Tazemetostat in Combination With Abiraterone + Prednisone or Enzalutamide in mCRPC – Wassim Abida
November 12, 2021
Tazemetostat is an enhancer of zeste homolog (EZH2) which is approved for use in patients with epithelioid sarcoma or relapsed/refractory follicular lymphoma. However, inhibition of EZH2 has been proposed to overcome resistance to the androgen signaling inhibitors (ASIs) based on preclinical prostate cancer models, in which the combination approach led to greater tumor growth reduction than each drug alone.
The authors performed a phase Ib/II global, open-label, randomized study (NCT04179864) of tazemetostat in combination with abiraterone and prednisone or enzalutamide. The phase Ib segment enrolled adults with mCRPC following a modified 3 + 3 design. The protocol allowed prior abiraterone and prednisone, enzalutamide, first-generation anti-androgen receptor therapy, or short-course chemotherapy. Following inclusion, patients received tazemetostat escalated to 800 mg twice daily (BID) with abiraterone 1000 mg once daily (QD) + prednisone 5 mg BID or enzalutamide 160 mg QD with tazemetostat escalated to 1600 mg BID. The primary endpoints were safety, tolerability, and recommended phase II dose (RP2D) of tazemetostat for each combination. Disease control rate (DCR) was assessed at 6 months. In phase II, those treated with abiraterone + prednisone will be randomized 1:1 to tazemetostat (at RP2D) in combination with enzalutamide or to enzalutamide alone.
Wassim Abida, MD, Ph.D. Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
ESMO 2021: Safety of Tazemetostat in Combination With Abiraterone/Prednisone or Enzalutamide in Patients With Metastatic Castration-Resistant Prostate Cancer
NCT04179864: Study of Tazemetostat With Enzalutamide or Abiraterone/Prednisone in Subjects With Castration Resistant Prostate Cancer Who Have Not Received Chemotherapy
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, a friend and colleague Dr. Wassim Abida, who's a GU medical oncologist, at Memorial Sloan Kettering Cancer Center, in New York. Thank you so much for being here with me today, Dr. Abida.
Wassim Abida: It's a pleasure being here.
Alicia Morgans: Wonderful. Well, the pleasure is all mine, because I'm excited to talk with you about the phase-I B portion, of a phase-I B-phase-II combination trial, that you and your team presented at ESMO 2021. And, this was really investigating the combination of tazemetostat with either abiraterone or enzalutamide, in patients with metastatic CRPC. Can you tell us a little bit about this study, why you were investigating tazemetostat? Because not all of us are really familiar with that agent, and then we can get into what you found.
Wassim Abida: Sure. I think just to give a broader background, I think many of us in prostate cancer, are seeing more aggressive disease emerge after the next generation hormonal agents, abiraterone-enzalutamide. Often with neuroendocrine differentiation, or loss of the adenocarcinoma phenotype, and de differentiation into a different phenotype, and that's a process called lineage plasticity. And, there's a lot of interest in targeting that lineage plasticity, and giving really alternatives to chemotherapy, which is generally the subsequent line of therapy.
So, tazemetostat is an epigenetic agent, essentially it inhibits EZH2, which is a methyltransferase. And, promotes the transcription of a variety of genes, and preclinical models have shown that tazemetostat and other EZH2 inhibitors, can reverse lineage plasticity, which promotes resistance to enzalutamide, and abiraterone. So, that's really the background in rationale for using tazemetostat in combination with other hormonal agents following the failure abiraterone-enzalutamide in prostate cancer.
Alicia Morgans: That makes a lot of sense. I think, gosh, if we could prevent lineage plasticity, we would be doing a huge service to our patient, for sure. And, I think you did mention that tazemetostat is actually an FDA approved agent in certain malignancies, is that true?
Wassim Abida: It is, in epithelioid sarcoma, follicular lymphoma, tazemetostat is an approved agent. So, we certainly have monotherapy safety data for this drug. And, given the background and the rationale for using in metastatic CRPC, in combination with enzalutamide and abiraterone, we are running the study which essentially has a phase-I B portion, a rapid dose escalation to assess the safety in combination with these agents. And, followed by a phase-II study. So, we've completed the phase-I B study, and this is what we reported ESMO. And, the phase-II portion of the study is ongoing currently.
Alicia Morgans: Great. And, I think just to remind everyone, of course, so phase-I B, is really focused, as you said, on dose escalation, understanding the safety and tolerability of agents, and in this case in combination with abiraterone-enzalutamide. So, can you tell us a little bit about what you found? Were there any concerning safety signals, or did things go relatively as planned?
Wassim Abida: Really as planned, tazemetostat as monotherapy [inaudible 00:03:08] indications of the very well-tolerated drug, so this was a rapid dose escalation, up to the standard approved dose with abiraterone, which is 800 milligrams twice daily, at the standard dose of abiraterone. And, then with enzalutamide, actually the plan was to go higher than the approved dose, because of predicted drug-drug interaction.
So, enzalutamide was predicted to reduce the serum concentrations of tazemetostat. And, the escalation was planned up to 1600 milligrams twice daily of tazemetostat, which is really double the approved dose. The escalation went very well, I would say that combination with both abiraterone-enzalutamide was very well tolerated. Main toxicities were really grade I-grade II fatigue, some nausea, some diarrhea, very unusual grade III events of fatigue. And, arthralgia, as well as hypertension, which are probably more related to the AR targeting agents here in the combination. So, all in all very well tolerated, and the recommended phase-II dose, particularly with enzalutamide was established at higher than the single agent tazemetostat doses, 1200 milligrams twice daily were with no significant toxicity concerns.
