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The PARP inhibitor fuzuloparib, added to abiraterone acetate and prednisone, significantly extended radiographic progression-free survival (rPFS) for people with metastatic castration-resistant prostate cancer (mCRPC), an interim analysis of the FUZUPRO trial revealed.

In addition, overall survival benefits were observed regardless of the patient’s DNA damage response (DDR) status, including those with DDR deficiency who often have more aggressive tumors. Furthermore, no known detrimental effect on overall survival was observed when DDR status was negative or unknown.

Adding a therapy to an existing regimen often raises concerns about toxicity. For example, in a meta-analysis of lung cancer treatments: three-drug regimens were associated with statistically significantly greater grade 3 and 4 hematologic toxicities than two-drug regimens.

“Most grade 3 or higher treatment-related adverse events [TRAEs] [with fuzuloparib plus abiraterone] were hematological toxicities, and no new safety signals were identified,” said lead investigator Dingwei Ye, MD, PhD, while presenting results at the American Society of Clinical Oncology (ASCO) 2026.

“Our findings support the use of fuzuloparib combined with abiraterone as first-line treatment for mCRPC,” added Ye, who is director of the Fudan University Prostate Cancer Center at Shanghai Cancer Center in Shanghai, China.

The Promise of PARP Inhibitors

Knowing a patient’s DDR status can guide therapy. Certain genetic mutations make prostate cancer more responsive to targeted treatment. That was the case in a study where olaparib improved outcomes vs abiraterone or enzalutamide for patients with mCRPC with BRCA alterations. PARP inhibitors like fuzuloparib, an investigational agent in the US, block DNA repair in tumor cells and allow damage to accumulate, thereby causing cancer cells to die.

Recent studies also revealed the antitumor effects of PARP inhibitors in mCRPC carrying homologous recombination repair (HRR) defects, Ye said. These include changes in the tumor suppressor genes BRCA1 and BRCA2, as well as in the ATM gene, which is involved in detecting DNA breaks and signaling proteins to repair them.

For the international, randomized, double-blind, placebo-controlled phase 3 FUZUPRO trial, Ye and colleagues recruited 496 participants at 107 sites. Adults with no prior PARP inhibitor therapy and an Eastern Cooperative Oncology Group performance status of 0 or 1 were included. The researchers stratified participants by positive vs negative/unknown DDR deficiency status, genetic changes, and other factors.

Survival Endpoints

A total 249 participants were randomly assigned to fuzuloparib 150 mg twice a day plus abiraterone acetate 1000 mg once a day plus prednisone 5 mg twice a day and another 247 received placebo plus abiraterone acetate and prednisone. They were treated until their disease progressed, they experienced intolerable toxicity, or they withdrew from the study. Median follow-up was 33 months.

The primary endpoint was rPFS according to blinded independent central review (BICR) assessment. The key secondary endpoint was overall survival. Additional secondary endpoints included investigator-rated rPFS; prostate-specific antigen (PSA) response rate; time to PSA progression; rPFS and overall survival by DDR and BRCA 1/2 status; other efficacy outcomes; and safety.

In addition to the ATM, BRCA1, BRCA2 genes, investigators assessed for changes in BRIP1, CHEK1, CHEK2, FANCA, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L genes.

Most baseline characteristics were similar between groups, with a mean age just over 70 years. The study population was 62%-63% Asian individuals, about one third White individuals, 0.4% Black or African American individuals, and 2%-3% not reported. About 62% of participants were recruited within Asia.

The Gleason score at diagnosis differed between groups, with 20% of the fuzuloparib group and 24% of the control group reporting a score < 8 and 77% and 68%, respectively, reporting scores ≥ 8.

Approximately 24% of the fuzuloparib group and 23% of the placebo group were DDR-deficient positive. The remaining 76% and 77%, respectively, had a DDR-negative or unknown status.

About 11% in each group were positive for BRCA1 or BRCA2 mutations, and the rest had a negative or unknown status.

The median PSA level at baseline was about 14 in both groups. Also, 43 participants or 17% in both groups had received cytotoxic chemotherapy or novel androgen-receptor-targeted treatment at their hormone-sensitive prostate cancer stage.

Key Findings

The median rPFS was 24.8 months in the fuzuloparib group vs 19.9 months in the placebo group in the BICR assessment (hazard ratio [HR], 0.71; P = .0034).

The secondary outcome, overall survival, was 41.9 months in the fuzuloparib group vs 36.8 months in the placebo group (HR, 0.96; P = .0367), suggesting a benefit, Ye said.

The rPFS benefit with fuzuloparib-abiraterone acetate and prednisone was generally consistent across clinically relevant subgroups, Ye said.

Among participants positive for DDR deficiency, the rPFS by BICR assessment was a median 27.7 months in the fuzuloparib group vs 13.9 months in the placebo group (HR, 0.51; P = .0039). Among the participants with negative or unknown DDR status, rPFS was a median 22.8 months in the fuzuloparib group vs 21.2 months in the placebo group (HR, 0.81; P = .0744).

BRCA 1/2 mutation-positive participants had a median rPFS by BICR assessment of 22 months in the fuzuloparib group vs 8 months in the placebo group (HR, 0.48; P = .0159). In the BRCA1- and BRCA2-negative or unknown status group, median rPFS was 24.8 months with fuzuloparib treatment vs 21.2 months with placebo (HR, 0.78; P = .0285).

Safety Considerations

TRAEs were reported by 82% in the fuzuloparib group and 76% in the placebo group.

The most common grade 3 or higher TRAEs were primarily hematologic, including anemia in 20%, decreased white blood cell count in almost 6%, decreased platelet count in 5%, and decreased neutrophil count in 5%.

Ye said these safety findings were not unexpected. “The grade 3 adverse events are anemia and nausea at levels that are quite similar to other reports on PARP inhibitors.”

Outside Perspective

“Fuzuloparib plus [abiraterone acetate and prednisone] emerges as a potential option for BRCA 1/2 mutation, androgen-receptor pathway inhibitor-naive, mCRPC patients,” said David Olmos, MD, PhD, a medical oncologist at Instituto de Investigación Hospital 12 de Octubre in Madrid, Spain, who was invited to comment on the research. “But no clear benefit was shown for non-BRCA HRR and non-HRR patients.”

Regarding overall survival, Olmos pointed out that the data are 83% mature, so “it is highly unlikely that the final overall survival analysis will change the result.”

Olmos also questioned how the investigators could assess these regimens for first-line treatment when 17% of participants had received prior chemotherapy or androgen receptor-targeted therapy.

Use of PARP inhibitors plus AR inhibitors in mCRPC “should be biomarker-driven and based on a balance of benefit vs tolerability,” Olmos said.

The study was funded by Jiangsu Hengrui Pharmaceuticals. Ye reported having no relevant financial disclosures. Olmos disclosed consulting or advising for AstraZeneca, Bayer, Janssen, Merck Serono, MSD Oncology, and Pfizer; receiving honoraria from Bayer and Janssen; receiving travel expenses from AstraZeneca Spain, Bayer, and Janssen; and his institution receiving research funding from Johnson & Johnson/Janssen and Pfizer. 

Damian McNamara is a freelance contributor to Medscape Medical News. He worked full-time for Medscape and WebMD from 2018 to 2024. Damian has a BA in chemistry and an MA in science, health and environmental reporting/journalism.