Next-Generation Cytotoxic Therapy Moves Forward in mCRPC

VERU-111, a next-generation form of chemotherapy, has shown promising signs of efficacy as a treatment option for men with metastatic castration-resistant prostate cancer (mCRPC) whose disease has progressed while receiving androgen receptor (AR)-targeting therapy.

Investigators are planning a phase 3 trial that will test VERU-111 against an alternative AR-blocking agent in men with mCRPC who have developed resistance to abiraterone acetate (Zytiga) or enzalutamide (Xtandi), which typically are administered in this treatment setting (Figure). Veru Inc, the company developing the agent, plans to launch the trial during the first quarter of 2021, pending discussions with the FDA.¹

Figure. Proposed Phase 3 Trial of VERU-111 in mCRPC

VERU-111 is an oral therapy that binds to the colchicine binding site on the microtubule to crosslink α and β tubulin, thus inhibiting microtubule polymerization. Preclinical findings show that the agent induces apoptosis in taxane-resistant and enzalutamide-resistant CRPC cell lines.²

Findings from a phase 1b/2 study (NCT03752099) showed that daily chronic administration of VERU-111 was feasible and safe in men with previously treated mCRPC, according to data presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.²

Investigators enrolled 39 patients across 7 sites in the United States. Eligible men with mCRPC had to have received 1 prior AR-targeted therapy; those who had received 1 line of taxane-based chemotherapy for mCRPC were included. The median age of participants was 74 years (range, 61-92), the median Gleason score was 8 (range, 5-10), and 95% had ECOG performance status scores of 0 or 1.²

In the first part of the study, investigators tested a 2-part dosing schedule using a standard 3 x 3 dose-escalation strategy across 10 dosing levels ranging from 4.5 mg to 81 mg daily. The recommended phase 2 dose was established as 63 mg daily.²

Outcomes were reported for a subset of 10 men who received VERU-111 monotherapy continuously at the recommended dose for 4 or more cycles. Of these patients, 6 had a decrease in prostate-specific antigen (PSA) levels, including 4 with a decrease of 30% or more and 2 with a decrease of 50% or more. The best objective tumor response comprised 2 patients with partial responses and 8 with stable disease. The median duration of treatment without radiographic progression was more than 11 months (range, 6-17) and half of the 10 men remained on study therapy at the time of presentation.²

Additionally, investigators presented results from 1 patient, an 88-year-old man with Gleason 9, node-only mCRPC who had previously received sipuleucel-T (Provenge), enzalutamide, and abiraterone. After VERU-111 therapy, a CT scan showed a 33% decrease in size to a nonpathologic node.² Further, the patient experienced a 63% reduction in PSA level within the first cycle of treatment and remained in the study for over 16 months.

In the safety population of 25 patients who had been treated with the recommended dose for at least 1 cycle, the most frequently observed drug-related adverse effects (AEs) included diarrhea (56%), nausea (24%), and decreased appetite, fatigue, dysgeusia, and weight loss (all, 12%). Most AEs were of grade 1 or 2 severity. An instance of fatigue that was resolved with a dose reduction was the only drug-related AE of grade 3 or worse at the 63-mg dose. Investigators did not record any reports of neurotoxicity in the study and no incidence of neutropenia at the 63-mg dosing level.²

Therapy May Fill Unmet Needs

The trial’s early findings are generating interest among experts in prostate cancer. “One impressive aspect of this study was the PSA declinations of 50% or more,” said Neal D. Shore, MD, medical director of Carolina Urologic Research Center in Myrtle Beach, South Carolina, in an interview with OncLive^®.

Shore said VERU-111’s oral route of administration could make it an attractive choice compared with traditional taxanes such as docetaxel and cabazitaxel (Jevtana), which are given intravenously. “Especially during the time of a pandemic, one recognizes the advantage for using an oral medication not requiring a clinic visit for administration,” he said. “The oral-based delivery may also appeal to clinicians who are not offering infusions within their clinics.”

