Oral EPI-7386 Monotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer - Russell Pachynski
March 3, 2023
Alicia Morgans is joined by Russell Pachynski to discuss EPI-7386, a first-in-class N-terminal domain androgen receptor (AR) inhibitor that suppresses androgen activity through a novel mechanism of action. Trial of this agent in a first-in-human study in heavily pre-treated patients with metastatic castration-resistant prostate cancer (mCRPC). Dr. Pachynski provides an overview of this section of the study, highlighting that in initial dose escalation phase of the trial, all eligible patients were included regardless of their prior treatment history. In the Phase Ib dose expansion part of the trial, Pachynski and colleagues aimed to move the drug earlier in the treatment pathway so patients who had already received docetaxel for castration-resistant disease were excluded. The reported data is based on a population of 45 heavily pretreated patients with mCRPC from both phase 1a and 1b patient populations.
Biographies:
Russell Pachynski, MD, Associate Professor of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Biographies:
Russell Pachynski, MD, Associate Professor of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
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Read the Full Video Transcript
Alicia Morgans: Hi, I'm so excited to be here with Russell Pachynski talking about the ESSA trial and a new approach to treatment of patients with metastatic CRPC that might already have progression of disease on AR targeted agents and other things perhaps in the earlier phases of this study, so thank you so much for being here.
Russell Pachynski: Sure, my pleasure.
Alicia Morgans: Wonderful. Well, tell me a little bit about this drug.
Russell Pachynski: So the ESSA compound, which as of now is EPI-7386, that's the drug name for now is actually a N terminal domain AR inhibitor, so it's a little different than some of the other drugs that are in development where they target AR for degradation. Some of those affect AR at the C terminal domain. This one actually binds to the N terminal domain and actually prevents eventually the dimerization of AR and downstream effects, so it's in a new class of these AR inhibitors.
Alicia Morgans: That's really exciting and I think so important as we consider different mechanisms of resistance to the AR pathway inhibitors that we use so commonly. Tell me a little bit about this. I think you had a first in human section of this study.
Russell Pachynski: This was a first in human dose escalation dose expansion. The first part of the trial had a kind of lower starting dose, 200 milligrams once daily and that in a three plus three design kind of got moved up and now we're at a BID dosing, so we're at 600 milligrams BID dosing on patients.
Alicia Morgans: Great. Is that what you then took into the Phase Ib that you're working on?
Russell Pachynski: Yeah, the expansion part, so the initial dose escalation part was kind of all comers, metastatic, castration resistant prostate cancer. You could have had chemotherapy, had AR signaling inhibitors, et cetera, and so those patients in the once daily dose escalation were relatively heavily pretreated. Now in the dose expansion at 600 milligrams twice a day, we've excluded patients who have had docetaxel for castration resistant disease so we're moving the drug a little earlier in that castration resistance setting.
Alicia Morgans: Very interesting. Tell me, are you seeing any evidence of early responses with this approach?
Russell Pachynski: Yeah, so we've already gotten some PSA responses. Alex Wyatt up in Canada is also looking at ctDNA responses so we've seen some of those responses as well. Using some complex AI radiographic algorithms, we've actually seen some of the lesions respond because there's heterogeneity throughout this so we can see some of those lesions respond even in patients who overall you would say, "Well, maybe we're not having a radiographic response."
Alicia Morgans: That is really exciting too and actually so exciting that even in this early phase work, you're integrating these very innovative strategies into that understanding of disease response. ctDNA and quantitative analysis for radiographic assessment are not necessarily always integrated, so that's really exciting.
Russell Pachynski: Yeah, and what we've seen obviously in the dose escalation cohort where we had post chemotherapy patients for example, looking at their kind of genomic landscape, we saw a lot more mutations obviously as you would expect and so now that we're in the pre-chemo setting, we see fewer of those. But even in some of those earlier patients that had more mutations, we were seeing some responses. It'll be interesting to see, as we look at this drug in earlier castration resistance setting, will we eventually see more responses. We're still early in what we call Phase Ib expansion cohort, but they're definitely plans and ongoing trial looking at moving this drug earlier.
Alicia Morgans: Very exciting. As you think about that, can you tell me a little bit about the toxicity profile?
Russell Pachynski: Toxicity, safety toxicity has been excellent to date, so there's been no DLTs, no dose limiting toxicities. There've been no treatment related SAEs actually, and I think about, I want to say 2 to 3% of grade threes. The majority of the toxicity has been fatigue, some GI, but overall grade I and II and even on the grade II side of things very well tolerated, and so that's why we were able to dose escalate and at 600 BID still seeing it's very well tolerated.
Alicia Morgans: Well that's very, very good to hear and I think encouraging as we think about next steps for this approach, are there plans to move it into additional studies?
Russell Pachynski: Yeah, so kind of alluded to there is an ongoing study through the PCCTC looking at combining it with enzalutamide in a little earlier setting in the castration resistance setting but we also have a window of opportunity study open in the non-metastatic castration resistance setting and kind of tentative plans to kind of do a combination study in that setting as well with apalutamide. We think moving it earlier, potentially combining it with other AR agents is going to just increase this efficacy.
Alicia Morgans: It's really exciting and if we can potentiate the effectiveness of these AR pathway inhibitors, prevent some of the alterations and the receptor that might lead then to resistance, we have great approaches to therapy that are very well tolerated and something that doesn't seem to add significant harm in terms of toxicity could be really a wonderful synergistic pair.
