Developments in metastatic castration-sensitive prostate cancer by the addition of Niraparib

Chemical structure of niraparib.

In October 2025, a phase 3 clinical trial from University College London revealed their developments in the treatment of metastatic castration-sensitive prostate cancer, in which a drug called niraparib was added to a drug regime using abiraterone and prednisone.

Phase 3 clinical trials are larger scale studies that test whether a new drug treatment is effective, safe and better than the drugs currently available on the market. These consist of a large group of patients for testing, 100s to 1000s, with randomised allocation of treatment and controls to reduce bias, so people aren't personally selected for treatment because for example, they may show a better long-term survival than another patient.

Niraparib is a type of drug called a PARP inhibitor. This means they inhibit an enzyme that repairs single strand DNA breaks in cancer cells. If a cancer cell cannot repair the DNA damage it has accumulated, the cell will undergo a form of controlled cell death, reducing the number of cancer cells in the tumour. Normal cells can fix the DNA repair through other mechanisms but in the prostate cancer cells used in this trial, they have mutations which mean they cannot effectively repair the DNA. These mutations are called BRCA1/2 and HRR gene mutations.

Abiraterone acetate is a drug which inhibits an enzyme which results in the depletion of androgens in testes, adrenal glands and prostate tissue. This means testosterone cannot be made, and consequently, prostate cancer cells are starved of the hormones they need to grow.

Prednisone is a drug that is used to inhibit cortisol synthesis, which helps to prevent unpleasant side effects that patient's may receive from the other drugs in the trial like high blood pressure, fluid retention of swelling and low levels of electrolytes.

What was unique about this trial is that previously, niraparib was only approved for later stage prostate cancer, specifically, prostate cancer that was resistant to castration, meaning we could not use hormone treatments for reliable results to stop tumour growth. This trial implemented the use of niraparib in prostate cancer that was still sensitive to hormone therapies like depleting androgens, as the cancer still used androgens like testosterone to grow. Over time, some prostate cancer tumours find other pathways that don't use androgens to grow. This trial hoped to achieve results using niraparib in an earlier stage of the disease with these HRR and BRCA1/2 mutations, potentially as a first-line therapy for cancer that is metastatic, meaning it has spread to other parts of the body.

The results showed us that combining these drugs improves progression-free survival for this type of prostate cancer, especially for BRCA1/2 and HRR gene mutations, compared to just using abiraterone alone. It also delayed symptoms and the need for further therapy. The side effects were manageable long-term. This means that PARP inhibitors like niraparib have potential to be effective in earlier prostate cancer stages to help delay the progression of the disease. The benefits of this drug combination are stronger because of the specific mutations the prostate cancer has developed, and so it is essential for patients to undergo genetic testing to investigate who will benefit most from this therapy.

However adding this extra drug did result in serious side effects for most of the patients taking the combination treatment such as high blood pressure and anaemia, causing some patients to need blood transfusions. However these were medically manageable, and only a small percentage of patients needed to stop treatment, and others cause pause or receive a lower dose to help reduce toxicity. Over time, patients adjusted to the treatment, however not all patients could tolerate the combination. This study shows that using niraparib earlier could delay disease progression and reduce the need for harmful chemotherapies or other aggressive treatments that could toxicity to the patient, but further studies are needed to back up this evidence and create more statistically significant findings.

The limitations of this study were that only the BRCA1/2 and the HRR gene mutations had enough patients to determine how well the treatment worked for them, so other patients with rarer mutations will have uncertain outcomes about the effectiveness or safety of the treatment. Patients could only receive 45 days of abiraterone and prednisone before entering the trial, so therefore we don't have evidence of how the combination works in patient's who have had longer androgen inhibitor treatment. Some patients could not join the trial because although they had HRR mutations, more specific results needed for trial eligibility were not received in time; a problem many patients face in the real-world, and can lead to negative consequences if the treatment is delayed due to delayed testing.

References:

Attard G, Agarwal N, Graff JN, Sandhu S, Efstathiou E, Özgüroğlu M, et al. Niraparib and abiraterone acetate plus prednisone for HRR-deficient metastatic castration-sensitive prostate cancer: a randomized phase 3 trial. Nature Medicine [Internet]. 2025 Oct 7; Available from: https://www.nature.com/articles/s41591-025-03961-8

Assessed and Endorsed by the MedReport Medical Review Board