Masofaniten in Prostate Cancer Phase 1/2 Trial: Data and Future Directions - Christos Kyriakopoulos
October 9, 2024
Christos Kyriakopoulos discusses the phase 1/2 trial of masofaniten plus enzalutamide in metastatic castration-resistant prostate cancer. Dr. Kyriakopoulos discusses the trial design, focusing on the completed phase 1 results and ongoing phase 2 study. The phase 1 data show the combination is well-tolerated with promising efficacy, including an 88% PSA-90 response rate in evaluable patients. The trial targets patients naive to second-generation AR inhibitors, with phase 2 expanding to more sites globally. Dr. Kyriakopoulos highlights the potential of this combination to improve upon enzalutamide monotherapy, especially in patients with risk factors for early treatment failure. They discuss the challenges of enrollment due to changing treatment landscapes and the potential future applications of masofaniten in prostate cancer treatment. Dr. Kyriakopoulos states the importance of continued patient enrollment to advance this promising therapy.
Biographies:
Christos Kyriakopoulos, MD, Oncologist, Division of Hematology, Medical Oncology and Palliative Care, University of Wisconsin, WI
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Wellstar MCG, Georgia Cancer Center, Augusta, GA
Biographies:
Christos Kyriakopoulos, MD, Oncologist, Division of Hematology, Medical Oncology and Palliative Care, University of Wisconsin, WI
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Wellstar MCG, Georgia Cancer Center, Augusta, GA
Read the Full Video Transcript
Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urological oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined on UroToday for an ESMO discussion with Dr. Christos Kyriakopoulos from the University of Wisconsin. Christos, thanks very much for joining us today.
Christos Kyriakopoulos: Hi, Dr. Klaassen, and thank you so much for the invitation to discuss the results of this very exciting trial.
Zachary Klaassen: Absolutely.
Christos Kyriakopoulos: So this is a trial that we have previously presented at different meetings, and more recently we provided an update at the 2024 ESMO meeting in Barcelona, Spain. This is an outline of the presentation. So as we know, second-generation androgen receptor inhibitors act directly or indirectly through the androgen receptor ligand-binding domain. Masofaniten, which is the study drug, is a small molecule of a novel class of drugs developed to interrupt androgen-driven transcription through a mechanism involving the N-terminal domain of the androgen receptor. And this is a new class of drugs that is called anitens. Preclinical studies have shown deeper blockade of the AR pathway and the subsequent potential benefit to prostate cancer patients through treatment with a combination of masofaniten plus enzalutamide. And for that reason, a phase one/two study is conducted in patients with metastatic castration-resistant prostate cancer disease, naïve to second-generation AR inhibitors, even though prior treatment with chemotherapy in the hormone-sensitive setting was permitted.
The study is designed as a phase one/two multicenter open-label study. The phase one part of the study tested escalating doses of masofaniten in combination with a fixed dose of enzalutamide, either at 120 milligrams daily or 160 milligrams daily. The main objective of the phase one was evaluation of the PK and safety of masofaniten plus enzalutamide when administered in combination, along with establishing the recommended phase two combination doses for both drugs to address potential drug-drug interactions. The phase one has been completed and we presented an update of the results at the most recent ESMO. The phase two is ongoing and it is open in 33 sites in the US, Canada, and Australia. And the plan is to activate it in 22 additional sites in Europe. The phase two part is a randomized study to either masofaniten plus enzalutamide versus enzalutamide alone, and the efficacy variables include proportion of patients with a decline in their PSA by more than 90%, time to PSA progression, overall response rate, as well as time to radiographic progression.
The phase one completed enrollment with 18 patients in four cohorts, and this is a summary of the baseline characteristics of the 18 patients. This is a busy slide. What I would like to point out is that 14 out of the 18 patients enrolled had at least two risk factors for early treatment failure to enzalutamide single agent based on models that had been developed from previous studies. Overall, the combination was safe and well tolerated at all different dose levels. Most frequent treatment-related adverse events were associated either with AR inhibition or with GI tract irritation, and all of them were either grade one or two, and overall consistent with what we expect from treatment with enzalutamide alone or from previous experience with treatment with masofaniten alone from previous studies. In cohort four, there was one grade rash which was maculopapular and that was deemed as probably related to the combination and was observed after administration of both masofaniten and enzalutamide during the DLT period. And for that reason, we expanded that cohort to enroll a total of seven patients. No additional DLTs were observed in the expanded cohort so the maximum tolerated dose was not reached.
