Results from the international phase 3 AMPLITUDE clinical trial (NCT04497844) sponsored by Janssen Research & Development, found that adding niraparib (Zejula®, Tesaro) to abiraterone acetate (Zytiga™; Johnson & Johnson)* + prednisone (AAP) can help slow cancer growth for people with metastatic castration-sensitive prostate cancer (mCSPC) with homologous recombination repair (HRR) gene alterations.
This outcome builds on findings from the previous MAGNITUDE study (NCT03748641), which led to the U.S. Food and Drug Administration (FDA) approval of niraparib with AAP for HRR-altered mCRPC.
The results from this study were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) , held May 30-June 3, 2025 in Chicago, Illinois.
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,” noted lead study author Gerhardt Attard, MD, PhD, FRCP, Cancer Institute, University College London, London, United Kingdom.
“The AMPLITUDE trial is the first to show that combining a PARP inhibitor with an androgen receptor pathway inhibitor both delays disease progression and postpones the onset of symptoms in HRR-altered mCSPC, supporting this combination as a new treatment option for these patients,” Attard added.
Approximately 1 in 4 people with mCSPC have alterations in the HRR genes. Examples of HRR genes include BRCA1, BRCA2, CHEK2, and PALB2. Research has shown that people with mCSPC with HRR gene alterations have reduced survival chances, and most patients with mCSPC will eventually develop mCRPC. By definition, mCSPC is earlier-stage disease where the cancer is still sensitive to hormone therapy, while mCRPC is more advanced as the cancer becomes resistant to these therapies. 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 a poly ADP-ribose polymerase (PARP) inhibitor niraparib combined with AAP helped slow cancer growth in people with mCRPC with 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.
Personalized treatment strategies
“Our aim with the AMPLITUDE study was to determine how long patients could live without their cancer worsening. What we found is that the combination of niraparib, abiraterone acetate, and prednisone is achieving just that, with the goal of offering patients precious quality time before the disease enters a more resistant phase,” explained Charles Drake, M.D., Ph.D., FAAP, Vice President, Prostate Cancer and Immunotherapy Disease Area Leader, at Johnson & Johnson Innovative Medicine.
“This breakthrough highlights the need for early initiation of personalized treatment strategies for patients with mCSPC and HRR alterations, particularly BRCA, who typically face more aggressive disease,” Drake further noted.
Study design
The study enrolled 696 patients with mCSPC with either germline or somatic HRR gene alterations. The median age of patients in the study was 68 years old. The patients had received no more than 6 months of treatment with androgen deprivation therapy (ADT). Eligible patients could have also received 6 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 (348 patients) or AAP with a placebo (348 patients). 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.
Outcome
The Phase 3 AMPLITUDE study of 696 patients with mCSPC and HRR alterations met its primary endpoint of rPFS. Patients with BRCA alterations (n=191) showed the greatest benefit of treatment with the combination of niraparib plus AAP, as the median rPFS was not reached compared to 26 months in patients treated with the placebo plus AAP, reducing the risk of radiographic progression or death by 48 percent (hazard ratio [HR] 0.52, 95 percent confidence interval [CI], 0.37-0.72, p<0.0001). In patients with any HRR alteration treated with the niraparib combination, median rPFS was also not reached in comparison to 29.5 months in patients treated with the placebo plus AAP, with a reduction in risk by 37 percent (HR 0.63, 95 percent CI, 0.49-0.80, p=0.0001).
These results also showed that treatment with the niraparib combination reduced the risk of symptomatic progression by 56 percent in patients with BRCA alterations (HR 0.44, 95 percent CI, 0.29-0.68, p=0.0001) and 50 percent in patients with HRR alterations (HR 0.50, 95 percent CI, 0.36-0.69, p<0.0001), meaning that patients experienced a longer delay to worsening symptoms and requiring radiation, surgical intervention, or needing a new anti-cancer therapy. The first interim analysis showed an early trend toward improved overall survival (OS) favoring the niraparib/AAP combination with a reduction in risk of death of 25 percent (HR 0.75, 95 percent CI, 0.51-1.11, p=0.15) in patients with BRCA alterations and 21 percent in HRR alterations (HR 0.79, 95 percent CI, 0.59-1.04, p=0.10); follow-up is ongoing for maturity of the data.
Adverse events
Serious grade 3/4 adverse events (AE) were more common in the niraparib combination. ompared to the placebo group, with anemia and hypertension being the most common. In this group, 75.2% of patients experienced serious or life-threatening side effects compared to 58.9% of those in the placebo group. The most common serious side effects were anemia and hypertension. However, treatment discontinuations due to AEs remained low (14.7 percent vs 10.3 percent). To date, the safety profile of niraparib plus abiraterone acetate and prednisone has been consistent with prior experiences. [2]
Summary of 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 (rPFS) compared to the placebo. In the patients who received niraparib, the median rPFS was not met, while the patients who received a placebo had a median rPFS of 29.5 months
- Overall, niraparib reduced the risk of cancer growth by 37% compared to AAP alone in all patients and by 48% in the subgroup of patients with BRCA1 or BRCA2 mutations.(37 percent (HR 0.63, 95 percent CI, 0.49-0.80, p=0.0001).
- The time until symptoms got worse was longer for patients who received niraparib compared to those who received a placebo.
- Researchers observed a trend toward improved overall survival in the niraparib group. However, these data were still immature, as they did not yet meet the criteria for statistical significance.
Next Steps
Future research will focus on exploring niraparib with AAP earlier in 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.
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Note:* The combination niraparib and abiraterone acetate is marketed as Akeega™.
Clinical trials
A Study of Niraparib in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone for the Treatment of Participants With Deleterious Germline or Somatic Homologous Recombination Repair (HRR) Gene-Mutated Metastatic Castration-Sensitive Prostate Cancer (mCSPC) (AMPLITUDE)
ClinicalTrials.gov ID NCT04497844
A Study of Niraparib in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone for Treatment of Participants With Metastatic Prostate Cancer (MAGNITUDE) – ClinicalTrials.gov ID NCT03748641
Highlights of prescribing information
Niraparib and abiraterone (Akeega™; Johnson & Johnson)[Prescribing Information]
Niraparib (Zejula®, GSK) Prescribing Information]
Abiraterone acetate (Zytiga™; Johnson & Johnson)[Prescribing Information]
Reference
[1] Attard G, Agarwal N, Graff J, Sandhu S, Efstathiou E, Özgüroğlu M, Pereira de Santana Gomes A, Vianna K, Luo H, Cheng H, Kim W, Varela C, Schaeffer D, Dibaj S, Li S, Shen F, Mundle SD, Olmos D, Chi K, Rathkopf D. Phase 3 AMPLITUDE trial: Niraparib (NIRA) and abiraterone acetate plus prednisone (AAP) for metastatic castration-sensitive prostate cancer (mCSPC) patients (pts) with alterations in homologous recombination repair (HRR) genes .J Clin Oncol 43, 2025 (suppl 17; abstr LBA5006)[Abstract]
[2] Attard, G., et al. (2025, May). Phase 3 AMPLITUDE trial: Niraparib and abiraterone acetate plus prednisone for metastatic castration-sensitive prostate cancer patients with alterations in homologous recombination repair genes. Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL.
Featured image: Chicago Riverwalk, Chicago, IL, USA; Used under the Unsplash License
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