A recently published randomized phase 3 clinical trial reported in Nature Medicine evaluated the clinical benefit of adding niraparib, a PARP inhibitor, to the standard treatment combination of abiraterone acetate and prednisone in men diagnosed with metastatic castration-sensitive prostate cancer (mCSPC) harboring specific homologous recombination repair (HRR) gene mutations.

The AMPLITUDE trial enrolled 696 patients identified through genomic profiling to have deleterious alterations in select HRR genes. The gene panel included BRCA1, BRCA2, BRIP1, PALB2, RAD51B, RAD54L, CDK12, CHEK2, and FANCA. Notably, ATM was not part of the gene panel evaluated in this study.
Patients were randomized to receive standard androgen deprivation therapy combined with either niraparib plus abiraterone acetate and prednisone or abiraterone acetate and prednisone alone.

Key outcomes demonstrated that the addition of niraparib significantly improved radiographic progression-free survival (rPFS). In patients with BRCA1 or BRCA2 mutations, median rPFS was not reached at the time of analysis in the combination arm, compared to 26.0 months in the control arm. The hazard ratio (HR) for progression or death in this subgroup was 0.52 (95% confidence interval [CI]: 0.37 to 0.72), reflecting a 48% reduction in risk.
Broadening the analysis to an HRR effector subgroup (which added BRIP1, PALB2, RAD51B, and RAD54L mutations) yielded a median rPFS not reached in the combination group versus 27.6 months in the control group, with an HR of 0.57 (95% CI: 0.42 to 0.77).

In the overall intention-to-treat population, median rPFS was also not reached for the combination therapy versus 29.5 months for the control, with an HR of 0.63 (95% CI: 0.49 to 0.80). Secondary endpoints, including time to symptomatic progression, favored the combination arm.

Safety profiles were consistent with previous studies of niraparib and abiraterone, with higher rates of grade 3 or 4 adverse events in the combination group (75.2%) compared to control (58.9%). These were chiefly hematologic toxicities such as anemia and hypertension, requiring clinical management.

These findings establish a treatment paradigm that incorporates PARP inhibition early in the disease course for mCSPC patients with select HRR gene alterations, emphasizing the role of precision medicine guided by tumor genomics.

Source.