Around 25% of mCSPC patients have HRR alterations—half involving BRCA—often leading to faster progression and worse outcomes. Niraparib, a potent PARP-1/2 inhibitor, is at the core of the AMPLITUDE trial—the first to show that combining a PARP inhibitor with an androgen receptor pathway inhibitor not only delays disease progression but also postpones symptom onset, marking a breakthrough treatment option for HRR-altered mCSPC.

Previous results from the MAGNITUDE clinical trial showed that treatment with the PARP inhibitor niraparib combined with abiraterone acetate and prednisone helped to slow cancer growth in people with mCRPC who had HRR gene alterations. These findings led the FDA to approve niraparib with abiraterone acetate and prednisone for these patients in 2023. In the AMPLITUDE clinical trial, researchers wanted to learn if the same benefits of niraparib could be seen in people with mCSPC.

In the AMPLITUDE trial involving 696 patients with mCSPC harboring HRR gene alterations, treatment with niraparib plus abiraterone acetate and prednisone (AAP) significantly improved outcomes compared to AAP plus placebo. After a median follow-up of 30.8 months, niraparib plus AAP reduced the risk of radiographic progression or death by 37%, with median rPFS not reached versus 29.5 months for placebo. These results also showed that treatment with the niraparib combination reduced the risk of symptomatic progression by 56 percent in patients with BRCA alterations and 50 percent in patients with HRR alterations, meaning that patients experienced a longer delay to worsening symptoms and requiring radiation, surgical intervention, or needing a new anti-cancer therapy. Overall survival data remain immature but show a positive trend favoring niraparib.

Safety analysis revealed higher rates of Grade 3 or 4 adverse events with niraparib (75.2%) compared to placebo (58.9%), primarily anemia and hypertension. Dose interruptions and reductions were more frequent in the niraparib arm, but treatment discontinuation rates remained low and comparable between groups.

KOL insights

This was a really exciting result, this is the first study to show efficacy for PARP inhibition and androgen receptor inhibition in CSPC, the benefit of which might be greatest in patients with BRCA mutations. – Expert Opinion

Improvements in rPFS are supported by a statistically significant benefit in time to symptomatic progression and a trend toward improved OS. In my opinion, AMPLITUDE supports niraparib plus AAP as a treatment option for patients in this poor prognostic disease group. – Expert Opinion

Conclusion

The addition of niraparib to standard AAP therapy demonstrated a meaningful clinical benefit in patients with mCSPC harboring HRR gene alterations, significantly reducing the risk of radiographic progression or death. The benefit was especially notable in patients with BRCA mutations, where nearly half experienced delayed disease progression. Although overall survival results are still maturing, early trends favor niraparib. The safety profile showed higher rates of adverse events such as anemia and hypertension, leading to dose modifications in some patients; however, discontinuation rates remained comparable. These findings support the potential of niraparib as a promising treatment option for this high-risk population, pending further survival data.

With nearly 20 years of leadership in prostate cancer, Johnson & Johnson sets a new milestone—becoming the first to show that a PARP inhibitor combo can benefit mCSPC patients in the AMPLITUDE study.

The FDA-approved therapies for mCSPC include androgen receptor inhibitors—TALZENNA, ERLEADA, and NUBEQA; generics of these drugs are emerging, increasing market competition. Emerging therapies such as capivasertib, ARV-110, and anti-B7-H3 ADCs are in clinical development to expand treatment options in this setting.