Triplet therapy with ADT, darolutamide, and biweekly docetaxel for high-risk metastatic castration-sensitive prostate cancer (TRIC): An open-label, single-arm phase II clinical trial.

TPS272 Background: Treatment strategies for metastatic castration-sensitive prostate cancer (mCSPC) have evolved substantially. Historically, androgen deprivation therapy (ADT) or combined androgen blockade (CAB) was standard; however, although ADT is initially effective, most patients develop resistance and progress to castration-resistant prostate cancer (CRPC). The prognosis after progression to metastatic CRPC (mCRPC) remains poor, with median overall survival (OS) reported at 9–35 months. To improve outcomes, intensive upfront treatment for mCSPC has become a focus. The ARASENS trial showed that ADT plus darolutamide (DAR) and triweekly docetaxel (DTX) significantly improved OS compared with ADT plus DTX in high-risk mCSPC. Our institution developed the Canazawa risk classification, defining high-risk disease as meeting at least two of the following: Gleason pattern 5, bone scan index (BSI) ≥1.5, and lactate dehydrogenase (LDH) ≥300 IU/L. Although ARASENS trial used DTX 75 mg/m² every three weeks for up to six cycles, this dose often causes severe toxicities in Japanese patients. In prior CRPC studies, we found that biweekly DTX 35 mg/m² maintained efficacy with fewer adverse events. Based on these results, we hypothesize that triplet therapy with ADT, DAR, and low-dose biweekly DTX may offer a favorable balance of efficacy and safety in Japanese patients with high-risk mCSPC. This phase II study will evaluate the efficacy and safety of this modified regimen. Methods: This single-arm, open-label phase II trial will enroll 30 patients with high-risk mCSPC at Kanazawa University Hospital by December 2029. After consent and histologic confirmation, patients will receive oral darolutamide twice daily for 18 weeks, LHRH analogue every 12 weeks unless surgically castrated, and intravenous DTX 35 mg/m² every two weeks for nine cycles (18 weeks). After chemotherapy, darolutamide and LHRH analogue will be continued. Patients will be assessed at baseline, day 1 of each cycle, at cycle 9 completion, and every three months thereafter. The primary endpoint is PSA response rate, defined as a ≥95% PSA decline from baseline at 3 and 6 months. Secondary endpoints include OS, time to castration resistance, radiographic and clinical progression-free survival, undetectable PSA rate, time to neuroendocrine and double-negative prostate cancer, symptomatic skeletal event (SSE)-free survival, time to first SSE, pain progression, subsequent therapy, cabazitaxel use, performance status decline, opioid use ≥7 days, safety, adverse events, and correlations between serum CCL2/CCL5 levels and treatment response. Clinical trial information: CRB4180005 .