Positive findings from the CAPTURE and AMPLITUDE trials highlight the importance of early testing patients for BRCA and HRR mutations
Over the past decade, the management of metastatic hormone-sensitive prostate cancer (mHSPC) has drastically changed. While androgen-deprivation therapy (ADT) remains the cornerstone treatment, several combination strategies have been shown to improve outcomes in patients with mHSPC compared with ADT alone. The addition of docetaxel or androgen receptor pathway inhibitors (ARPis) to ADT has significantly extended survival in patients with mHSPC compared with ADT alone (N Engl J Med. 2015 Aug 20;373(8):737-46; N Engl J Med. 2017 Jul 27;377(4):352-360). More recently, the combination of ADT plus docetaxel plus abiraterone or darolutamide has demonstrated superior efficacy to ADT plus docetaxel (Lancet. 2022 Apr 30;399(10336):1695-1707).
With multiple options available, prognostic assessment is crucial to support treatment decisions. Tumour burden (low or high volume) and timing of metastatic disease (synchronous or metachronous) are the main disease features used in daily practice to estimate outcomes and guide clinicians, while tumour biology has not been factored in the treatment decision-making process since no biomarker were integrated in the numerous studies shaping the current treatment landscape of mHSPC. However, an early signal of change towards a biomarker-driven care in this setting was captured at the 2025 ASCO Annual Meeting.
In Chicago, data were presented from the CAPTURE study, which examined the prognostic role of mutations in Homologous Recombination Repair (HRR) genes including BRCA1/2 in mHSPC patients receiving the current standard treatment. The study was simultaneously published in the Annals of Oncology (Ann of Oncol, Volume 35, Issue 5, 458 – 472). HRR and BRCA alterations were described in 28% and 12% of patients, respectively, who showed significantly worse outcomes than those without, regardless of tumour burden. Among patients with BRCA defects those with low-volume disease had a 10-month longer survival than those with high-volume disease whilst the difference was 30 months among patients without BRCA defects. The outcomes of BRCA patients did not differ by treatment with ARPi or docetaxel. These findings clearly highlight the need to integrate tumour biology into treatment decision algorithms as well as the need of new treatment strategies for these patients.
Results from the first biomarker-driven phase III trial conducted in the mHSPC setting were also presented. The primary analysis of the AMPLITUDE trial demonstrated that the addition of a PARP inhibitor to an ARPi prolongs radiographic progression-free survival (rPFS) in patients with mHSPC harbouring BRCA and other HRR alterations. The trial evaluated niraparib and abiraterone acetate plus prednisone (AAP) versus placebo plus AAP and found that the risk of radiographic progression or death was reduced by 37% and by 48% in HRR and BRCA patients, respectively with the addition of niraparib to abiraterone. Whilst a clear advantage is demonstrated for patients with BRCA defects, the benefit in patients with other HRR mutations is difficult to assess as each gene group comprises a relatively small number of patients.
Taken together, findings from both trials highlighted the importance of identifying genetic alterations in mHSPC to tailor therapeutic options to our patients.
