Neoadjuvant fuzuloparib combined with abiraterone for localized high-risk prostate cancer (FAST-PC): A single-arm phase 2 study

Highlights•Neoadjuvant PARPi + ARSi shows efficacy with manageable toxicity in high-risk PCa•Biallelic HRR/BRCA2 alterations correlate with faster PSA decline•Post-treatment analysis reveals MYC suppression and reduced proliferation-related pathways•Drug-tolerant persister cells exhibit enhanced EMT and AP-1 activationSummaryPreclinical studies suggest synergistic effects between androgen receptor inhibitors and poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors. This phase 2 trial (NCT05223582) evaluates neoadjuvant fuzuloparib plus abiraterone in 35 treatment-naive men with localized high-risk prostate cancer. Patients receive six cycles of therapy followed by radical prostatectomy. Primary endpoints are pathological complete response (pCR) and minimal residual disease (MRD, ≤5 mm). The combined pCR/MRD rate is 46% (95% confidence interval [CI]: 29%–63%), with a 53% 2-year biochemical progression-free survival rate. Grade ≥3 adverse events occur in 23% of patients. Biallelic homologous recombination repair/BRCA2 alterations correlate with faster prostate-specific antigen decline. Post-treatment genomic analyses reveal reduced MYC amplification and proliferation markers, alongside activated epithelial-mesenchymal transition/activator protein 1 (AP-1) pathways. The trial meets its primary endpoint, demonstrating feasibility and preliminary efficacy, while exploratory biomarkers may guide future studies.Graphical abstract