Sabizabulin in Men with Metastatic Castration Resistant Prostate Cancer - Mark Markowski
October 31, 2021
In this UroToday discussion between Alicia Morgans and Mark Markowski, they discuss the results of a Phase 1b/2 study of sabizabulin, an androgen receptor transport disruptor, in men with metastatic castration-resistant prostate cancer (mCRPC) who failed an androgen receptor targeting agent. Sabizabulin is an oral agent that inhibits microtubule assembly as well as disrupts androgen receptor transport from the cytoplasm to the nucleus. Dr. Markowski highlights the study design and rationale. Dr. Markowski discusses the preliminary safety data and the early efficacy in the phase 2. In closing, they highlight the phase 3 study of sabizabulin in metastatic CRPC for patients that have had prior treatment with one AR targeted therapy. These promising results have led to a randomized Phase 3 clinical trial (VERACITY; NCT04844749), which is underway to evaluate the efficacy and safety of sabizabulin versus an alternative ARTA in men with mCRPC who progressed on at least on prior ARTA.
Biographies:
Mark Markowski, MD, Ph.D., Medical Oncologist, Kimmel Cancer Center, Sibley Memorial Hospital
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Biographies:
Mark Markowski, MD, Ph.D., Medical Oncologist, Kimmel Cancer Center, Sibley Memorial Hospital
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Related Content:
ESMO 2021: Phase Ib/II Study of Sabizabulin (VERU-111), an Androgen Receptor Transport Disruptor, in Men with Metastatic Castration Resistant Prostate Cancer (mCRPC) Who Failed an Androgen Receptor Targeting Agent
Evaluating the Efficacy of Sabizabulin in The Treatment of Metastatic Castration-Resistant Prostate Cancer – Robert Dreicer
A Phase 1b/2 Study of Sabizabulin, a Novel Oral Cytoskeleton Disruptor, in Men With Metastatic Castration-Resistant Prostate Cancer with Progression on an Androgen Receptor Targeting Agent.
ESMO 2021: Phase Ib/II Study of Sabizabulin (VERU-111), an Androgen Receptor Transport Disruptor, in Men with Metastatic Castration Resistant Prostate Cancer (mCRPC) Who Failed an Androgen Receptor Targeting Agent
Evaluating the Efficacy of Sabizabulin in The Treatment of Metastatic Castration-Resistant Prostate Cancer – Robert Dreicer
A Phase 1b/2 Study of Sabizabulin, a Novel Oral Cytoskeleton Disruptor, in Men With Metastatic Castration-Resistant Prostate Cancer with Progression on an Androgen Receptor Targeting Agent.
Read the Full Video Transcript
Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute in Boston. I'm so excited to have here with me today, Dr. Mark Markowski, who is an Assistant Professor of Oncology and a GU Medical Oncologist at Johns Hopkins in Baltimore. Thank you so much for being here with me today, Mark.
Mark Markowski: Thanks for having me.
Alicia Morgans: Wonderful. So, I wanted to talk with you about an ESMO presentation that your team put on this year at ESMO 2021, really interesting data looking at VERU-111 or sabizabulin, which is a new androgen receptor transport disruptor that we are trying to understand the use for in men with metastatic CRPC. A really interesting phase 1b/2 study. Can you tell us a little bit about it?
Mark Markowski: Sure. So we conducted a phase 1b/2 study with VERU-111 or sabizabulin in men with metastatic castration-resistant prostate cancer. And these are for men who have had prior treatment with at least one AR-targeted therapy, such as abiraterone. And for the phase 1 part of the study, we allowed up to one taxane chemotherapy. For phase 2, we did not allow prior chemotherapy. And so, as you said, this is an oral, alpha-beta, microtubule polymerization inhibitor, and we have seen activity at least pre-clinically across multiple tumor types, prostate cancer being one of them. And so since we do have success with taxane-based chemotherapies in prostate cancer, we felt like this was a logical place to start for the phase 1 study.
Alicia Morgans: I think that makes a lot of sense. And I think that we have heard about this drug in prior presentations and had some preliminary safety data. Can you share some of that from the 1b?
