Enfortumab vedotin (EV) as monotherapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results of stage I of a phase 2 trial.
Authors: Swami Umang , Maughan Benjamin L. , Boucher Kenneth M. , Nordblad Blake , Lloyd Jennifer , Batten Julia , Phunrab Tenzin Kunsang , Quertinmont Joshua , Kohli Manish , Gupta Sumati , Agarwal Neeraj 
Published: January 2024

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Background: EV is an antibody-drug conjugate consisting of a fully human antibody directed against the extracellular domain of Nectin-4, which is conjugated to a microtubule-disrupting agent, monomethyl auristatin E (MMAE) by a protease-cleavable linker. In animal models of prostate cancer, metastatic lesions showed high membranous Nectin-4 expression (PMID: 30767361). We aimed to investigate EV in pts with mCRPC. Methods: This IRB-approved, investigator-initiated, single-arm, single-center, phase 2 study administered EV at 1.25 mg/kg IV on days 1, 8, and 15 of 28 days cycle. Key eligibility criteria: ≥18 years age, mCRPC with histologically/cytologically confirmed adenocarcinoma without small cell histology, performance status ≤ 1, adequate organ function, prior treatment (Rx) with ≥3 cycles of docetaxel and at least one androgen-receptor pathway inhibitor, received/refused all therapies shown to improve overall survival except cabazitaxel which is exclusionary. Primary objective: To assess antitumor activity of EV as determined by one of the following: 1) objective response by RECIST 1.1 in those with measurable disease, 2) confirmed conversion of circulating tumor cell count (CTC) to <5/7.5 mL blood, 3) PSA decline of ≥ 50%, and 4) stable disease for ≥ 6 months per PCWG3 modified RECIST 1.1. Simon’s two-stage design was used. The null hypothesis (H0) that true response rate (RR) is 25% is tested against a one-sided alternative. In stage I if ≤3 responses were 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 (type I error rate 0.046, power 0.854 when true RR is 50%). Results: Herein, we present results of 11 pts treated on stage I of study. All pts were non-Hispanic white with median age of 72 years (range 43-78). Median number of prior systemic therapies in addition to castration: 5 (range 3-8). Median follow-up of the cohort was 9 months (range 1-13). 4/11 had RECIST measurable disease and 7/11 had CTC ≥5 at baseline. Overall 7/11 (64%) pts had protocol-defined response (5/11 PSA 50% responses, 3/4 objective response, 4/7 confirmed CTC response and 2/11 ≥ 6 months on Rx). Of the 9 pts who discontinued Rx, 8 discontinued due to disease progression (1 withdrew consent). Median number of completed cycles were 6 (range: 2-12) and median radiographic progression-free survival was 5.5 months (95% CI 5.3-not reached). Most common grade 3/4 treatment-related adverse events (TRAEs) were anemia, AST increase, dry skin, fatigue, hyperglycemia, rash, leucopenia (1 pt each) and nausea and decrease in neutrophil (2 pts each). 8 pts had dose interruptions and dose reductions. No Grade 5 TRAEs. Conclusions: EV showed promising efficacy and an acceptable safety profile in pts with heavily treated refractory mCRPC. Further enrollment in stage 2 of the trial is ongoing. Clinical trial information: NCT04754191 .