“Oral delivery of a taxane or microtubule- or tubulin-inhibitor mechanism of action would be a significant addition to our therapeutic armamentarium,” Shore added.

Although microtubule-targeting agents (MTAs), including taxanes and vinca alkaloids, are effective and widely used for treating a variety of cancers, resistance and toxicity can limit their clinical efficacy. In prostate cancer, resistance also builds up in patients who receive AR-targeting therapies. Approximately 15% to 25% of men do not respond to AR inhibitors and 75% to 85% progress within 9 to 15 months.³

Furthermore, as AR-targeting agents such as enzalutamide, darolutamide (Nubeqa), apalutamide (Erleada), and abiraterone are approved for earlier lines of treatment, patients with metastatic disease who progress on these agents need new options, according to Philip W. Kantoff, MD, chair of the Department of Medicine and George J. Bosl Chair at Memorial Sloan Kettering Cancer Center in New York, New York.

According to Kantoff, a 2014 Giants of Cancer Care^® award winner in the genitourinary cancer category, novel therapies such as VERU-111 may allow patients to overcome acquired resistance to AR inhibitors. “Androgen-blocking agents are either introduced in the context of metastatic hormone-sensitive prostate cancer, nonmetastatic CRPC, or mCRPC,” he said in an interview with OncLive^®. “It is leaving a void where we don’t have many drugs right now, so there is still a need for new therapies in mCRPC.”

Future Directions

The phase 2 portion of the study reported at ESMO 2020 is fully enrolled with 40 patients, Veru announced in September.⁴ The open label, single-arm trial will evaluate VERU-111 for efficacy and safety in patients who have become resistant to at least 1 AR-targeting therapy but who have not received intravenous (IV) chemotherapy in the metastatic setting. The key efficacy end point of the phase 2 portion is radiographic imaging of progression-free survival (rPFS).

Looking ahead, Veru is making plans for a phase 3 trial that would enroll 250 men with mCRPC who have rising PSA levels and tumor progression while receiving AR-targeting therapy. Participants would be randomized to receive either VERU-111 continuously at 63 mg daily or standard therapy with either abiraterone or enzalutamide, depending upon their prior treatment. The primary end point would be rPFS, with secondary end points of overall survival, time to IV chemotherapy, pain progression, and PSA responses.⁵

VERU-111 also has demonstrated antitumor activity in preclinical models of other tumor types, including taxane-resistant triple-negative breast cancer and lung cancer, pancreatic cancer, and melanoma.5 Additionally, the agent is currently undergoing testing as a potential treatment for coronavirus disease 2019 (COVID-19) in a phase 2 trial (NCT04388826). Investigators are seeking to randomize 40 patients with COVID-19 who are at high risk for acute respiratory distress syndrome to either 18 mg of VERU-111 or placebo. The primary efficacy end point for the 62-day study is the proportion of patients alive and without respiratory failure at day 29.

References

1. 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 November 20, 2020. https://bit.ly/2IMkPj7
2. Markowski M, Eisenberger MA, Tutrone R, et al. Phase Ib/ II study of VERU-111, novel, oral tubulin inhibitor, in men with metastatic castration resistant prostate cancer (mCRPC) who failed an androgen blocking agent. Ann Oncol. 2020;31(suppl 4):S507-S549. doi:10.1016/annonc/annonce275
3. Antonarakis ES. Current understanding of resistance to abiraterone and enzalutamide in advanced prostate cancer. Clin Adv Hematol Oncol. 2016;14(5):316-319.
4. Veru completes enrollment of phase 2 clinical trial of VERU-111, novel oral drug for metastatic prostate cancer. News release. Veru Inc. September 29, 2020. Accessed November 10, 2020. bit.ly/32tycLl
5. The prostate cancer company: novel medicines. Veru Inc. Accessed November 20, 2020. https://bit.ly/2ILVBBq