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

5056 Background: VERU-111 is an oral cytoskeletal disruptor that disrupts microtubules supporting the cytoskeleton and has 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 mCRPC also resistant to androgen receptor targeting agents. Methods: In the phase 1b component of the study, a 3+3 design with escalating oral dosing of 4.5 mg to 81 mg (7 days on drug/14 days off per 21-day cycle) was utilized. The schedule was also expanded to continuous dosing/cycle. The phase 2 portion utilized 63 mg daily dosing to evaluate efficacy in approximately 40 taxane-naïve men with mCRPC that have failed at least one androgen receptor targeting agent. Results: In the phase 1b portion of the study, 30 taxane-naïve men with mCRPC and a median age of 76 (61-92) were enrolled. 8 had received prior enzalutamide, 12 abiraterone and 10 both. 8 men had bone mets, 5 lymph node, 5 mixed and 1 had soft tissue metastases at study entry. The MTD of VERU-111 is 72mg (3/11 men had grade 3 diarrhea) and the recommended phase 2 dose is 63mg. Grade 3 diarrhea was not observed at doses ≤ 63mg per day and the most common non-dose limiting AEs were mild to moderate nausea, vomiting, diarrhea, and fatigue, with no observed neurotoxicity or neutropenia. Efficacy was assessed by PSA and bone/CT scans. In men treated for ≥ 4 continuous 21-day cycles, 6/10 (60%) had PSA declines, 4(40%) men had ≥ 30% declines and 2(20%) ≥ 50% declines compared to their 21-day cycle baseline PSA. Median PFS is currently 12 months (6-23+ months) with 3 patients continuing on study, 2 of which have been on study for approximately 2 years. In patients receiving at least a single dose of ≥ 63 mg daily (n=19), objective tumor responses were seen in 3 men (16%). The median rPFS in these patients is currently 12.4 months. In the phase 2 portion of the study, 55% of the patients had bone only metastases, 11% had nodal only, 32% had mixed bone and nodal disease and 3% had visceral disease at study entry. 6/32 (19%) were previously treated with abiraterone alone, 12/32 (38%) with enzalutamide alone, and 14/32 (44%) had abiraterone in combination with enzalutamide, proxalutamide or apalutamide. The phase 2 portion of the study is ongoing and objective tumor responses have been observed including a CR and PRs and PSA decreases >50%. Patients have been on study as long as 9 months. Conclusions: This phase 1b/2 clinical trial, demonstrates that oral daily dosing of VERU-111 has a favorable safety profile and that chronic dosing is feasible. The recommended phase 2 dose of 63mg daily has significant durable antitumor activity. These data support a potential prominent role of VERU 111 for the treatment of men with mCRPC who previously failed an androgen receptor targeting agent and prior to the administration of intravenous chemotherapy. Clinical trial information: NCT03752099.