In terms of efficacy, out of the 18 patients enrolled in the four cohorts, 11 are still on treatment and seven of those 18 patients discontinued treatment with five of them due to disease progression and two of them due to non-related events while achieving a decline in their PSA by 90% or more. The first of these two patients developed a brain abscess that was not related to the treatment and the second one passed away from cardiac disease that was neither related to the cancer nor to the treatment. Two out of the 18 patients were non-evaluable per study protocol due to limited drug exposure. As we can see, 88% of the evaluable patients had a PSA decline of 90% or more, and 63% of patients had an undetectable PSA. These rapid, deep, and durable responses were independent from starting PSA levels, combination doses, or previous chemotherapy. From the five patients with measurable disease, three of them experienced partial radiographic response. As of now and after a median follow-up of 15.2 months, the phase one masofaniten plus enzalutamide data is immature for time-to-event parameters since 11 out of the 18 patients are still in treatment. However, this data compares favorably compared to historic data from other studies with enzalutamide in that setting, but of course all the limitations of cross-trial comparisons and the small number of patients in the phase one cohort. However, this data supports the initiation of the phase two randomized trial, which is ongoing.
So in conclusion, the combination of masofaniten and enzalutamide at all dose schedules tested in the phase one part continues to be well tolerated and efficacy parameters were shown to be durable in that patient population. Of note, the majority of patients enrolled in the phase one part presented with two or more risk factors for early failure to enzalutamide based on previous models. In terms of efficacy, 88% of patients achieved a decline in their PSA of 90% or more, and after a median follow-up of 15.2 months, time-to-event parameters continue to compare favorably with historic data with single-agent enzalutamide in that patient population.
The phase two part of the study is ongoing and it is currently open in 33 sites in the US, Canada, and Australia, and the expansion to include 22 additional sites in Europe, in France, Spain, and Belgium is ongoing. So this is my last slide. First and foremost, I would like to thank all the patients and their families for participating in the study. Of course, ESSA Pharma for sponsoring the study, as well as all the investigators and the research staff for all their great work. So thank you and I'm happy to answer any questions.
Zachary Klaassen: Christos, thanks so much for that great presentation to see another update of this important phase one/phase two trial. I think you hinted at it twice in the presentation, the phase two is ongoing, there's going to be expansion in Europe. How is enrollment going so far and when may we see some data from that phase two portion of the trial?
Christos Kyriakopoulos: Enrollment is going well. We also expect that once all the sites are on board, things will go even faster. I think one of the major challenges in terms of enrollment is the fact that, as we know, most patients nowadays receive treatment with a second-generation AR inhibitor in the hormone-sensitive setting. There are still patients who start treatment with ADT alone and eventually they will develop castration-resistant disease and will need additional treatment with a second-generation AR inhibitor. So those patients are still out there. It's hard to predict; however, based on current projections, I think we're on schedule.
Zachary Klaassen: Great, that's excellent. The fun part about doing these discussions is we can sort of discuss where these things may fit into the landscape. So in your opinion, let's say the phase two plays out well and we get a good combination between masofaniten and enzalutamide. How may masofaniten fit into the landscape of not just mCRPC but maybe we see it move up further in the disease space? What's your opinion on that?
Christos Kyriakopoulos: I think that's a great question. Of course, it's a rapidly changing field. It's hard to predict because there are a lot of other drugs in the pipeline. I think that if the study is positive, the combination of masofaniten plus enzalutamide could be used in any setting where enzalutamide might be a good option for patients with prostate cancer. Again, that remains to be seen. Additional studies will probably need to be conducted, but that's where I see the combination of masofaniten and enzalutamide moving in the future.
Zachary Klaassen: And I think too with the PSA-90 results we're seeing some great responses, at least in the phase one, so hopefully we see that in the phase two as well. So I think excellent discussion. Maybe a couple of take-home messages for our listeners today based on the phase one data you presented.