Mark Markowski: Sure, absolutely. And I think safety was really important to us as we were bringing a new agent on board. And so we spent a lot of time trying to design at least a phase 1 study, and so if you have looked at how phase 1 was designed, we did do a typical three plus three design, but we started patients one week on, two weeks off on treatment. If they did well on that treatment, we increased the frequency to two weeks on, one week off, and if they did well, they got daily dosing. So there was inpatient, not necessarily dose escalation, but the frequency was increased in those patients who did well. So we started at a very low dose and we felt like this was a way where we can kind of clear focus on safety, but it did allow patients to increase their frequency to give them the best chance of possibly responding to the drug.
And so it was a nice balance there. So, we did find that the drug was safe and most of the side effects were low grade and were GI related, so nausea and diarrhea were the big dose-limiting toxicities. We also saw some fatigue. Interestingly enough, unlike taxing chemotherapies, we did not see any neurotoxicity or cytopenias, and so this was all GI-related, which we would expect with an oral drug. But again, well-tolerated at the 63 mg dosing cohort, and those patients were daily dosing. So we were able to do daily dosing with this agent, which was nice.
Alicia Morgans: Yeah, I agree that that is nice. And it's, it's nice for patients to not have to remember a start and a stop all the time. And I also really like that the way you designed this allowed patients to increase that dose within that individual patient because sometimes phase 1 can be tough. Everybody does get the drug, but sometimes people get a very low dose or maybe they're on a very high dose, as we're still trying to find the optimal dose. So that's a very interesting design, so I commend you and the team.
So share with us a little more about the phase 2. Did we see any early efficacy?
Mark Markowski: So we did, so right now we just presented the data for objective response. And so we did see an objective response rate of about 25%. So there was anti-tumor activity and then there was another percentage of patients that did not achieve a PR, that 30% reduction, but did have disease stability and even small decreases in tumor volume. So we were really pleased about that. We combined some of the phase 1 and phase 2 data to present data on about 55 patients, and so that's a reasonable patient population. We did see in RPFS of seven, eight months, which was very nice, some patients have been on for years. We had patients for up to two years. And so I think clearly when we look at the data, there is preliminary activity and there is a phase 3 study that's already in progress, and so I think that's going to be the tell-all here, is that study going to be positive? And if so, I think that is great news for this drug.
Alicia Morgans: So two years, that's a really long time. And I agree with you, does speak to early efficacy. If you can take a patient population and keep that patient with stable disease for that long of a period, I think that is very, very encouraging. Can you tell us a little bit about the phase 3?
Mark Markowski: So phase 3 is a randomized phase 3. Again, metastatic CRPC for patients that have had prior treatment with one AR targeted therapy. So this does not allow for prior chemotherapy. Patients are randomized in a two-to-one fashion, two to one to the VERU-111 compound versus an alternative AR targeted therapy, right? So if you had prior abi, you may randomize them to enzalutamide or vice versa. And the primary endpoint is RPFS, and we are looking for about 250 patients and this study is being led by Dr. Dreicer at the University of Virginia.
Alicia Morgans: Great. Well, I really do look forward to that and I appreciate you taking the time to talk with us today about this drug and really kind of shed light on the tolerability, which I think is going to be really important for patients. And of course, those early signs of efficacy. So if you could just sum up this ESMO 2021 presentation, what would that be? What's your message?
Mark Markowski: I think we have a new oral microtubule inhibitor that is showing some preliminary activity in men with metastatic CRPC with reasonable toxicity. And so this might be a nice oral agent for patients to go on after an oral abiraterone or enzalutamide-like medicine. And we will see. We will see where this fits in the spectrum of prostate cancer therapies.
Alicia Morgans: I look forward to it. So thank you so much for taking the time today. Congratulations on your presentation, and we appreciate your expertise as always.
Mark Markowski: Thanks very much.
Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute in Boston. I'm so excited to have here with me today, Dr. Mark Markowski, who is an Assistant Professor of Oncology and a GU Medical Oncologist at Johns Hopkins in Baltimore. Thank you so much for being here with me today, Mark.
Mark Markowski: Thanks for having me.
Alicia Morgans: Wonderful. So, I wanted to talk with you about an ESMO presentation that your team put on this year at ESMO 2021, really interesting data looking at VERU-111 or sabizabulin, which is a new androgen receptor transport disruptor that we are trying to understand the use for in men with metastatic CRPC. A really interesting phase 1b/2 study. Can you tell us a little bit about it?
