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Frontline Therapy in Newly Diagnosed Metastatic HSPC

Panelists: Judd Moul, MD, Duke Cancer Institute; Neeraj Agarwal, MD, Hunstman Cancer Institute; Tanya Dorff, MD, City of Hope National Medical Center; Alicia Morgans, MD, PhD, Northwestern University Feinberg School of Medicine
Published: Thursday, Sep 12, 2019



Transript: 

Judd Moul, MD:
I want to follow up on Tanya’s point that with regard to the ENZAMET trial. Can we talk about this issue of docetaxel possibly being better than the oral agents? I know Alicia may want to comment on that and dissect some of the data that just came out on the survival curves.

Alicia Morgans, MD, MPH: Sure. I would say it’s not necessarily a valid assessment of whether docetaxel is better.

Judd Moul, MD: OK.

Alicia Morgans, MD, MPH: I’ll put that out. It was important and really interesting. I’m keen to hear Tanya’s thoughts on this because it’s a big part of her discussion. In the ENZAMET trial, the control arm was the combined antigen blockade, and the treatment arm was with enzalutamide in addition to ADT [androgen deprivation therapy]. There was an amendment very soon after the trial opened to allow patients to receive concurrent docetaxel while they were getting these treatments, because the CHAARTED data came out, and we needed to ensure that they could continue to enroll on their trial with a treatment that was very clearly able to prolong survival in the metastatic hormone-sensitive setting.

More than half the patients in the trial, in both arms, received docetaxel. There is a group of patients who potentially had triple therapy—ADT, docetaxel plus enzalutamide, or this other agent. When we looked at the subgroup analysis, the patients who had the combination did not seem to get additional benefit from the enzalutamide. The data may not be mature yet. We’ve probably pushed that survival curve out because we’ve now increased survival in both the control arm and the treatment arm with the addition of docetaxel. In 2 or 3 years, we may see a separation of these curves and the addition of enzalutamide. The question remains whether immediate enzalutamide is important or if we could add the enzalutamide if the disease progresses to metastatic CRPC [castration-resistant prostate cancer]. That’s how I read it, because the benefit from the addition of enzalutamide seemed to be centered on those patients who did not get docetaxel. Is docetaxel essentially sufficient? Is it better than enzalutamide? Maybe it’s enough, and I’d love to hear Tanya’s thoughts.

Judd Moul, MD: That’s a great point.

Tanya Dorff, MD: Yes, I agree that while you can give triple therapy, I don’t see any data yet that show a real advantage to doing so. Christopher Sweeney of the Dana-Farber Cancer Institute did highlight that toxicity was greater from having enzalutamide added to docetaxel, compared with the older-generation agents. You’re definitely getting more toxicity, and it’s unclear how much more benefit you get, so I think the major take-home is that you can either use docetaxel, enzalutamide, ABI [abiraterone], or apalutamide.

It’s probably the exception, rather than the rule, that you would want to do a maintenance-type therapy after docetaxel. I think there’s no hard evidence that if you wait until PSA [prostate-specific antigen] is rising and start the enzalutamide at that point, you would lose ground. We can dissect all that from these data directly.

Judd Moul, MD: What I hear you all saying is that you can have that patient in front of you with newly diagnosed metastatic prostate cancer. We obviously know he needs traditional ADT. We all agree that he’s going to need either leuprolide, degarelix, or orchiectomy as his basis. Then you have the choice of 6 cycles of docetaxel or abiraterone acetate with 5 mg of prednisone-apalutamide or enzalutamide. We have that menu option. What you’re also saying is that if, after fully informed counseling, that patient chooses the docetaxel, you should generally do those 6 cycles of docetaxel and then hold off on additional therapy until they have a further recurrence. Is that it?

Alicia Morgans, MD, MPH: Continue ADT.

Judd Moul, MD: Continue traditional ADT, but the clinicians should not feel compelled to add in ABI [abiraterone] right away, or ENZA [enzalutamide] or APA [apalutamide], whether concomitantly with the docetaxel or right after those 6 cycles. Is that what I’m hearing?

Alicia Morgans, MD, MPH: I would agree.

Neeraj Agarwal, MD: Yes, although we don’t have the data to support that yet.

Judd Moul, MD: Right.

Alicia Morgans, MD, MPH: No. I would say there’s a hard no on concomitant docetaxel and enzalutamide, without the evidence of benefit, and with the demonstration of the increased toxicity from ENZAMET [metastatic enzalutamide]. I would say that’s a hard no.

Judd Moul, MD: Are there any other comments about metastatic, newly diagnosed M1 hormone-sensitive prostate cancer before we move on?

Tanya Dorff, MD: I think we would be remiss not to mention the STAMPEDE data that came out regarding radiation to the primary.

