Sabizabulin Deemed Safe in Metastatic Castration-Resistant Prostate Cancer

A large unmet need remains for patients with metastatic castration-resistant prostate cancer (mCRPC), as therapeutic options for patients, especially those taken orally, are limited. Because of this, a phase 1b/2 study was designed to evaluate the safety and tolerability of treatment with sabizabulin (VERU-111), a novel, oral agent, in patients with mCRPC.

“We need more oral therapies for patients. We have [intravenous] therapies that can be toxic and patients are a little bit reluctant, so oral therapies are needed,” stated Mark Markowski, MD, PhD, in an interview with Targeted Oncology^TM. “Then, we need therapies that get away from the AR-targeting therapy access. A lot of what we do in prostate cancer focuses on hormone therapy and hormone manipulation because it works, but there's a quality-of-life impact to that.”

The phase 1b/2 trial examined sabizabulin in men mCRPC who h’ve had prior treatment and progression on an androgen receptor (AR)–targeting agent. In the first part of the study, patients enrolled were those with mCRPC treated with at least 1 AR–targeting agent. A 3 + 3 design was used in the dose escalation portion of the study and enrolled a total of 40 patients.

Each patient was administered sabizabulin daily and orally at a dose of 4.5-81 mg. The primary goal of this portion of the trial was to determine the recommended phase 2 dose.

Phase 2 of the study tested a daily dose of 63 mg in patients who received no prior chemotherapy. Efficacy was assessed using PCWG3 and RECIST 1.1 criteria. The primary and secondary end points of this portion were efficacy, radiographic progression-free survival (PFS), and overall response rates (ORR).

Data suggested that sabizabulin was safe and had mild toxicities shown. Adverse events reported in patients were primarily grade 1 or 2 and included fatigue and GI toxicities such as diarrhea and nausea. Despite these adverse events, most patients did very well. Additionally, preliminary activity was demonstrated in phase 2 with tumor reduction, an ORR in the 20% to 30% range, and PFS between 9-12 months.

In the interview, Markowski, assistant professor of oncology, at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Oncology, discussed how the findings from this phase 1b/2 trial of sabizabulin within this patient population may influence future research with the oral agent.

Can you explain this study of sabizabulin in men with advanced mCRPC?

This is a phase 1b/2 study involving a compound sabizabulin, also called VERU-111, in men with metastatic castration resistant prostate cancer. Sabizabulin is an orally dosed alpha beta tubulin inhibitor. Similar to a taxane chemotherapy, this is found in oral form. We did a dose escalation in phase 1 with about 40 patients. We determined the recommended phase 2 dose, and we conducted the phase 2 study, which was a single arm study, in a similar patient population now looking at efficacy.

What were the methods and design of the study?

It is a phase 1 study initially. We had a dose escalation study, 40 patients were enrolled, and we allowed men with metastatic castration resistant prostate cancer who have had treatment with at least 1 AR targeted therapy and up to 1 taxane chemotherapy for the phase 1 portion of it. It’s a traditional phase 1 study where patients started at a low dose, but we did allow for intrapatient dose-escalation. Patients were initially started at 1 week on 2 weeks off. If they did well, they went up to 2 weeks on, 1 week off, and then eventually daily dosing.

As we worked our way through the dose escalation, we determined that 63 mg per day continuously dosed was going to be the recommended phase 2 dose, and we did not identify a maximum tolerated dose, so we went up to 72 mg and began to see a little bit more GI toxicities. We decided to move down to 63 mg and move that forward. With the phase 2 study, again, that is the 63 mg/day continuously dosed cohort with a similar patient population, but this cohort did not allow for prior chemotherapy. At 63 milligrams, we were looking at efficacy, radiographic progression-free survival, and overall response rates.

Can you discuss the safety and efficacy results found in the trial?

For the phase 1, dose finding study looking at safety, we did find that sabizabulin was pretty safe. It had mild toxicity, grade 1 or 2 primarily, and mostly fatigue and GI toxicities were diarrhea, nausea, and most patients did very well. We had a few grade 3 toxicities in the GI tract. Those were managed well with dose interruption or dose reduction. Again, from the safety perspective, patients did quite well in phase 1.

