The international phase III AMPLITUDE clinical trial has demonstrated that adding the PARP inhibitor niraparib to standard hormone therapy significantly slows cancer progression in patients with metastatic castration-sensitive prostate cancer (mCSPC) who harbor homologous recombination repair (HRR) gene alterations. The results, presented at the 2025 ASCO Annual Meeting, build upon previous findings that led to FDA approval of this combination for more advanced disease stages.
Study Design and Patient Population
The AMPLITUDE trial enrolled 696 patients with mCSPC carrying either germline or somatic HRR gene alterations, with a median age of 68 years. More than half of participants (55.6%) had alterations in the BRCA1 or BRCA2 genes, while most patients presented with aggressive tumor features, including lymph node involvement or advanced-stage disease at diagnosis.
Patients were randomly assigned to receive either niraparib combined with abiraterone acetate plus prednisone (AAP) or AAP with placebo, with 348 patients in each arm. Eligible participants had received no more than six months of androgen deprivation therapy and could have received up to six cycles of docetaxel or AAP treatment for 45 days or fewer if their cancer had spread beyond lymph nodes.
"Metastatic castration-sensitive prostate cancer is a heterogeneous disease with diverse responses to therapies. Although a combination of androgen receptor pathway inhibitors has improved survival in patients with this diagnosis, certain genomic alterations, such as those in the HRR pathway, confer poor prognosis," said lead study author Gerhardt Attard, MD, PhD, FRCP, of the Cancer Institute, University College London.
Efficacy Outcomes
At a median follow-up of 30.8 months, the study achieved its primary endpoint, demonstrating significant improvement in radiographic progression-free survival. The median radiographic progression-free survival was not reached in the niraparib group, compared to 29.5 months in the placebo group.
The combination therapy reduced the risk of cancer growth by 37% compared to AAP alone across all patients. In the subset of patients with BRCA1 or BRCA2 mutations, the risk reduction was even more pronounced at 48%. Additionally, patients receiving niraparib experienced longer time until symptom worsening compared to those receiving placebo.
While researchers observed a trend toward improved overall survival in the niraparib group, these data remain immature and have not yet reached statistical significance.
Safety Profile
The addition of niraparib to standard therapy came with increased toxicity. Serious or life-threatening adverse effects occurred in 75.2% of patients in the niraparib group compared to 58.9% in the placebo group. The most common serious adverse effects were anemia and hypertension.
Treatment discontinuation due to adverse effects was higher in the niraparib group, with 15% of patients stopping treatment compared to 10% in the placebo group.
Clinical Significance and Future Directions
The findings represent the first demonstration that PARP inhibitor combination therapy can benefit patients in the hormone-sensitive setting, extending beyond the previously established benefits in castration-resistant disease.
"This trial emphasizes the importance of germline and somatic testing in patients with metastatic prostate cancer at the time of diagnosis; homologous recombination repair mutations have been identified in up to 25% of patients with metastatic disease, and this study shows that early intervention with a PARP inhibitor may improve outcomes," said Bradley McGregor, MD, Director of Clinical Research for the Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute.
Approximately one in four people with mCSPC has alterations in HRR genes, including BRCA1, BRCA2, CHEK2, and PALB2. Research has shown that patients with mCSPC who have HRR gene alterations face reduced survival chances, with most eventually progressing to metastatic castration-resistant prostate cancer.
Future research will explore the use of niraparib with AAP earlier in disease evolution and investigate combinations with other drugs that have complementary mechanisms of action for prostate cancer at different stages. The study was funded by Janssen Research & Development, LLC.
