Anaplastic Features in Advanced Prostate Cancer With and Without DNA Damage Repair Mutations

Abstract

Background: Anaplastic prostate cancer has a poor prognosis with limited treatment options. Seven clinical features of anaplastic prostate cancer have been prospectively identified. In this phase II clinical trial, we identified mutations, including DNA damage repair (DDR) mutations, in patients with metastatic castration-resistant prostate cancer (mCRPC) who were treated with durvalumab and olaparib and determined how many of them can be described as anaplastic, and we examined the overlap between anaplastic features and DDR mutations. Methods: Eligible patients with mCRPC received prior enzalutamide, abiraterone, or both. Patients were treated with durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg p.o. every 12 hours until disease progression or unacceptable toxicity. Patients underwent mandatory baseline biopsies of metastatic lesions. Results: Baseline characteristics were similar between anaplastic and nonanaplastic patients. Eleven patients (20%) displayed clear anaplastic features, and 43 (78.2%) lacked anaplastic features. In the anaplastic group, 2/11 (18.2%) had germline DRR mutations, and 4/11 (36.3%) had somatic DDR mutations. In the nonanaplastic group, 7/43 (16.3%) had germline mutations, and 13/43 (30.2%) had somatic mutations. Median progression-free survival (PFS) times in patients with anaplastic features (6.5 months) and without anaplastic features (5.1 months) were similar (hazard ratio 0.998, P = .996). Conclusions: Patients with and without anaplastic features appear to have similar total rates of DDR mutations and also similar rates of somatic and germline DDR mutations. Patients with anaplastic features have a trend toward improved PFS when treated with olaparib and durvalumab compared with nonanaplastic patients.