Emerging data from the observational, prospective CAPTURE project underscore the prognostic and therapeutic implications of homologous recombination repair (HRR) mutations, particularly BRCA, in metastatic prostate cancer, and these findings could help drive future research initiatives and clinical strategies, according to David Olmos, MD, PhD.1
“It is very important that we start incorporating these tests from the beginning of the disease,” Olmos said. “We [have] shown that [HRR alterations] have a significant impact on how patients are going to benefit from standard treatments.”
In the second part of the interview, Olmos discussed how these findings inform treatment decision-making, the potential impact of PARP inhibitors and ongoing trials such as to improve outcomes for patients harboring HRR alterations, and the importance of incorporating early genomic screening into standard practice. In the first part of the interview, Olmos detailed key findings from the prospective CAPTURE trial on the incidence of HRR alterations in patients with metastatic hormone-sensitive prostate cancer (mHSPC) and outcomes by mutational status.2
OncLive: How did findings from the mHSPC cohort of the CAPTURE trial add to the knowledge of the role of HRR alterations in this disease setting?
In this trial, we did not focus on safety; however, based on what we have from our registries so far, the tolerability [of standard treatments] appears to be consistent with expectations, [irrespective of HRR alteration status].
The important point to add is that, at [the 2025 ASCO Annual Meeting], we will [saw data from the phase 3] AMPLITUDE trial [NCT04497844], which was the first trial [to evaluate] the addition of PARP inhibitors to a hormonal-based doublet. [AMPLITUDE] reflects how much of a need [there is] for new treatments in this population [with HRR alterations].
How might the data from CAPTURE inform future approaches to risk stratification and management strategies in metastatic prostate cancer?
There are several key messages to take forward. First, patients [with] HRR mutations, such as BRCA, might respond to any standard option. However, even with treatment intensification, [patients with HRR alterations may] still have poor outcomes, at least until trials demonstrate that we can reverse that poor [prognosis].
The second important finding from this study is that the interval from biochemical progression to radiographic progression—and even to overall survival—is much shorter in patients with [HRR] mutations, especially BRCA. Therefore, we have to monitor these patients more closely and maybe cannot rely solely on prostate-specific antigen [(PSA) levels] because these patients tend to progress much earlier, even with lower PSA values. That is very important.
Also, when you have HRR alterations with mutations in BRCA or other HRR genes, it is more important to consider the biology associated with those alterations rather than just counting metastases or determining whether metastases have occurred. These patients have a [poor prognosis], independent of other prognostic factors. We have to start implementing that [knowledge when making treatment decisions and conducting research]. Even if we do not have access to a PARP inhibitor, we have to intensify treatment for these patients.
What future research questions have emerged from these findings, and what planned next steps are being considered to further explore these areas?
Now that we have [data from] the first two CAPTURE cohorts for metastatic castration-resistant prostate cancer and mHSPC…We [plan to pool the data] to look for more rare alterations and [evaluate] other genes in more detail, [as well as examine] the patterns of progression, including whether we have to monitor [patients] differently [based on] the mutation and if we can [identify] some differences in treatment response patterns.Response is probably not the same for all [patients], particularly when comparing those receiving cytotoxic-based therapy vs novel hormone therapy.
Outside the CAPTURE project, [we plan] to look in more detail [at] patients receiving triplets because overall [exposure] was less than 15% in our cohort. [The use of triplets in mHSPC] has been [increasing in] use in practice more recently, [particularly] in the last 2 [to] 3 years. [What is] probably not fully answered yet is how these patients [perform] with triplet therapy. Our [feeling is] that [triplet therapy] will be better than a doublet, but [it is] probably not even enough [for patients with HRR alterations]. Our hope that AMPLITUDE can change the natural history of the disease in these patients [with the addition of a PARP inhibitor]. Hopefully, PARP inhibitors are going to change this treatment history, and that will also bring forward the screening [of these patients]. Even at present, if we don’t have PARP inhibitors [indicated for mHSPC], it is important that we identify these patients [early] because we are showing that it’s important to understand the biology associated with the mutation and how the disease behaves, rather than [only] counting metastases.”
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
- DiEugenio, J. Observational study associates BRCA and other HRR gene alterations with poorer outcomes in mHSPC. OncLive. August 24, 2025. Accessed August 25, 2025. https://www.onclive.com/view/observational-study-associates-brca-and-other-hrr-gene-alterations-with-poorer-outcomes-in-mhspc