Judd Moul, MD: OK.

Tanya Dorff, MD: A lot of these patients will present without having had the prior radical prostatectomy. They’re metastatic at diagnosis. In CMP [comprehensive metabolic panel], low-volume patients did appear to have a failure-free survival advantage. It wasn’t overall survival from radiation to the prostate. I think this an intriguing and emerging question, whether or not cytoreduction of the primary is beneficial. I’d encourage people to consider supporting 1 of the many trials that are going to ask—now that we have intensified systemic therapy using abiraterone, enzalutamide, or apalutamide—is there still a benefit from looking at the primary? There’s a SWOG S1802 trial, which will allow either radical prostatectomy or radiation to the primary. It’s randomized against treating with systemic therapy only. There’s also the SIMCAP study out of the Rutgers Cancer Institute of New Jersey. I think we need to answer that question, not only for cancer control, which is obviously very important, but also for quality of life and regarding the urinary comorbidity of having that prostate primary in place.

Neeraj Agarwal, MD: I agree with you. We need to support any trial that is evaluating the role of whether primary prostate should be surgically removed. That trial is available pretty much everywhere across the country.

I think TITAN and ENZAMET will lead to the approval of apalutamide and enzalutamide in the coming months. This will allow many more patients of ours who were not able to receive intensive therapy for multiple reasons—either lack of tolerability to chemotherapy, concerns about steroids, or affordability of abiraterone—to gain access to it. I think these 2 agents are very welcome steps in this direction, and they will make it much easier, especially for urologists, to treat these patients.

Judd Moul, MD: That’s a very good point. Alicia, you get the final word on this section.

Alicia Morgans, MD, MPH: I agree wholeheartedly with what Tanya said. We do need to think about addressing the primary and having an educated conversation based on the STAMPEDE data and enrolling in trials looking at patients with metastatic hormone-sensitive disease, particularly in low-volume patients. Oligometastatic disease is another big question. There are some really exciting trials looking at that. I would say that aside from barriers like co-pay issues and comorbidities, every patient should be considered for dual therapy in the metastatic hormone-sensitive setting. That thought needs to cross every clinician’s mind. If the answer is “No, we’re not going to use dual therapy,” they need to document that, have that conversation with the patient, and know that they’ve thought about the question. I do think the standard of care now is a dual-therapy approach. It’s not for everyone, but it should be considered in everyone walking through the door.

Judd Moul, MD: Combined androgen blockade—maximal entries from blockade. Thirty years later, it’s proven.


Transcript Edited for Clarity

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Transript: 

Judd Moul, MD:
I want to follow up on Tanya’s point that with regard to the ENZAMET trial. Can we talk about this issue of docetaxel possibly being better than the oral agents? I know Alicia may want to comment on that and dissect some of the data that just came out on the survival curves.

Alicia Morgans, MD, MPH: Sure. I would say it’s not necessarily a valid assessment of whether docetaxel is better.

Judd Moul, MD: OK.

Alicia Morgans, MD, MPH: I’ll put that out. It was important and really interesting. I’m keen to hear Tanya’s thoughts on this because it’s a big part of her discussion. In the ENZAMET trial, the control arm was the combined antigen blockade, and the treatment arm was with enzalutamide in addition to ADT [androgen deprivation therapy]. There was an amendment very soon after the trial opened to allow patients to receive concurrent docetaxel while they were getting these treatments, because the CHAARTED data came out, and we needed to ensure that they could continue to enroll on their trial with a treatment that was very clearly able to prolong survival in the metastatic hormone-sensitive setting.

More than half the patients in the trial, in both arms, received docetaxel. There is a group of patients who potentially had triple therapy—ADT, docetaxel plus enzalutamide, or this other agent. When we looked at the subgroup analysis, the patients who had the combination did not seem to get additional benefit from the enzalutamide. The data may not be mature yet. We’ve probably pushed that survival curve out because we’ve now increased survival in both the control arm and the treatment arm with the addition of docetaxel. In 2 or 3 years, we may see a separation of these curves and the addition of enzalutamide. The question remains whether immediate enzalutamide is important or if we could add the enzalutamide if the disease progresses to metastatic CRPC [castration-resistant prostate cancer]. That’s how I read it, because the benefit from the addition of enzalutamide seemed to be centered on those patients who did not get docetaxel. Is docetaxel essentially sufficient? Is it better than enzalutamide? Maybe it’s enough, and I’d love to hear Tanya’s thoughts.

Judd Moul, MD: That’s a great point.