Then we did see preliminary activity in phase 2. We saw some tumor reduction; we had an objective response rate in the 20% to 30% range. What we found is that patients were on the study for a long time. Progression-free survival was in the range of 9 to 12 months, but we had patients on study for 3 years and that they continue on study. There was some good disease control and in addition to some of the responses in terms of tumor reduction, we saw a lot of disease stability that was durable.

With the toxicity of VERU-111, we saw that it does have similar properties to a taxane chemotherapy, but we did not see those side effects. We don't see the neurotoxicity or the cytopenias that we commonly see with taxanes. It seems to be better tolerated than the taxanes were in terms of the side effect profile. That was an interesting finding and good for patients.

How has this study influenced future research of sabizabulin?

This was the first study that was done in men with sabizabulin. A lot of preclinical work went into this showing some preliminary activity in prostate cancer, breast cancer, pancreatic cancer, etc. There may be other studies and other tumor types coming down the pipeline soon.

The trial we're most interested in right now is the phase 3 VERACITY study [NCT04844749] that was opened based on the results of this trial. Again, that's a phase 3 study. It is randomized with patients with metastatic castration resistant prostate cancer after 1 AR-targeted therapy. They get randomized to the VERU-111 compound, or an alternative AR-targeted agent with the primary end point being radiographic progression-free survival. That study is open and ongoing. We are optimistic to look at efficacy in that study.

What do you believe is next in regard to research in the prostate cancer space?

I think there are a number of different agents coming down the pipeline for prostate cancer that are pretty exciting. There is a whole field of bispecific T-cell engagers and numerous phase 1 and 2 studies looking at that, so that's going to be very exciting. From an immunotherapy perspective, there are a number of studies with bipolar androgen therapy where patients are receiving high doses of testosterone. We're seeing some preliminary activity there, so those are 2 compounds.

Then, there are combination studies with lutetium PSMA. It's exciting to see what we are going to pair with or what we are going to use this VERU-111 compound with, like lutetium PSMA or other therapies. I think there's an endless supply of different drug combinations that we're looking at. I think the future for prostate cancer, particularly in advanced prostate cancer, is bright.

What unmet needs still need to be filled in the mCRPC space?

We need more oral therapies for patients. We have [intravenous] therapies that can be toxic and patients are a little bit reluctant, so oral therapies are needed. Then, we need therapies that get away from the AR-targeting therapy access. A lot of what we do in prostate cancer focuses on hormone therapy and hormone manipulation because it works, but there's a quality-of-life impact to that.

In prostate cancer, maybe early in prostate cancer for local disease or radiation or even biochemical recurrence, there are ways that we can take advantage of biomarkers. If you have a BRCA2 mutation or an NMR deficiency, can we use targeted therapies early on and perhaps delay hormone therapy, but preserve some of that efficacy with PARP inhibitors or immunotherapy? That is a huge unmet need in general and in prostate cancer. Maybe we should think about it more as the quality-of-life impact of lifelong hormone therapy. There are studies that are looking at that, but that's something I would focus on.

What should community oncologists keep in mind when treating patients with this disease?

The tough part about treating advanced cancer is that we don't know exactly how we should cycle our different agents. We are starting to understand that a little bit more, but it's hard on everybody when you treat prostate cancer to know what's the way. What is the first-line, second-line, third-line, fourth? We don't have a clear delineation of therapy and that makes it hard.

I think 1 piece advice for community providers is when you have patients on these therapies, give it some time, even if the PSA is rising. If the PSA is rising, it's okay to keep patients on for a little bit longer, and not to just react reflexively to PSA changes, because what ends up happening is that you cycle through a lot of the drugs that we have, and we don't have an endless supply of treatments, and you end up with fairly refractory resistant prostate cancer with patients that have generally low burden of disease. It's hard to treat those patients because we've gone through them. Patients progress on treatment but give it some time. If you see progression on a scan or clinical progression, maybe that's the indication to move on to other therapies.