REINFORCE: A phase III randomized trial of treatment intensification with docetaxel in metastatic hormone-sensitive prostate cancer patients without deep PSA response after initial apalutamide therapy.

Abstract

TPS5147 Background: Androgen deprivation therapy (ADT) plus androgen receptor pathway inhibitors (ARPIs) is the standard of care for metastatic hormone-sensitive prostate cancer (mHSPC). However, a substantial proportion of patients fail to achieve a deep prostate-specific antigen (PSA) response, which is consistently associated with worse outcomes. Deep PSA response has emerged as a robust early prognostic marker across multiple phase III trials. Patients lacking this favorable PSA decline represent a poor-risk subgroup with limited treatment personalization. Docetaxel improves survival in high-volume mHSPC and may benefit biologically aggressive disease identified by suboptimal early PSA response. REINFORCE evaluates a PSA-guided strategy of treatment intensification with docetaxel in patients without deep PSA response after apalutamide. Methods: REINFORCE is an international, multicenter, open-label, phase III randomized trial. Eligible patients are men ≥18 years with histologically confirmed mHSPC, ECOG performance status ≤1, PSA > 5 ng/ml at diagnosis of metastatic disease, ≤12 weeks of ADT before apalutamide, adequate organ function, who have received apalutamide plus ADT for 24–30 weeks, have not progressed, and have failed to achieve a deep PSA response. Deep PSA response is defined as PSA ≤ 0.2 ng/ml or PSA response ≥ 90% in combination with a PSA ≤4 ng/ml. Approximately 320 patients from 85 sites located in 6 countries will be randomized 1:1 to treatment intensification with docetaxel (75 mg/m² every 3 weeks for 6 cycles) plus continued apalutamide and ADT, or continuation of apalutamide plus ADT alone. Randomization is stratified by metastasis timing (synchronous vs metachronous), presence of visceral metastases, and PSA at study entry (≤4 vs > 4 ng/mL). The primary endpoint is event-free survival (EFS), defined as time from randomization to PSA progression, radiographic progression of soft tissue, visceral or bone lesions, according to PCWG3, or death from any cause. Secondary endpoints include time to castration resistance, radiographic and PSA progression-free survival, overall survival, safety, PSA response rates, and patient-reported outcomes. Preliminary evidence suggests that apalutamide is associated with a ≲ 10% decrease in docetaxel AUC; a dedicated pharmacokinetic sub-study will assess docetaxel drug-drug interaction and bioequivalence when co-administered with apalutamide. An independent data monitoring committee will oversee patient safety, including an early safety review after the first 18 patients included, review a pre-planned interim efficacy analysis, and evaluate pharmacokinetic data, providing recommendations to the sponsor regarding study continuation. Clinical trial information: 2025-524408-30-00.