ENCORE: A phase 2 trial of enfortumab vedotin (EV) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

Abstract

TPS294 Background: EV, an antibody-drug conjugate (ADC), consists of a fully human antibody directed against the extracellular domain of Nectin-4 (N4), which is conjugated to a microtubule-disrupting agent, monomethyl auristatin E (MMAE), by a protease-cleavable linker. MMAE disrupts tubulin polymerization leading to mitotic arrest and apoptosis. N4 RNA is expressed in prostate tissue, but its expression levels in mCRPC are currently unknown. In animal models of prostate, metastatic lesions showed a very high (++++) membranous N4 expression and correlated with advanced disease (PMID: 30767361). In prostate cancer cell lines engineered to express N4 (PC3-Nectin-4), the hybridoma version of EV: AGS-22M6E, demonstrated potent dose-dependent cytotoxicity (PMID: 27013195). MMAE destabilizes microtubules in contrast to stabilization by taxanes and has shown anti-tumor activity in taxane refractory cell lines and in mCRPC pts with prior taxane therapy (PMID: 31742767). We initiated a phase 2 trial of EV in pts with mCRPC. Methods: This IRB approved, investigator-initiated, single-arm, single-center, non-randomized, open-label study will enroll 34 pts. EV will be administered at 1.25 mg/kg IV on days 1, 8, and 15 of 28- day cycle. Key eligibility criteria: ≥18 years age, mCRPC with histologically/cytologically confirmed adenocarcinoma without small cell histology, ECOG performance status ≤ 1, adequate organ function, prior treatment with ≥3 cycles of docetaxel, at least one androgen-receptor axis targeting agent, received/refused all therapies shown to improve overall survival (OS) except cabazitaxel which is exclusionary. Primary objective: To assess the antitumor activity of EV as determined by one of the following: objective response by RECIST 1.1, confirmed conversion of circulating tumor cell count (CTC) to <5/7.5 mL blood, PSA decline of ≥ 50% (per PCWG3) and stable disease for ≥ 6 months per PCWG3 modified RECIST 1.1. Simon’s two-stage design will be used. The null hypothesis (H0) that true response rate (RR) is 25% will be tested against a one-sided alternative. In first stage if ≤3 responses are observed of 11 pts, the study will be stopped. Otherwise, 23 additional pts will be accrued (total 34). H0 will be rejected if ≥13 responses are observed in 34 pts. This design yields type I error rate of 0.046 and power of 0.854 when true RR is 50%. Secondary endpoints: safety, tolerability, progression-free survival (radiological, clinical and PSA), OS, duration of PSA50% response, CTC conversion rate from ≥5/7.5 ml at baseline to <5/7.5 ml, PSA% change from baseline to 12 weeks and maximum PSA% decline from week 12 until treatment discontinuation. 3 patients have been enrolled. Clinical trial information: NCT04754191 .