The STAMPEDE2 platform trial is set to evaluate the combination of niraparib and abiraterone in patients with metastatic hormone-sensitive prostate cancer (mHSPC) harboring deleterious alterations in homologous recombination repair (HRR) genes. This Phase III multicenter trial aims to improve overall survival by using upfront abiraterone with niraparib compared to standard androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPI). The trial specifically targets patients with BRCA1, BRCA2, or CDK12 mutations, and it allows for co-enrollment in other STAMPEDE2 comparisons, such as those involving lutetium-PSMA or SABR.
Rationale for the Combination Therapy
Patients with HRR-altered tumors often experience worse outcomes, suggesting they may benefit from treatment intensification. While single-agent PARP inhibitors are currently licensed for use in castration-resistant settings for biomarker-selected patients, responses are often short-lived, and resistance develops rapidly. Combining PARP inhibitors with ARPIs like abiraterone can have a synergistic effect. Data from the Phase II BRCAAway study indicated that the median progression-free survival (PFS) on a combination of olaparib and abiraterone significantly exceeded that of either agent alone.
Trial Design and Patient Selection
Eligible patients for the STAMPEDE2 trial must have a known deleterious mutation in BRCA1, BRCA2, or CDK12. Patients can have already started ADT or ARPI for up to six months, provided there is no evidence of progression. Participants are randomized in a 1:1 fashion, with the investigational arm receiving a single dual-action tablet containing both niraparib and abiraterone. The control arm receives an ARPI as decided by their physician. Additionally, patients can receive docetaxel or local radiotherapy to the prostate, as determined by their clinician. The primary endpoint of the trial is overall survival.
Biomarker-Driven Treatment Intensification
The decision to focus on BRCA1/2 and CDK12 mutations was driven by the need to identify poor prognosis patients who require treatment intensification while avoiding unnecessary toxicity for those who would not benefit. As Mahaz Kayani noted, data from STAMPEDE1 showed that a significant percentage of patients were still in disease remission after seven years on abiraterone alone, indicating that further treatment isn't always necessary. The trial aims to provide robust overall survival data to determine the benefit of using upfront PARP inhibition in combination with an ARPI agent for patients with these specific mutations.
Future Adaptations and Potential Impact
The STAMPEDE2 platform's design allows for future adaptations based on emerging data. If evidence suggests that another combination of PARP inhibitor and ARPI is superior, the platform could incorporate an additional comparison to test that combination. Sarah Howlett emphasized that the trial will provide crucial overall survival data to inform the use of PARP inhibitors and other agents in early versus late settings, offering patients the opportunity to receive a novel combination of treatments within the platform.
