Novel Compound Looks to Shake Up mCRPC Treatment Landscape

Mark Christopher Markowski, MD, PhD

Androgen deprivation therapy serves as the first-line treatment option for patients with metastatic prostate cancer; however, disease progression typically occurs within 1 to 2 years of hormonal therapy.¹ Data have shown that androgen receptor–targeting agents including enzalutamide (Xtandi), abiraterone acetate (Zytiga)/prednisone, darolutamide (Nubeqa), and apalutamide (Erleada) have elicited response for patients with metastatic castration-resistant prostate cancer (mCRPC), but approximately 75% of patients progress and up to 25% do not respond to initial therapy.²

The need for safe and effective therapeutic options prior to the initiation of chemotherapy remains an unmet need in the treatment landscape. To that end, investigators have commenced a phase 3 study of sabizabulin (VERU-111) for the treatment of patients with mCRPC who have failed prior treatment with at least 1 androgen receptor–targeting agent.^3,4

“What I always find tough when we’re designing these studies is that we have a number of different agents to treat mCRPC, but it’s always difficult when we think about sequencing those agents,” Mark Christopher Markowski, MD, PhD, said in an interview with OncologyLive®. Markowski is an assistant professor of oncology at Johns Hopkins University School of Medicine in Baltimore, Maryland.

The discovery of an agent with a unique mechanism of action led investigators to examine sabizabulin, an oral therapy that binds to the colchicine binding site on the microtubule to crosslink α and β tubulin and inhibits microtubule polymerization.⁵

“Where do you put a compound like this in the treatment paradigm?” Markowski asked. “I think it is always challenging, and what we’ve come up with here is that we’d like to target [the use of] this agent after some of the oral androgen targeted therapies,” he said. “If [a patient has] progressed on abiraterone, then maybe this is a compound for [them]. I think if we have to think about the future [that] this compound is maybe a way to delay taxane chemotherapy.”

The VERACITY trial (NCT04844749) will evaluate the novel small molecule against available alternate androgen receptor–targeting agents including enzalutamide, abiraterone/prednisone, darolutamide, and apalutamide.³ Eligible patients with rising prostate-specific antigen (PSA) levels and tumor progression while receiving androgen receptor–targeting therapy will be randomized 2:1 (Figure³).

“We’re going to recruit approximately 250 [patients] at a number of different sites….We’re going to look at radiographic progression-free survival [rPFS] as our end point, and hopefully, once the study is fully enrolled and we start getting data, we’ll have a positive result,” Markowski said.

Sabizabulin for Patients With mCRPC³

The Path to Phase 3

The initiation of the trial follows demonstrated antitumor activity and a favorable safety with the agent observed in data from the phase 1b expansion cohort and the population enrolled in the phase 2 evaluation of the recommended dose. Markowski presented updated data on the study as part of the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting in June. In their conclusions, the authors of the poster noted that sabizabulin was “well tolerated with no reports of significant neutropenia or neurotoxicity” and that “daily chronic drug administration [was] feasible and safe.”⁵

In the phase 1b component of the study, investigators leveraged a 3 + 3 design, escalating the dosage of oral sabizabulin 4.5 mg to 81 mg over 21-day cycles (7 days on drug, followed by 14 days off). The expansion cohort of the trial used a continuous dosing schedule similar to that used in the phase 2 portion, in which the recommended phase 2 dose of 63 mg daily was used.⁵

Efficacy for the 30 patients enrolled in the phase 1b portion was assessed by PSA level and bone/CT scans. For the 10 patients who received at least 4 continuous 21-day cycles of treatment, 60% had reported PSA declines, with 40% of patients reporting a decline of at least 30% and 20% reporting a decline of at least 50% compared with baseline PSA levels.

At the time of presentation at 2021 ASCO, the median rPFS was 12.4 months in those who received sabizabulin at a dose of at least 63 mg. The phase 2 portion of the trial is ongoing, with investigators reporting that some patients have remained on study for more than 9 months, objective tumor responses have been observed and include complete and partial responses, and some patients have had PSA decreases greater than 50%.

A combined analysis of the patients from both portions of the study who received at least the recommended 63-mg dose was also reported. In the intention-to-treat population (n=29), the objective response rate was 20.7% and comprised 5 partial responses and 1 complete response. This rate of response was slightly improved in an analysis of 26 patients who would qualify for enrollment in the phase 3 study at 23.1%.⁶

“I think the most important part is the safety profile,” Markowski said. “The mechanism of the drug, it’s a microtubule or polymerization inhibitor, and we wanted to see what the toxicity profile of the [sabizabulin] compound looked like compared with taxane chemotherapies.”