Russell Pachynski: Yeah, I think an important point is that as this binds to the end terminus of the AR and we've seen some of this, we need to have a larger data set but potentially can affect ARV7 and other AR variants, whereas some of the other inhibitors or degraders that bind to the C terminus might not be effective in that and we've seen that with some other compounds. I think this drug and these types of drugs that are N terminal domain inhibitors have a very promising future.
Alicia Morgans: Wonderful. Well, I really appreciate you taking the time to talk this through and of course congratulate you and your team and thank your patients for the work that you're doing on this study and we look forward to hearing future results as they come in. Thank you so much for your time.
Russell Pachynski: Great, thank you.
Alicia Morgans: Hi, I'm so excited to be here with Russell Pachynski talking about the ESSA trial and a new approach to treatment of patients with metastatic CRPC that might already have progression of disease on AR targeted agents and other things perhaps in the earlier phases of this study, so thank you so much for being here.
Russell Pachynski: Sure, my pleasure.
Alicia Morgans: Wonderful. Well, tell me a little bit about this drug.
Russell Pachynski: So the ESSA compound, which as of now is EPI-7386, that's the drug name for now is actually a N terminal domain AR inhibitor, so it's a little different than some of the other drugs that are in development where they target AR for degradation. Some of those affect AR at the C terminal domain. This one actually binds to the N terminal domain and actually prevents eventually the dimerization of AR and downstream effects, so it's in a new class of these AR inhibitors.
Alicia Morgans: That's really exciting and I think so important as we consider different mechanisms of resistance to the AR pathway inhibitors that we use so commonly. Tell me a little bit about this. I think you had a first in human section of this study.
Russell Pachynski: This was a first in human dose escalation dose expansion. The first part of the trial had a kind of lower starting dose, 200 milligrams once daily and that in a three plus three design kind of got moved up and now we're at a BID dosing, so we're at 600 milligrams BID dosing on patients.
Alicia Morgans: Great. Is that what you then took into the Phase Ib that you're working on?
Russell Pachynski: Yeah, the expansion part, so the initial dose escalation part was kind of all comers, metastatic, castration resistant prostate cancer. You could have had chemotherapy, had AR signaling inhibitors, et cetera, and so those patients in the once daily dose escalation were relatively heavily pretreated. Now in the dose expansion at 600 milligrams twice a day, we've excluded patients who have had docetaxel for castration resistant disease so we're moving the drug a little earlier in that castration resistance setting.
Alicia Morgans: Very interesting. Tell me, are you seeing any evidence of early responses with this approach?
Russell Pachynski: Yeah, so we've already gotten some PSA responses. Alex Wyatt up in Canada is also looking at ctDNA responses so we've seen some of those responses as well. Using some complex AI radiographic algorithms, we've actually seen some of the lesions respond because there's heterogeneity throughout this so we can see some of those lesions respond even in patients who overall you would say, "Well, maybe we're not having a radiographic response."
Alicia Morgans: That is really exciting too and actually so exciting that even in this early phase work, you're integrating these very innovative strategies into that understanding of disease response. ctDNA and quantitative analysis for radiographic assessment are not necessarily always integrated, so that's really exciting.
Russell Pachynski: Yeah, and what we've seen obviously in the dose escalation cohort where we had post chemotherapy patients for example, looking at their kind of genomic landscape, we saw a lot more mutations obviously as you would expect and so now that we're in the pre-chemo setting, we see fewer of those. But even in some of those earlier patients that had more mutations, we were seeing some responses. It'll be interesting to see, as we look at this drug in earlier castration resistance setting, will we eventually see more responses. We're still early in what we call Phase Ib expansion cohort, but they're definitely plans and ongoing trial looking at moving this drug earlier.
Alicia Morgans: Very exciting. As you think about that, can you tell me a little bit about the toxicity profile?
Russell Pachynski: Toxicity, safety toxicity has been excellent to date, so there's been no DLTs, no dose limiting toxicities. There've been no treatment related SAEs actually, and I think about, I want to say 2 to 3% of grade threes. The majority of the toxicity has been fatigue, some GI, but overall grade I and II and even on the grade II side of things very well tolerated, and so that's why we were able to dose escalate and at 600 BID still seeing it's very well tolerated.
Alicia Morgans: Well that's very, very good to hear and I think encouraging as we think about next steps for this approach, are there plans to move it into additional studies?
Russell Pachynski: Yeah, so kind of alluded to there is an ongoing study through the PCCTC looking at combining it with enzalutamide in a little earlier setting in the castration resistance setting but we also have a window of opportunity study open in the non-metastatic castration resistance setting and kind of tentative plans to kind of do a combination study in that setting as well with apalutamide. We think moving it earlier, potentially combining it with other AR agents is going to just increase this efficacy.
Alicia Morgans: It's really exciting and if we can potentiate the effectiveness of these AR pathway inhibitors, prevent some of the alterations and the receptor that might lead then to resistance, we have great approaches to therapy that are very well tolerated and something that doesn't seem to add significant harm in terms of toxicity could be really a wonderful synergistic pair.
Russell Pachynski: Yeah, I think an important point is that as this binds to the end terminus of the AR and we've seen some of this, we need to have a larger data set but potentially can affect ARV7 and other AR variants, whereas some of the other inhibitors or degraders that bind to the C terminus might not be effective in that and we've seen that with some other compounds. I think this drug and these types of drugs that are N terminal domain inhibitors have a very promising future.
Alicia Morgans: Wonderful. Well, I really appreciate you taking the time to talk this through and of course congratulate you and your team and thank your patients for the work that you're doing on this study and we look forward to hearing future results as they come in. Thank you so much for your time.
Russell Pachynski: Great, thank you.