Alicia Morgans: That's so important, I think, we often are concerned that we're looking only for toxicity, but to your point, when there are drug-drug interactions, we also need to ensure that we have what we expect to be doses that will have some anti-tumor effect. So, really that is a key and critical part of what you and the team did. So, congratulations on getting that done, and I'm glad that things seem to be relatively well tolerated, and without new and concerning safety signals. So, can you tell me a little bit about the phase-II? I understand that's actually ongoing at this time.
Wassim Abida: Yes. So, just to come back to your point Dr. Morgans, I do think it's really important to ensure that we're reaching a good dose, but tolerability, I think for this class of agents, particularly in combination with a second line AR targeted agent, is really important. So, the study essentially was designed for patients who had progressed on abiraterone-enzalutamide, to cross over to the other drug in combination with tazemetostat, that's the design, and that's really the plan for the phase-II.
So, we know that when a patient progresses on abiraterone, for example, their duration of benefit on a second line enzalutamide, typically is short. And, so I think safety in the setting is really important when we're adding a second agent, because the patient can't cross over to chemotherapy for example, which is the most common second line option, particularly as their disease progresses rapidly. But, we're all interested in a well tolerated combination that prolongs the efficacy of a second line hormonal agent. So, I think that safety, and tolerability is really important in this setting. We're talking about two oral agents here, second line enzalutamide plus tazemetostat that's well tolerated. So, if we have benefit from that combination, then I think it would be very important for our patient population.
Alicia Morgans: I Agree. And, wonder if you saw any signs of early, or early signs of efficacy, which is difficult in these early phase trials, but how did the drugs seem to do?
Wassim Abida: So, the, in terms of efficacy, we looked at, as secondary endpoints PSA responses, and I should, I think the interesting data here is looking specifically the combination with enzalutamide, which is the majority of the patients. So, 14 out of the 21 patients in the phase-I B were on enzalutamide, and really 12 out of this 14 had already received abiraterone before. So, this was a, almost entirely a population of second line enzalutamide patients. I would say in terms of PSA responses, the PSA response was roughly 40%, PSA 30 response in this patient population. And, the previously reported, and it's difficult to benchmark with other studies, but typically about a third of patients who are receiving second line enzalutamide, will have a PSA 30 response or more. So, it's a small study, I'm not claiming that 40% is higher than a third, but it's roughly in the ballpark that we expect.
The caveat to that is, with these epigenetic agents, we really don't know that PSA response is the right marker to look at. We're looking for really disease stabilization, and what I can say is that about half the patients who were in phase-I B had, were on study for more than six months, which is typically a cutoff that we think of for a second line agent as a potential benchmark. And, there are a total of five patients who are still on the combination of enzalutamide plus tazemetostat, as of the data cutoff here. So, what we're hoping for is a PFS benefit, with a combination compared with second line enzalutamide by itself. So, that is where the phase-II is going. Phase-II is ongoing, currently it's a randomized study, looking at enzalutamide alone in the second line, after abiraterone, versus enzalutamide plus tazemetostat, looking for a PFS benefit for the combination.
Alicia Morgans: And, that's really interesting. And, I wonder, now we don't necessarily always do this in a phase-II, but I wonder if this combination moves forward, are you thinking of targeting a specific patient population? That's at high risk for lineage plasticity, or that may be showing early signs? What do you think?
Wassim Abida: That's an excellent question. And, that's the difficulty with these epigenetic agents. There are certainly data from preclinical models that suggests benefit in the lineage plasticity phenotypes, which we generally think of, we generally can define those genomically by loss of two tumor suppressors, P53 and RB, P53 and P10. Those typically have a lineage plasticity behavior, and a higher likelihood to differentiate into neuroendocrine, other phenotypes.
So, at this point the study is not selected, but there are required biopsies and biomarker component to the study. So, as we gather more data, and look at biomarkers for instance, does the presence of a P53 mutation, is that associated with a longer duration of benefit? So, we hope that some of the biomarker work, that's associated with the study, will guide us on what populations may benefit more. But, currently the study is unselected, and it's open to patients who have progressed on first line abiraterone, who are chemotherapy naive, and they can receive either second line enzalutamide alone, or in combination. And, it's open to patients with neuroendocrine differentiated disease as well, because we certainly want to capture patient who have clinical evidence, or histological evidence of neuroendocrine differentiation.
Alicia Morgans: That's actually fantastic, because there are not many trials that, allow that particular histologic phenotype into a trial. So, I commend you and the team. And, I really sincerely look to see if there are any signals in those subgroups, particularly though of course, numbers will be small in a phase-II. We may not see, what, enough patients to actually a clear distinction there, but really interesting. And, of course your interest in correlatives is going to help us there as well. So, if you had to sum up this phase-I B, and where we're potentially going with tazemetostat in combination with enzalutamide, maybe more so even than with abiraterone, what would that summary be?
Wassim Abida: I would say it's early days for epigenetic agents, and metastatic CRPC, but this is a very interesting area. We know that epigenetic modulation is important in resistance to next generation hormonal agents. We don't fully understand the mechanism, and, but I would say that the study is important to understand EZH2 inhibition in particular, in the context of resistance to hormonal agents in prostate cancer. I think we're going to gather some interesting data, and I hope you will see clinical benefit.
Alicia Morgans: Fantastic. Well, I really appreciate your time and your expertise. Good luck on the phase-II as well. And, we'll make sure that we have some information for those who are watching this video to be able to find sites for this phase-II may be open, so that patients can be referred or patients can refer themselves to potentially get involved. Very, very exciting work. Thank you so much for your time.
Wassim Abida: Thank you, Dr. Morgans.