In an analysis of the most prevalent adverse effects (AEs) from patients treated with the 63-mg dose of sabizabulin across the phase 1b and 2 studies (n = 54), the most commonly reported all-grade AEs included diarrhea (59.3%), fatigue (33.3%), nausea (31.5%), and decreased appetite (31.5%).5 In terms of diarrhea, 88% of the reported incidents were grade 1 and 2 and medically manageable. “Most of the [AEs] that we saw were GI [gastrointestinal] related—nausea, some diarrhea—and they were low grade and easily manageable with oral medicines or just stopping the drug,” Markowski added.

Investigators noted that they anticipate diarrhea to occur less in the phase 3 study because of better oral bioavailability of the phase 3 dosage formulation, which should result in reduced exposure of nonabsorbed sabizabulin to the gastrointestinal tract.⁵

The Future of Sabizabulin for mCRPC

Of note in the efficacy data, at the time of presentation, the median PFS was 12 months (95% CI, 6-23+), with 3 patients continuing on study, 2 of whom have been on study for approximately 2 years.⁵

“We are seeing durable disease stability, and I think that was a bit of a surprise,” Markowski said. “Many patients on the study, maybe they didn’t achieve a 30% decrease in their tumor volume, but they certainly didn’t have disease progression, and they’ve [remained] on the study for a long time. We’re really seeing nice durable effects, and I think that’s what we’re trying to emphasize here.”

VERACITY investigators hypothesize that the median rPFS will double for those treated with sabizabulin at approximately 7.4 months vs 3.7 months for those randomized to receive an alternative androgen receptor–targeting agent. Secondary end points of the trial include objective response rate, duration of objective response, interim analysis of overall survival, time to intravenous chemotherapy, and pain progression.^3,5

Investigators also plan to stratify patients by measurable disease vs boneonly disease and if the patient has failed 1 vs more than 1 prior androgen receptor–targeting agent. They anticipate that a significant proportion (> 30%) of patients randomized into the study will have measurable disease at baseline.³

As the phase 3 trial rolls out, Markowski reflected on the available data and concluded, “I think that hopefully we’re going to put [sabizabulin] on individuals’ radar. As we move forward with the phase 3 [trial], investigators are going to be looking for [these] data [and asking], ‘Is this a viable option for prostate cancer? And I think the answer is ‘yes.’ ”

VERACITY is actively enrolling patients across 40 sites in the US.³

References

1. Karantanos T, Corn PG, Thompson TC. Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. Oncogene. 2013;32(49):5501-5511. doi:10.1038/onc.2013.206
2. Schmidt KT, Huitema ADR, Chau CH, Figg WD. Resistance to second-generation androgen receptor antagonists in prostate cancer. Nat Rev Urol. 2021;18(4):209-226. doi:10.1038/ s41585-021-00438-4
3. Efficacy evaluation of VERU-111 for mCRPC in patients who have failed at least one androgen receptor targeting agent (VERACITY). ClinicalTrials.gov. Updated August 2, 2021. Accessed August 3, 2021. https://clinicaltrials.gov/ct2/ show/NCT04844749
4. Veru enrolls first patient in phase 3 VERACITY clinical trial of sabizabulin (VERU-111) in metastatic castration resistant and androgen receptor targeting agent resistant prostate cancer. News release. Veru Inc. June 25, 2021. Accessed August 3, 2021. bit.ly/3Cdu8zd
5. Markowski MC, Tutrone RF, Eisenberger MA, et al. VERU-111, an oral cytoskeleton disruptor, to treat men with metastatic castration-resistant prostate cancer (mCRPC) who failed an androgen receptor targeting agent. J Clin Oncol. 2021;39(suppl 15):5056. doi:10.1200/JCO.2021.39.15_ suppl.5056
6. Markowski MC, Eisenberger MA, Tutrone RF, et al. Clinical study of VERU-111, an oral cytoskeletal disruptor, in metastatic castration-resistant prostate cancer (mCRPC) who failed an androgen receptor targeting agent. J Clin Oncol. 2021;39(suppl 6):131. doi:10.1200/JCO.2021.39.6_ suppl.131