Accelerating Drug Development in Hormone-Naïve Prostate Cancer through Multimodal Therapy Strategies: The MetaCURE Phase 2 Randomized Clinical Trial

PURPOSE: To accelerate prostate cancer drug development and identification of promising therapies, we aimed to establish a framework for a multimodal therapy (MMT) approach using intermediate endpoints of efficacy due to treatment. PATIENTS AND METHODS: In the MetaCURE trial, patients with untreated, high-risk localized (cohort A) or low-volume metastatic (cohort B) disease were randomized 1:1 to apalutamide or apalutamide and abiraterone acetate plus prednisone and androgen deprivation therapy for 10 months. Cohort B also received stereotactic body radiotherapy (RT) at 4 months. All patients underwent a radical prostatectomy (6 months ± postoperative RT at 10 months). The primary endpoint was pathologic complete response (pCR; no residual tumor) or minimal residual disease (MRD; ≤5 mm residual carcinoma), and the secondary endpoint an undetectable PSA following testosterone (T) recovery (T ≥ 150 ng/dL) at 24 months. RESULTS: A pCR or MRD was achieved in 4 [12%; 90% confidence interval (CI), 4%-26%] and 5 (15%; 90% CI, 6%-29%) patients in cohorts A and B, respectively. Undetectable PSA and T-recovery at 24 months occurred in 20 (61%; 95% CI, 42%-77%) patients in cohort A and 13 (39%; 95% CI, 23%-58%) patients in cohort B. CONCLUSIONS: MMT for newly diagnosed high-risk localized and low-volume metastatic prostate cancer is feasible, safe, and provides a rapid readout of efficacy. A significant proportion of patients, including those with oligometastatic disease, maintained an undetectable PSA following T-recovery at the 2-year endpoint. These results have informed the design of an adaptive trial using MMT on a continuous basis to prioritize effective approaches for further study.