VERU-111 Shows Potential for Safe, Long-Term Treatment in Metastatic CRPC

VERU-111 (sabizabulin) targets the microtubular mitotic mechanism in patients with metastatic castration-resistant prostate cancer (CRPC); thus, the agent provides an opportunity for oral administration that can still produce the same benefit as taxanes with fewer toxicities, according to Eric Klein, MD.

A phase 1/2 study (NCT03752099), the results of which were presented during the 2021 Genitourinary Cancers Symposium, enrolled 30 patients with metastatic CRPC in whom an androgen receptor–targeting agent has failed; these patients were taxane naïve.1 Data from the phase 1b portion of the trial indicated that 60% of 10 patients who reached at least four 21-day cycles of continuous dosing with VERU-111 experienced a decline in prostate-specific antigen. In total, 40% of men experienced a decline of 30% or more from baseline, and 20% experienced a decline of 50% or more.

Updated data presented during the 2021 ASCO Annual Meeting showed that among the intent-to-treat population comprised of 29 patients, VERU-111, when given at a dose of 63 mg, elicited an objective response rate of 20.7%;2 this included 5 partial responses and 1 complete response. In all patients who were given a dose of 63 mg or higher, the median radiologic progression-free survival (rPFS) was estimated to be 7.4 months; however, the median rPFS had not yet been reached at the time of the presentation for the phase 2 portion of the research.

“It is exciting to have a novel agent and a new class of drug that we have not had before. [With this agent, we are] able to hit a target that we know is important in prostate cancer: mitotic spindle apparatus,” Klein said. “Having a drug that may be given orally and is better tolerated than chemotherapy should help more patients [receive] a [treatment] that will help them.”

In an interview with OncLive®, Klein, the chair of Cleveland Clinic’s Glickman Urological & Kidney Institute, discussed the promise of VERU-111 in patients with metastatic CRPC and other research efforts that are generating excitement in the paradigm.

OncLive®: What is the mechanism of action of VERU-111?

Klein: The way to think about this [this agent] is [that it is] like an oral taxane. [VERU-111] is a microtubular inhibitor and so, it has the same target that taxanes do. However, the oral formulation will be easier to [administer than taxanes] if it works as well, or if we find the right spot for it. [VERU-111] should [also] have fewer systemic adverse effects [AEs].

What makes this a promising approach for patients with prostate cancer?

This is promising because we know that prostate cancer is sensitive to agents that target the microtubular mitotic mechanism. We know that because both docetaxel and cabazitaxel are

approved for use in [patients with] metastatic CRPC because they work effectively to reduce disease burden that make patients feel better and live longer.

Data with this agent were presented during the 2021 Genitourinary Cancers Symposium. What were the key takeaways from this research?

The goal [of the phase 1 trial] was to establish a maximum-tolerated dose and to prove safety [so that we can] plan for what a phase 3 trial would look like. The drug was [found to be] well tolerated. This is going to serve as the basis going forward in terms of designing a phase 3 trial.

You also served as a co-author on a study that examined adverse pathology as a predictor of distant metastasis and prostate cancer mortality. What should be taken away from this research?

This [research] relates to biomarkers that we use to help choose patients for active surveillance. Several genomic tests are on the market, [including] Decipher Prostate Biopsy, Oncotype DX Genomic Prostate Score Test, Prolaris, and ProMark. One of the things [these tests] predict is the presence of adverse pathology, [including] Gleason grade 4+3 or greater, or disease outside of the prostate. Those genomic markers predict for the presence of adverse pathology better than standard clinical parameters. What we show with these data is that this [information] is important because adverse pathology has a meaningful impact on patients' lives. If [a patient has] adverse pathology, [they] are at a higher risk of metastasis or [death].

The implication is that if [a patient has] a high genomic score with 1 of these tests, that [may] suggest the presence of adverse pathology, and that should not be ignored. You should look a little harder and [try to] find the higher-grade cancer, or you could consider a patient on surveillance who has a high score to be followed more closely. You could also treat the patient just based on the genomic score.

What other efforts are you excited about?

The prostate-specific membrane antigen [PSMA] positron emission tomography [PET] data; they are very interesting and exciting and will be a gamechanger. PSMA PET is currently available at very limited sites in the United States. [However], when used for staging, it is probably equally accurate to our standard modalities, like magnetic resonance imaging. As such, [this approach] is going to help us determine who has metastatic disease vs who does not, and it also allows us to select an appropriate therapy.

Maybe the even more impressive data [we have seen is with] lutetium-177 dotatate [Lutathera] for patients with metastatic CRPC. That [product] seems to work as well as, or better [than], chemotherapy [in this population].

References

1. Markowski MC, Eisdenberger 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):131-131. doi:10.1200/JCO.2021.39.6_suppl.131
2. Markowski MA, 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

Editor’s Note: This interview was conducted prior to the 2021 ASCO Annual Meeting.