Tanya Dorff, MD: Yes, I agree that while you can give triple therapy, I don’t see any data yet that show a real advantage to doing so. Christopher Sweeney of the Dana-Farber Cancer Institute did highlight that toxicity was greater from having enzalutamide added to docetaxel, compared with the older-generation agents. You’re definitely getting more toxicity, and it’s unclear how much more benefit you get, so I think the major take-home is that you can either use docetaxel, enzalutamide, ABI [abiraterone], or apalutamide.

It’s probably the exception, rather than the rule, that you would want to do a maintenance-type therapy after docetaxel. I think there’s no hard evidence that if you wait until PSA [prostate-specific antigen] is rising and start the enzalutamide at that point, you would lose ground. We can dissect all that from these data directly.

Judd Moul, MD: What I hear you all saying is that you can have that patient in front of you with newly diagnosed metastatic prostate cancer. We obviously know he needs traditional ADT. We all agree that he’s going to need either leuprolide, degarelix, or orchiectomy as his basis. Then you have the choice of 6 cycles of docetaxel or abiraterone acetate with 5 mg of prednisone-apalutamide or enzalutamide. We have that menu option. What you’re also saying is that if, after fully informed counseling, that patient chooses the docetaxel, you should generally do those 6 cycles of docetaxel and then hold off on additional therapy until they have a further recurrence. Is that it?

Alicia Morgans, MD, MPH: Continue ADT.

Judd Moul, MD: Continue traditional ADT, but the clinicians should not feel compelled to add in ABI [abiraterone] right away, or ENZA [enzalutamide] or APA [apalutamide], whether concomitantly with the docetaxel or right after those 6 cycles. Is that what I’m hearing?

Alicia Morgans, MD, MPH: I would agree.

Neeraj Agarwal, MD: Yes, although we don’t have the data to support that yet.

Judd Moul, MD: Right.

Alicia Morgans, MD, MPH: No. I would say there’s a hard no on concomitant docetaxel and enzalutamide, without the evidence of benefit, and with the demonstration of the increased toxicity from ENZAMET [metastatic enzalutamide]. I would say that’s a hard no.

Judd Moul, MD: Are there any other comments about metastatic, newly diagnosed M1 hormone-sensitive prostate cancer before we move on?

Tanya Dorff, MD: I think we would be remiss not to mention the STAMPEDE data that came out regarding radiation to the primary.

Judd Moul, MD: OK.

Tanya Dorff, MD: A lot of these patients will present without having had the prior radical prostatectomy. They’re metastatic at diagnosis. In CMP [comprehensive metabolic panel], low-volume patients did appear to have a failure-free survival advantage. It wasn’t overall survival from radiation to the prostate. I think this an intriguing and emerging question, whether or not cytoreduction of the primary is beneficial. I’d encourage people to consider supporting 1 of the many trials that are going to ask—now that we have intensified systemic therapy using abiraterone, enzalutamide, or apalutamide—is there still a benefit from looking at the primary? There’s a SWOG S1802 trial, which will allow either radical prostatectomy or radiation to the primary. It’s randomized against treating with systemic therapy only. There’s also the SIMCAP study out of the Rutgers Cancer Institute of New Jersey. I think we need to answer that question, not only for cancer control, which is obviously very important, but also for quality of life and regarding the urinary comorbidity of having that prostate primary in place.

Neeraj Agarwal, MD: I agree with you. We need to support any trial that is evaluating the role of whether primary prostate should be surgically removed. That trial is available pretty much everywhere across the country.

I think TITAN and ENZAMET will lead to the approval of apalutamide and enzalutamide in the coming months. This will allow many more patients of ours who were not able to receive intensive therapy for multiple reasons—either lack of tolerability to chemotherapy, concerns about steroids, or affordability of abiraterone—to gain access to it. I think these 2 agents are very welcome steps in this direction, and they will make it much easier, especially for urologists, to treat these patients.

Judd Moul, MD: That’s a very good point. Alicia, you get the final word on this section.

Alicia Morgans, MD, MPH: I agree wholeheartedly with what Tanya said. We do need to think about addressing the primary and having an educated conversation based on the STAMPEDE data and enrolling in trials looking at patients with metastatic hormone-sensitive disease, particularly in low-volume patients. Oligometastatic disease is another big question. There are some really exciting trials looking at that. I would say that aside from barriers like co-pay issues and comorbidities, every patient should be considered for dual therapy in the metastatic hormone-sensitive setting. That thought needs to cross every clinician’s mind. If the answer is “No, we’re not going to use dual therapy,” they need to document that, have that conversation with the patient, and know that they’ve thought about the question. I do think the standard of care now is a dual-therapy approach. It’s not for everyone, but it should be considered in everyone walking through the door.

Judd Moul, MD: Combined androgen blockade—maximal entries from blockade. Thirty years later, it’s proven.


Transcript Edited for Clarity
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