Mark Markowski: Sure. So we conducted a phase 1b/2 study with VERU-111 or sabizabulin in men with metastatic castration-resistant prostate cancer. And these are for men who have had prior treatment with at least one AR-targeted therapy, such as abiraterone. And for the phase 1 part of the study, we allowed up to one taxane chemotherapy. For phase 2, we did not allow prior chemotherapy. And so, as you said, this is an oral, alpha-beta, microtubule polymerization inhibitor, and we have seen activity at least pre-clinically across multiple tumor types, prostate cancer being one of them. And so since we do have success with taxane-based chemotherapies in prostate cancer, we felt like this was a logical place to start for the phase 1 study.
Alicia Morgans: I think that makes a lot of sense. And I think that we have heard about this drug in prior presentations and had some preliminary safety data. Can you share some of that from the 1b?
Mark Markowski: Sure, absolutely. And I think safety was really important to us as we were bringing a new agent on board. And so we spent a lot of time trying to design at least a phase 1 study, and so if you have looked at how phase 1 was designed, we did do a typical three plus three design, but we started patients one week on, two weeks off on treatment. If they did well on that treatment, we increased the frequency to two weeks on, one week off, and if they did well, they got daily dosing. So there was inpatient, not necessarily dose escalation, but the frequency was increased in those patients who did well. So we started at a very low dose and we felt like this was a way where we can kind of clear focus on safety, but it did allow patients to increase their frequency to give them the best chance of possibly responding to the drug.
And so it was a nice balance there. So, we did find that the drug was safe and most of the side effects were low grade and were GI related, so nausea and diarrhea were the big dose-limiting toxicities. We also saw some fatigue. Interestingly enough, unlike taxing chemotherapies, we did not see any neurotoxicity or cytopenias, and so this was all GI-related, which we would expect with an oral drug. But again, well-tolerated at the 63 mg dosing cohort, and those patients were daily dosing. So we were able to do daily dosing with this agent, which was nice.
Alicia Morgans: Yeah, I agree that that is nice. And it's, it's nice for patients to not have to remember a start and a stop all the time. And I also really like that the way you designed this allowed patients to increase that dose within that individual patient because sometimes phase 1 can be tough. Everybody does get the drug, but sometimes people get a very low dose or maybe they're on a very high dose, as we're still trying to find the optimal dose. So that's a very interesting design, so I commend you and the team.
So share with us a little more about the phase 2. Did we see any early efficacy?
Mark Markowski: So we did, so right now we just presented the data for objective response. And so we did see an objective response rate of about 25%. So there was anti-tumor activity and then there was another percentage of patients that did not achieve a PR, that 30% reduction, but did have disease stability and even small decreases in tumor volume. So we were really pleased about that. We combined some of the phase 1 and phase 2 data to present data on about 55 patients, and so that's a reasonable patient population. We did see in RPFS of seven, eight months, which was very nice, some patients have been on for years. We had patients for up to two years. And so I think clearly when we look at the data, there is preliminary activity and there is a phase 3 study that's already in progress, and so I think that's going to be the tell-all here, is that study going to be positive? And if so, I think that is great news for this drug.
Alicia Morgans: So two years, that's a really long time. And I agree with you, does speak to early efficacy. If you can take a patient population and keep that patient with stable disease for that long of a period, I think that is very, very encouraging. Can you tell us a little bit about the phase 3?
Mark Markowski: So phase 3 is a randomized phase 3. Again, metastatic CRPC for patients that have had prior treatment with one AR targeted therapy. So this does not allow for prior chemotherapy. Patients are randomized in a two-to-one fashion, two to one to the VERU-111 compound versus an alternative AR targeted therapy, right? So if you had prior abi, you may randomize them to enzalutamide or vice versa. And the primary endpoint is RPFS, and we are looking for about 250 patients and this study is being led by Dr. Dreicer at the University of Virginia.
Alicia Morgans: Great. Well, I really do look forward to that and I appreciate you taking the time to talk with us today about this drug and really kind of shed light on the tolerability, which I think is going to be really important for patients. And of course, those early signs of efficacy. So if you could just sum up this ESMO 2021 presentation, what would that be? What's your message?
Mark Markowski: I think we have a new oral microtubule inhibitor that is showing some preliminary activity in men with metastatic CRPC with reasonable toxicity. And so this might be a nice oral agent for patients to go on after an oral abiraterone or enzalutamide-like medicine. And we will see. We will see where this fits in the spectrum of prostate cancer therapies.
Alicia Morgans: I look forward to it. So thank you so much for taking the time today. Congratulations on your presentation, and we appreciate your expertise as always.
Mark Markowski: Thanks very much.