VERU-111 Gains Traction in Overcoming Acquired Resistance in mCRPC

Philip W. Kantoff, MD

The introduction of androgen receptor (AR) inhibitors has had a dramatic impact on the treatment of men with metastatic castration-resistant prostate cancer (mCRPC); however, many of these agents are being moved into earlier lines of treatment, decreasing the number of effective options for patients in the metastatic setting, said Philip W. Kantoff, MD.

For patients who progress on AR inhibitors, novel therapies are needed to overcome acquired resistance, added Kantoff.

“Androgen-blocking agents are either introduced in the context of metastatic hormone-sensitive prostate cancer [mHSPC], nonmetastatic CRPC, or mCRPC,” said Kantoff. “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.”

During the 2020 ESMO Congress, a virtual presentation of a phase 1b/2 study (NCT03752099) showed that daily chronic administration of the novel, oral tubulin inhibitor VERU-111 was feasible and safe in men with previously treated mCRPC. Additionally, VERU-111 showed evidence of antitumor activity, including prostate-specific antigen reduction, objective tumor responses, and durable responses.

The maximum-tolerated dose (MTD) of 72 mg of daily VERU-111 was reached; grade 3 diarrhea was an observed dose-limiting toxicity.

The phase 2 portion of the trial is ongoing and is evaluating the recommended phase 2 dose of 63 mg of daily VERU-111 in 21-day cycles. At that dosing level, patients have not experienced neutropenia, neurotoxicity, or grade 3 diarrhea.

In an interview with OncLive^® during the ESMO Virtual Congress 2020, Kantoff, chair of the Department of Medicine and George J. Bosl Chair at Memorial Sloan Kettering Cancer Center, and a 2014 Giants of Cancer Care^® in Genitourinary Cancer, discussed the evolving treatment landscape of mCRPC, the early efficacy data demonstrated with VERU-111, and other emerging areas of research that are poised to impact the prostate cancer paradigm.

OncLive^®: Are AR inhibitors still being prescribed in the metastatic castration-resistant setting?

Kantoff: Over the past 10 years or so, a variety of drugs have been introduced, mainly in the metastatic castration-resistant setting. Over the past 5 years, many of these drugs have been moved earlier on in the paradigm to treat patients with either mHSPC or nonmetastatic CRPC. A lot of the drugs that had been used 5 years ago for mCRPC, are now being used earlier.

Drugs like the androgen-signaling inhibitors or the newer-generation antiandrogens like

enzalutamide [Xtandi], darolutamide [Nubeqa], apalutamide [Erleada], and abiraterone acetate [Zytiga] are now being used earlier. Docetaxel, which is a taxane that has [similar] antitubulin activity to VERU-111, is sometimes being used earlier. [On the other hand, docetaxel] is sometimes held for mCRPC.

How are patients who progress on AR inhibitors treated?

[AR inhibitors] seem to work better earlier on and are more frequently used [in that setting]. However, when a patient becomes resistant to agents such as abiraterone, enzalutamide, darolutamide, or apalutamide, their ability to be treated successfully with another one of those agents is minimal.

That is when we move on to drugs like a taxane (docetaxel, cabazitaxel [Jevtana]) or sipuleucel-T [Provenge], which is an immunotherapy agent that was approved 10 years ago. That is generally what we do, [but we also recommend that patients] go on a clinical trial.

How do taxanes compare with other agents that are active against tubulin, such as VERU-111?

VERU-111 is a drug that is active against tubulin. Taxanes are also active against tubulin, and they have other activities. Therefore, VERU-111 may have other activities as well. That is sort of the story around these drugs.

The taxanes, namely docetaxel and cabazitaxel, have modest activity in mCRPC, and at least docetaxel has more significant activity in mHSPC. [VERU-111] is a drug that may be very similar to docetaxel in that it inhibits the same target. Moreover, the interesting feature about this drug is that it is an oral agent, which holds a lot of advantages for patients in terms of convenience.

In a small phase 1b study of several dozen patients, the toxicity [with VERU-111] was less than we anticipated; there was not a lot of hematopoietic toxicity or neurologic toxicity. [Investigators] arrived at a [recommended] phase 2 dose, which seemed to be very well tolerated. [VERU-111] also has the potential advantage of being better tolerated.

A phase 3 study is going forward, [evaluating VERU-111 in patients with] mCRPC who have gone through a second-generation antiandrogen or androgen-signaling agent, like abiraterone or enzalutamide. Then it becomes a choice of what to do. Patients can either go on another androgen-signaling agent or VERU-111. We know that a second androgen-signaling agent in that context doesn’t work well at all. Perhaps [VERU-111] works better and provides an advantage with regard to radiographic progression-free survival or overall survival. We’ll have to see. I haven’t seen a lot of the details of the study, but this is what I have gleaned from [brief research].

Ultimately, it is hard to [explain what the differences are between taxanes and VERU-111 because] the phase 1b data [with VERU-111] are really limited. That was a dose-escalation study and many patients weren’t treated at the MTD. We need to [evaluate] a much larger group of patients or do a randomized study of one versus the other [to say definitively].

In the same patient population, you were the co-author of an early study examining enzalutamide and crizotinib (Xalkori). What was the concept for that trial?

c-MET expression is one of the mechanisms of resistance [to enzalutamide]. If we inhibit cMET in addition to giving a drug like enzalutamide, we might be able to get a better response rate. The results of the phase 2 study were promising, but again, a limited number of patients were enrolled. How do we compare [the combination with other options]? Should [the combination] go forward? Whether it should be brought to a phase 3 study [remains to be seen].

What other areas of prostate cancer research look promising?

One area that I am very interested in is DNA repair. We have very limited agents that address DNA repair gene abnormalities, those being the PARP inhibitors. Trying to improve upon PARP inhibition by adding other agents to them is an area that I am very interested in.

Another area that we are working on is resurrecting the concept that BCL-2 expression goes up in the context of androgen deprivation therapy [ADT]. Using a BCL-2 inhibitor with ADT might be beneficial. These are things that I work on in my lab that are potentially translational.

Finally, a very exciting area is radiopharmaceuticals, particularly those that target prostate-specific membrane antigen. There have been some really exciting data with the lutetium small molecule in advanced prostate cancer. That is the subject of a phase 3 study that we should hear about pretty soon.

Then there is the use of alpha particles, like actinium-225, which is much more potent than the beta particle lutetium. The activity of that agent is very impressive. There is the area of trying to combine antibody-drug conjugates with small molecule conjugates that have different properties.

Immuno-oncology, so far, has been a bit disappointing with the checkpoint inhibitors. That is an area that we need to build upon to see what we can do to overcome the relatively [bleak responses we’re seeing with] immunotherapy [in] prostate cancer.

Reference:

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 blocking agent. Presented at: ESMO Virtual Congress 2020; September 19-21, 2020; virtual. Abstract 615MO.