Christos Kyriakopoulos: Sure. I think that what we have seen based on the phase one data is that the combination of masofaniten and enzalutamide is well tolerated. Again, some side effects were observed, but again, these are consistent with previous experience and most of them were grade one or two. On the other hand, there is a strong signal from the combination of masofaniten plus enzalutamide, so it is important to continue enrolling patients in the phase two study in order to get the results that we're hoping to get. And I think the last take-home message is that it is very important for providers and investigators to enroll patients in important studies like this one in order to complete them and get the results as soon as possible and potentially move these regimens to clinical practice with a significant benefit for patients.
Zachary Klaassen: Great take-home message and thanks again for joining us on UroToday and for your time and expertise.
Christos Kyriakopoulos: Thank you very much. Thank you.
Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urological oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined on UroToday for an ESMO discussion with Dr. Christos Kyriakopoulos from the University of Wisconsin. Christos, thanks very much for joining us today.
Christos Kyriakopoulos: Hi, Dr. Klaassen, and thank you so much for the invitation to discuss the results of this very exciting trial.
Zachary Klaassen: Absolutely.
Christos Kyriakopoulos: So this is a trial that we have previously presented at different meetings, and more recently we provided an update at the 2024 ESMO meeting in Barcelona, Spain. This is an outline of the presentation. So as we know, second-generation androgen receptor inhibitors act directly or indirectly through the androgen receptor ligand-binding domain. Masofaniten, which is the study drug, is a small molecule of a novel class of drugs developed to interrupt androgen-driven transcription through a mechanism involving the N-terminal domain of the androgen receptor. And this is a new class of drugs that is called anitens. Preclinical studies have shown deeper blockade of the AR pathway and the subsequent potential benefit to prostate cancer patients through treatment with a combination of masofaniten plus enzalutamide. And for that reason, a phase one/two study is conducted in patients with metastatic castration-resistant prostate cancer disease, naïve to second-generation AR inhibitors, even though prior treatment with chemotherapy in the hormone-sensitive setting was permitted.
The study is designed as a phase one/two multicenter open-label study. The phase one part of the study tested escalating doses of masofaniten in combination with a fixed dose of enzalutamide, either at 120 milligrams daily or 160 milligrams daily. The main objective of the phase one was evaluation of the PK and safety of masofaniten plus enzalutamide when administered in combination, along with establishing the recommended phase two combination doses for both drugs to address potential drug-drug interactions. The phase one has been completed and we presented an update of the results at the most recent ESMO. The phase two is ongoing and it is open in 33 sites in the US, Canada, and Australia. And the plan is to activate it in 22 additional sites in Europe. The phase two part is a randomized study to either masofaniten plus enzalutamide versus enzalutamide alone, and the efficacy variables include proportion of patients with a decline in their PSA by more than 90%, time to PSA progression, overall response rate, as well as time to radiographic progression.
The phase one completed enrollment with 18 patients in four cohorts, and this is a summary of the baseline characteristics of the 18 patients. This is a busy slide. What I would like to point out is that 14 out of the 18 patients enrolled had at least two risk factors for early treatment failure to enzalutamide single agent based on models that had been developed from previous studies. Overall, the combination was safe and well tolerated at all different dose levels. Most frequent treatment-related adverse events were associated either with AR inhibition or with GI tract irritation, and all of them were either grade one or two, and overall consistent with what we expect from treatment with enzalutamide alone or from previous experience with treatment with masofaniten alone from previous studies. In cohort four, there was one grade rash which was maculopapular and that was deemed as probably related to the combination and was observed after administration of both masofaniten and enzalutamide during the DLT period. And for that reason, we expanded that cohort to enroll a total of seven patients. No additional DLTs were observed in the expanded cohort so the maximum tolerated dose was not reached.
