Clinical study of VERU-111, an oral cytoskeletal disruptor, in metastatic castration-resistant prostate cancer (mCRPC) who failed an androgen receptor targeting agent.
Authors: Markowski Mark Christopher , Eisenberger Mario A. , Tutrone Ronald F. , Pieczonka Christopher Michael , Getzenberg Robert H. , Rodriguez Domingo , Barnette K. Gary , Steiner Mitchell S. , Saltzstein Daniel R. , Antonarakis Emmanuel S. 
Published: March 2021

131 Background: VERU-111 is an oral, cytoskeletal disruptor that crosslinks α & ß tubulin and inhibits microtubule polymerization with no affinity for multidrug resistance proteins. A Phase 1b/2 clinical study has been conducted to establish the maximum tolerated dose (MTD) and evaluate the preliminary efficacy in men with progressive mCRPC resistant to androgen receptor targeting agent (ARTA). Methods: In the Phase 1b portion of the study, a 3+3 design with escalating oral dosing of 4.5 - 81 mg (7 days on drug/14 days off per 21 day cycle) was utilized. After no dose limiting toxicity was observed, the dose was increased in the next cohort. The schedule was also expanded in those completing the 7 days on/14 days off cycle to continuous dosing/cycle. The recommended Phase 2 study dose is 63 mg daily and the trial is fully enrolled with 40 taxane-naiive men with mCRPC that have failed at least one ARTA. Results: In the Phase 1 portion of the study, 30 taxane-naïve mCRPC men with a median age of 76 (61-92) were enrolled. 8 received prior enzalutamide, 12 abiraterone and 10 both. 8 men had bone mets, 5 lymph node, 5 mixed and 1 had soft tissue metastases. The MTD of VERU-111 is 72mg (3 /11 men had Grade 3 diarrhea). No Grade 3 diarrhea was observed at doses < 72 mg per day. At doses < 72mg/d, the most common AEs were mild to moderate nausea, vomiting, diarrhea, and fatigue, with no observed neurotoxicity or neutropenia. In the Phase 1b, antitumor activity was assessed by PSA and bone/CT scans in men that were treated for ≥ 4 continuous 21-day cycles. 6/10 (60%) had PSA declines: 4 (40%) men had ≥ 30% and 2(20%) ≥ 50% declines compared to their 21 day cycle baseline. Based on PCWG3/RECIST 1.1 criteria, objective tumor responses were seen in 2 men (soft tissue and bone). Median duration of response is 11 months (6-18+ months). In the Phase 2 portion of the study, 49% had bone only metastases, 54% have bone only metastases, 11% have nodal disease, 32% had mixed bone and nodal disease and 3% had visceral disease. This portion of the study is ongoing and results will be reported. 9/29 (31%) had previously abiraterone, 10/29 (34%)( enzalutmide, 7/29 (24%) both enzalutmide and abiraterone and 4/29 (14%) apalutamide. Conclusions: Based upon this Phase 1b/2 clinical trial, oral VERU-111 has a favorable safety profile allowing for chronic administration and significant and durable antitumor activity. The daily dose of 63mg is being tested in the fully enrolled Phase 2 portion. Oral administration, safe long-term treatment and evidence of antitumor activity highlight a potential prominent role of VERU 111 for the treatment of men with mCRPC who failed an androgen receptor targeting agent. Clinical trial information: NCT03752099.