A focused drug mixture delays superior prostate most cancers in males with particular DNA repair gene mutations.
A large international study led by researchers at UCL has found that a new combination of drugs may substantially slow the progression of an advanced and potentially fatal form of prostate cancer in men with certain genetic mutations.
Published in Nature Medicine, the Phase III AMPLITUDE trial evaluated whether adding niraparib, a targeted therapy classified as a PARP inhibitor, to the standard regimen of abiraterone acetate and prednisone (AAP) could improve patient outcomes.
The study included men with advanced prostate cancer that had spread to other areas of the body, who were beginning first-line treatment and carried mutations in genes responsible for a crucial DNA repair process called homologous recombination repair (HRR).
The genetic link behind aggressive prostate cancer
These HRR genes are essential for fixing damaged DNA, and when they are defective, cancer cells can grow and spread more aggressively. Around one in four patients with advanced prostate cancer have such genetic alterations, most commonly in BRCA1, BRCA2, CHEK2, or PALB2.
The current standard of care for advanced prostate cancer is AAP (or similar drugs), with about one in five patients also receiving docetaxel chemotherapy. However, cancers with HRR mutations tend to advance more rapidly under these treatments, leading to faster disease progression and reduced survival.
Under the direction of Professor Gerhardt Attard from the UCL Cancer Institute, the trial involved 696 men across 32 countries, with a median age of 68. Half were treated with the combination of niraparib and AAP, while the other half received AAP with a placebo. More than half of the participants (55.6%) had mutations in the BRCA1 or BRCA2 genes.
The trial was double-blind, meaning neither patients nor doctors knew which treatment was being administered.
Significant delay in disease progression
Professor Attard said: “Although current standard treatments are very effective for the majority of patients with advanced prostate cancer, a small but very significant proportion of patients have limited benefit. We now know that prostate cancers with alterations in HRR genes account for a significant group of patients whose disease recurs quickly and has an aggressive course. By combining with niraparib we can delay the cancer returning and hopefully significantly prolonging life expectancy.
“These findings are striking because they support widespread genomic testing at diagnosis with the use of a targeted treatment for patients who stand to derive the greatest benefit.
“For cancers with a mutation in one of the eligible HRR genes, where niraparib has been approved, a doctor should consider a discussion that balances the risks of side effects against the clear benefit to delaying disease growth and worsening symptoms.”
Side effects and safety considerations
While the treatment was generally well tolerated, side effects were more common in the niraparib group. Significantly more cases of anemia and high blood pressure were reported with niraparib, and 25% of patients required blood transfusions. Treatment-related deaths were also higher in the niraparib group (14 versus 7), though overall discontinuation rates remained low.
The study’s authors note that while the results are promising, further research is needed to confirm long-term survival benefits and to explore the impact of newer imaging techniques and broader genetic testing.
Globally, an estimated 1.5 million men are diagnosed with prostate cancer each year. In the UK, prostate cancer is the most common cancer in men, with more than 56,000 men diagnosed every year, and around 12,000 men die from the disease each year.
Reference: “Niraparib and abiraterone acetate plus prednisone for HRR-deficient metastatic castration-sensitive prostate cancer: a randomized phase 3 trial” by Gerhardt Attard, Neeraj Agarwal, Julie N. Graff, Shahneen Sandhu, Eleni Efstathiou, Mustafa Özgüroğlu, Andrea J. Pereira de Santana Gomes, Karina Vianna, Hong Luo, Geoffrey T. Gotto, Heather H. Cheng, Won Kim, Carly R. Varela, Daneen Schaeffer, Kassie Kramer, Susan Li, Benoit Baron, Fei Shen, Suneel D. Mundle, Sharon A. McCarthy, David Olmos, Kim N. Chi and Dana E. Rathkopf, 7 October 2025, Nature Medicine.
DOI: 10.1038/s41591-025-03961-8
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