Neoadjuvant Niraparib Fails to Produce Substantial Pathologic Responses After Radical Prostatectomy in DDR-Deficient Prostate Cancer

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Treatment with neoadjuvant niraparib (Zejula) prior to planned radical prostatectomy failed to generate complete or partial pathologic responses among patients with prostate cancer harboring heterogenous DNA damage repair (DDR) alterations, according to results from a phase 2 pilot study (NCT04030559) presented during the 2025 American Urological Association Annual Meeting.1

Among all enrolled patients, the biochemical progression-free survival (bRFS) rate at 27 months was 56%. Following treatment, 3, 1, 1, and 3 patients had T2N0R0, T2N0R1, T2N1R0, and T3aN0R1 disease, respectively. Notably, best prostate-specific antigen (PSA) responses were reported in patients with 2 DNA repair pathways altered. Neoadjuvant niraparib was generally well tolerated among previously untreated patients, with only 1 patient experiencing a grade 3 or higher adverse effect (thrombocytopenia) requiring dose reduction.

Notably, 1 patient with a germline BRCA2 mutation, BRCA2 copy number alteration, and somatic ATM loss of function (LOF) mutation experienced a notable change in PSA with radiographic regression on MRI. According to this case study of resistance mechanisms, tissue levels of somatic alterations decreased on niraparib and rising BRCA2 reversion mutations were detected.

“Variable responses even in the face of bi-allelic BRCA2 loss suggest that additional biomarkers to identify patients most likely to benefit are needed,” Marc Dall’Era, MD, professor and chair of the Department of Urologic Surgery at the University of California (UC) Davis School of Medicine and a member of the UC Davis Cancer Center, and colleagues, wrote in a presentation of the data.

Study Overview and Baseline Characteristics

This investigator-initiated trial enrolled patients with histologically or cytologically confirmed prostate cancer that is clinically localized, and classified as high or very high risk per National Comprehensive Cancer Network (NCCN) guidelines.2 Patients must have chosen radical prostatectomy as their primary treatment, and display 1 or more alterations in a gene involved in DDR primarily through the homologous recombination pathway. This includes BRCA1/2, ATM, CHEK1/2 FANCA, FANCD2, FANCL, GEN1, NBN, PALB2, RAD51, RAD51c, and BRIP1. An ECOG performance status of 0 or 1 and a life expectancy of at least 10 years was also required.

Eligible patients were screened for somatic or germline DDR gene alterations.1 Upon enrollment, patients received 300 mg of neoadjuvant niraparib per day for 12 weeks. Treatment continued until disease progression or unacceptable toxicity.2 After the completion of treatment, patients underwent their planned radical prostatectomy. Follow-up occurred every 3 months for 2 years, and every 6 months thereafter for up to 3 years.

The study’s primary end point was pathologic response rate, which included pathologic complete responses and minimal residual disease.1,2 Secondary end points included bRFS and other molecular end points.1

Of the planned 30 patients, 11 have been enrolled onto the study. The median age was 67 years (range, 56-74), and 82% had a family history of cancer. The median PSA at diagnosis was 10.7 ng/mL (range, 2.9-33.8). A total of 1, 0, 3, 4, and 3 patients were categorized as being in International Society of Urological Pathology grade groups 1, 2, 3, 4, and 5, respectively.

Key germline mutations included BRCA2 (n = 3 patients with LOF mutations; n = 2 with additional loss-of heterozygosity), MSH6 (n = 1), and CHEK2 (n = 1). Somatic mutations were reported in ATM (n = 3), SPOP (n = 4), KMT2C (n = 1), KMT2D (n = 3), PPP2R1A (n = 1), ZFHX (n = 1), and ZMYM3 (n = 2).

References

1. Dall’Era MA. Mitsiades N, Parikh M, et al Neoadjuvant niraparib in men with DNA repair gene deficient clinically localized prostate cancer: results from a phase 2 investigator-initiated trial. Presented at: American Urological Association Annual Congress; April 26-29, 2025; Las Vegas, NV. MP07-01.
2. Niraparib before surgery in treating patients with high risk localized prostate cancer and DNA damage response defects. ClinicalTrials.gov. Updated January 7, 2025. Accessed April 26, 2025. https://clinicaltrials.gov/study/NCT04030559