Results from the international phase III AMPLITUDE clinical trial found that adding niraparib to abiraterone acetate plus prednisone (AAP) may help to slow cancer growth for people with metastatic castration-sensitive prostate cancer (mCSPC) with homologous recombination repair (HRR) gene alterations. The research was presented at the 2025 ASCO Annual Meeting (Abstract LBA5006).
These results build on findings from the previous MAGNITUDE study, which led to the U.S. Food and Drug Administration (FDA) approval of niraparib with AAP for HRR-altered metastatic castration-resistant prostate cancer (mCRPC).
About the Study
“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. Therefore, there is still a need for treatments that are tailored to patients whose tumors harbor HRR alterations,” said lead study author Gerhardt Attard, MD, PhD, FRCP, of the Cancer Institute, University College London, United Kingdom.
Approximately one in four people with mCSPC has alterations in the HRR genes. Examples of HRR genes include BRCA1, BRCA2, CHEK2, and PALB2. Research has shown that people with mCSPC who have HRR gene alterations have reduced survival chances, and most patients with mCSPC will eventually develop metastatic castration-resistant prostate cancer. People with mCRPC often have a poor prognosis and a poor response to treatment.
Previous results from the MAGNITUDE clinical trial showed that treatment with the PARP inhibitor niraparib combined with AAP helped to slow cancer growth in people with mCRPC who had HRR gene alterations. These findings led the FDA to approve niraparib with AAP 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.
The study enrolled 696 patients with mCSPC who had either germline or somatic HRR gene alterations. The median age of patients in the study was 68. The patients had received no more than 6 months of treatment with androgen-deprivation therapy. Eligible patients could have also received six or fewer cycles of docetaxel and/or treatment with AAP for 45 days or fewer if their metastatic cancer had spread outside the lymph nodes.
The patients were randomly assigned to receive either niraparib with AAP (n = 348) or AAP with a placebo (n = 348). Of the patients, more than half (55.6%) had alterations in the BRCA1 or BRCA2 genes. Most of the patients also had tumors with aggressive features, such as cancer that had spread to the lymph nodes or was already at an advanced stage at the time of diagnosis.
Key Findings
At a median follow-up of just over 2.5 years (30.8 months), the researchers found that niraparib significantly improved radiographic progression–free survival compared with placebo. In the group of patients who received niraparib, the median radiographic progression–free survival was not met, whereas the group of patients who received a placebo had a median radiographic progression–free survival of 29.5 months. Overall, niraparib reduced the risk of cancer growth by 37% compared with AAP alone in all patients and by 48% in the subgroup of patients with BRCA1 or BRCA2 mutations.
The time until symptoms worsened was longer for patients who received niraparib compared with those who received a placebo.
Researchers observed a trend toward improved overall survival in the niraparib group. However, these data are still immature, as they did not yet meet the criteria for statistical significance.
Serious adverse effects were more common in the niraparib group. In this group, 75.2% of patients experienced serious or life-threatening adverse effects compared with 58.9% of those in the placebo group. The most common serious adverse effects were anemia and hypertension. More patients in the niraparib group also discontinued treatment because of adverse effects (15% vs 10% in the placebo group).
Next Steps and Clinical Significance
Future research will focus on exploring the use of niraparib with AAP earlier in the disease evolution. Researchers will also continue to study niraparib with AAP given in combination with other drugs that have complementary mechanisms of action for prostate cancer at different stages.
“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. While the combinations of novel hormone therapies and PARP inhibitors have already been shown to improve outcomes in the castrate-resistant setting, this is the first trial to show that the addition of a PARP inhibitor to abiraterone may have a role in the hormone-sensitive setting in those with homologous recombination repair–deficient prostate cancer,” said Bradley McGregor, MD, Director of Clinical Research for the Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute and an ASCO expert in genitourinary cancers.
Disclosure: The study was funded by Janssen Research & Development, LLC. For disclosures of the study authors, visit coi.asco.org.