In terms of efficacy, out of the 18 patients enrolled in the four cohorts, 11 are still on treatment and seven of those 18 patients discontinued treatment with five of them due to disease progression and two of them due to non-related events while achieving a decline in their PSA by 90% or more. The first of these two patients developed a brain abscess that was not related to the treatment and the second one passed away from cardiac disease that was neither related to the cancer nor to the treatment. Two out of the 18 patients were non-evaluable per study protocol due to limited drug exposure. As we can see, 88% of the evaluable patients had a PSA decline of 90% or more, and 63% of patients had an undetectable PSA. These rapid, deep, and durable responses were independent from starting PSA levels, combination doses, or previous chemotherapy. From the five patients with measurable disease, three of them experienced partial radiographic response. As of now and after a median follow-up of 15.2 months, the phase one masofaniten plus enzalutamide data is immature for time-to-event parameters since 11 out of the 18 patients are still in treatment. However, this data compares favorably compared to historic data from other studies with enzalutamide in that setting, but of course all the limitations of cross-trial comparisons and the small number of patients in the phase one cohort. However, this data supports the initiation of the phase two randomized trial, which is ongoing.
So in conclusion, the combination of masofaniten and enzalutamide at all dose schedules tested in the phase one part continues to be well tolerated and efficacy parameters were shown to be durable in that patient population. Of note, the majority of patients enrolled in the phase one part presented with two or more risk factors for early failure to enzalutamide based on previous models. In terms of efficacy, 88% of patients achieved a decline in their PSA of 90% or more, and after a median follow-up of 15.2 months, time-to-event parameters continue to compare favorably with historic data with single-agent enzalutamide in that patient population.
The phase two part of the study is ongoing and it is currently open in 33 sites in the US, Canada, and Australia, and the expansion to include 22 additional sites in Europe, in France, Spain, and Belgium is ongoing. So this is my last slide. First and foremost, I would like to thank all the patients and their families for participating in the study. Of course, ESSA Pharma for sponsoring the study, as well as all the investigators and the research staff for all their great work. So thank you and I'm happy to answer any questions.
Zachary Klaassen: Christos, thanks so much for that great presentation to see another update of this important phase one/phase two trial. I think you hinted at it twice in the presentation, the phase two is ongoing, there's going to be expansion in Europe. How is enrollment going so far and when may we see some data from that phase two portion of the trial?
Christos Kyriakopoulos: Enrollment is going well. We also expect that once all the sites are on board, things will go even faster. I think one of the major challenges in terms of enrollment is the fact that, as we know, most patients nowadays receive treatment with a second-generation AR inhibitor in the hormone-sensitive setting. There are still patients who start treatment with ADT alone and eventually they will develop castration-resistant disease and will need additional treatment with a second-generation AR inhibitor. So those patients are still out there. It's hard to predict; however, based on current projections, I think we're on schedule.
Zachary Klaassen: Great, that's excellent. The fun part about doing these discussions is we can sort of discuss where these things may fit into the landscape. So in your opinion, let's say the phase two plays out well and we get a good combination between masofaniten and enzalutamide. How may masofaniten fit into the landscape of not just mCRPC but maybe we see it move up further in the disease space? What's your opinion on that?
Christos Kyriakopoulos: I think that's a great question. Of course, it's a rapidly changing field. It's hard to predict because there are a lot of other drugs in the pipeline. I think that if the study is positive, the combination of masofaniten plus enzalutamide could be used in any setting where enzalutamide might be a good option for patients with prostate cancer. Again, that remains to be seen. Additional studies will probably need to be conducted, but that's where I see the combination of masofaniten and enzalutamide moving in the future.
Zachary Klaassen: And I think too with the PSA-90 results we're seeing some great responses, at least in the phase one, so hopefully we see that in the phase two as well. So I think excellent discussion. Maybe a couple of take-home messages for our listeners today based on the phase one data you presented.
Christos Kyriakopoulos: Sure. I think that what we have seen based on the phase one data is that the combination of masofaniten and enzalutamide is well tolerated. Again, some side effects were observed, but again, these are consistent with previous experience and most of them were grade one or two. On the other hand, there is a strong signal from the combination of masofaniten plus enzalutamide, so it is important to continue enrolling patients in the phase two study in order to get the results that we're hoping to get. And I think the last take-home message is that it is very important for providers and investigators to enroll patients in important studies like this one in order to complete them and get the results as soon as possible and potentially move these regimens to clinical practice with a significant benefit for patients.
Zachary Klaassen: Great take-home message and thanks again for joining us on UroToday and for your time and expertise.
Christos Kyriakopoulos: Thank you very much. Thank you.