CHAPTER-Platform-201: Phase 2 trial of pimitespib plus enzalutamide for patients with metastatic castration-resistant prostate cancer.

TPS296 Background: Metastatic castration-resistant prostate cancer (mCRPC) patients (pts), especially those who experience disease progression while on androgen receptor signaling inhibitor (ARSI) therapy, have a poor prognosis and limited treatment options. Although taxanes are an available options, a second ARSI is more frequently used in this setting because of the toxicity of taxanes, pts’ preference, and comorbidities. However, the efficacy of a second ARSI is limited because of cross-resistance. The main mechanisms of cross-resistance are androgen receptor (AR) genomic alterations (AR amplification and mutation), AR splice variants, and upregulation of the glucocorticoid receptor (GR) and components of the PI3K/AKT pathway. Therefore, new treatment options for mCRPC after ARSI therapy are urgently needed. Pimitespib (PIMI) is a novel heat shock protein 90 (HSP90) inhibitor approved for treating Gastrointestinal Stromal Tumor. HSP90 is a molecular chaperone and forms the structure of client proteins. Many of HSP90's client proteins, such as AR and GR, which represent components of the PI3K/AKT pathway, have been identified as prostate cancer-related proteins required for tumor development; their activation depends on HSP90. PIMI suppresses the expression of AR and GR, which are client proteins related to bypass pathways, such as the PI3K/AKT pathway, by inhibiting HSP90 expression; this may help overcome acquired resistance to ARSI. This phase 2 study investigated the efficacy of PIMI in combination with enzalutamide (ENZ) in pts with mCRPC refractory to ARSI. Methods: This phase 2 study was conducted in pts with mCRPC who showed disease progression on one ARSI. The study includes two parts: feasibility part (FP) and expansion part (ExP). The FP is evaluated with six pts to determine the maximum tolerated dose of PIMI (160 mg/day or 120 mg/day, orally; 5 days on/2 days off) in combination with a standard dose of ENZ (160 mg/day, orally; once daily). The ExP is an open-label, randomized trial evaluating the efficacy and safety of a determined dose of PIMI in combination with ENZ versus ENZ monotherapy. Forty pts are randomized 1:1 to each arm. The primary endpoint of FP is dose-limiting toxicity, and ExP is blinded independent central review of radiographic progression-free survival (rPFS). The secondary endpoints include investigator-assessed rPFS, overall survival, objective response rate, pharmacokinetics, and safety. Among pts for whom mCRPC was diagnosed, those with histologically or cytologically confirmed prostate adenocarcinoma and prior refractory status to one ARSI are eligible for enrollment. Pts who had received taxanes for mCRPC are excluded. Enrollment began in July 2023 and is currently ongoing. Clinical trial information: 2031230263 .