Accelerating Drug Development in Hormone-Naïve Prostate Cancer Through Multi-Modal 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 multi-modal therapy (MMT) approach using intermediate endpoints of efficacy due to treatment. 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 at 4 months. All patients underwent a radical prostatectomy (6 months +/- postoperative radiotherapy 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 prostate-specific antigen (PSA) following testosterone (T) recovery (T ≥150 ng/dl) at 24 months. Results: A pCR or MRD was achieved in 4 (12%; 90% 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%) in cohort B. Conclusion: MMT for newly diagnosed high-risk localized and low-volume metastatic PC 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-years. These results have informed the design of an adaptive trial using MMT on a continuous basis to prioritize effective approaches for further study.