomes if they were treated with ADT plus docetaxel intensification vs ADT plus a novel hormonal agent. We could not identify differences in the BRCA-mutated population; rPFS and OS were equal across both strategies. However, for patients [without BRCA mutations], the rPFS was much longer with novel hormonal agents compared with docetaxel-based doublets, although OS was similar.
References
Olmos D, Lorente D, Jambrina A, et al. Impact of somatic/germline homologous recombination repair (HRR) alterations on metastatic hormone-sensitive prostate cancer (mHSPC) outcomes by disease volume. J Clin Oncol. 2025;43(suppl 16):5094. doi:10.1200/JCO.2025.43.16_suppl.5094
Olmos D, Lorente D, Alameda D, et al. Presence of somatic/germline homologous recombination repair (HRR) mutations and outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) receiving first-line (1L) treatment stratified by BRCA status. J Clin Oncol. 2023;41(suppl 16):5003. doi:10.1200/JCO.2023.41.16_suppl.5003