VERU-111 Shows Early Promise and Safety in mCRPC After Progression on AR Therapy

A novel tubulin inhibitor VERU-111 has demonstrated promising early antitumor activity and tolerability in men with metastatic castration-resistant prostate cancer (mCRPC) who have failed prior androgen receptor (AR) therapy, according to the results of a phase 1b/2 study (NCT03752099).¹

“VERU-111 appears to be well tolerated in our phase 1 study. Seventy-three mg daily was the maximum tolerated dose; however, given toxicities, we elected to move forward with 63 mg per day continuous dosing. Daily chronic drug administration is safe and feasible, and we have shown preliminary evidence of antitumor activity including PSA [prostate-specific antigen] reductions, objective responses, and some durable responses,” summarized Mark C. Markowski, MD, PhD, when presenting the findings in a poster presentation during the 27th Annual Prostate Cancer Foundation Scientific Retreat.

Based on the positive results of the phase 1b portion and meetings with the FDA in July 2020, the developer, Veru Inc, plans to initiate a pivotal phase 3 trial by the first quarter of 2021. The FDA has already provided input on the design of the phase 3 trial and designated that the primary end point would be radiographic progression-free survival. Final protocols for the phase 3 trial will be submitted to the FDA by the end of the fourth quarter of 2020.²

The phase 2 portion of the current study has already enrolled a full 40 patients with mCRPC who have failed at least 1 prior AR-targeting therapy and intravenous chemotherapy and is assessing the use of VERU-111 in these patients at the recommended phase 2 dose. The primary end point is radiographic progression-free survival.

VERU-111 is an oral, first-in-class, selective small molecule that binds to the colchicine binding site to crosslink both the α and β tubulin subunits of microtubules. In preclinical studies, VERU-111 demonstrated the ability to decrease production of β tubulin isoforms, cleave the PARP protein, and induce apoptosis in both taxane-resistant and enzalutamide (Xtandi)–resistant CRPC cell lines.¹

The dose-escalation phase 1b portion of the clinical trial enrolled 39 men with mCRPC following at least 1 prior AR-targeted therapy across 7 sites in the United States. Patients were allowed to have received up to 1 prior lines of taxane-based chemotherapy for metastatic disease.

The study explored 2 potential dosing schedules: a 7-day dosing schedule with VERU-111 administered orally at each dose level for 7 days on and 14 days off in 21-day cycles, and an expanded dose schedule of 14 days on and 7 days off if the 7-day dosing schedule was tolerated. If the expanded dosing was tolerated, then VERU-111 would be given continuously. Doses of VERU-111 from 4.5 mg to 81 mg were explored.

Of the 39 patients, the median age was 74 years (range, 61-92) and patients had a median Gleason score of 8 (range, 5-10). The majority of patients had an ECOG performance status of 0 (54%) and metastatic disease to the bone (55%). Prior therapy included abiraterone acetate (Zytiga) in 79%, enzalutamide in 64%, abiraterone and enzalutamide in 44%, and taxane-based chemotherapy in 23%.

Ten patients were graduated to continuous dosing of VERU-111 and have received at least 4 cycles of continuous dosing. In these patients, the best objective tumor responses seen included 2 partial responses and 8 patients with stable disease. The median duration of treatment without radiographic progression was more than 11 months (range, 6.0-18). Sixty percent had a decrease in PSA levels, with 20% having a decrease of ≥50%. Three of the patients are still on treatment. An additional 2 objective responses were observed in patients who have not yet reached 4 cycles.

Across all dose levels, the most frequent treatment-related adverse events (AEs) were diarrhea, fatigue, and nausea. Grade ≥3 treatment-related AEs included diarrhea in 3 patients, fatigue in 3, nausea in 3, anemia in 1, and vomiting in 1 patient. Incidence of treatment-related AEs increased at dose levels of 63 mg and above. As such, the recommended phase 2 dose of VERU-111 was determined to be 63 mg.

“The maximum tolerated dose was 72 mg per day daily dosing; however, given the 3 instances of grade 3 or higher diarrhea, we elected to move forward with the 63 mg daily dose cohort. Of note, we saw few instances of neutropenia and we did not observe significant neuropathy,” said Markowski, assistant professor of oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland.

A total of 25 patients were treated at the 63 mg daily dose for at least 1 cycle of treatment. Among these patients, observed drug-related AEs included diarrhea in 56%, nausea in 24%, decreased appetite in 12%, fatigue in 12%, dysgeusia in 12%, weight loss in 12%, vomiting in 8%, and low white blood cell count in 8%. Most AEs were either grade 1 or 2. Only one patient experienced a drug-related grade 3 AE of fatigue at the 63-mg dose. The fatigue resolved when the dose was reduced to 54 mg.

Among 16 evaluable patients treated with 63 mg or higher of VERU-111, the median duration of treatment was 5.8+ months and the mean duration was 6.8+ months (range, 0-15.4). Five patients discontinued treatment due to AEs. Of the other 11 patients, the median duration of treatment was 9.8+ months and the mean duration was 9.0+ months (range, 2-15.4+).

Seven patients remained on the study as of data cutoff. Their median duration of exposure was 10.5+ months and the mean duration was 10.2+ months (range, 4.2-15.4+).

_References:

_{1. Markowski MC, Eisenberger MA, Tutrone R, et al. Phase 1b/2 study of VERU-111, novel, oral tubulin inhibitor, in men with metastatic castration resistant prostate cancer (mCRPC) who failed an androgen receptor targeting agent. Presented at: 27th Annual Prostate Cancer Foundation Scientific Retreat; October 20-23, 2020; Virtual.}

_{2. Veru receives positive input from FDA on phase 3 pivotal trial to evaluate VERU-111 in metastatic castration resistant prostate cancer. News release. Veru Inc. July 23, 2020. Accessed October 22, 2020. https://bit.ly/3kliZTz}