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Alicia Morgans: Hi, I'm delighted to have here with me today, Dr. Chris Sweeney, who is a GU medical oncologist and Professor of Medicine at Harvard's Dana Farber Cancer Institute. Thank you so much for being here.

Chris Sweeney: Great honor to be back, Alicia.

Alicia Morgans: Of course. Well, I wanted to speak with you today about a really exciting trial that you have presented at ASCO 2019, actually a plenary session. So can you tell us a little bit about your study?

Chris Sweeney: So, it's a great honor to have presented the plenary presentation of ENZAMET. This is a study of men with metastatic hormone-sensitive prostate cancer who are starting testosterone suppression, which takes away the testosterone obviously and the fuel for prostate cancer. What we've seen is that when we've added chemotherapy to those patients, there's a benefit. So in this study, we have patients who start the testosterone suppression and we stratified by whether the physicians were going to add docetaxel or not. So, in this study half that half the patients got testosterone suppression with enzalutamide and half got testosterone suppression with docetaxel and 250 got randomized to enzalutamide and about 250 got the testosterone suppression with a nonsteroidal. So in this study, it's basically standard of care, testosterone suppression plus a nonsteroidal like bicalutamide, nilutamide or flutamide versus testosterone suppression with enzalutamide and some patients got docetaxel.

Alicia Morgans: And then what percentage of patients approximately got docetaxel in addition to the hormone suppression plus enzalutamide or a hormone suppression plus bicalutamide or flutamide?

Chris Sweeney: About two-thirds of patients with high volume disease got docetaxel and so it's about, the study cohort is approximately 250 who've got testosterone suppression, docetaxel plus enzalutamide and another 250 who got testosterone suppression plus docetaxel plus bicalutamide or flutamide or nilutamide.

Alicia Morgans: Okay.

Chris Sweeney: So it's a subgroup analysis. We actually had a prespecified subgroup of interest, namely the patients who got docetaxel, especially the high volume patients. The reason for that is because we didn't power it for separate analysis, but we wanted to look at it as a unique entity. So for the overall study, we see there's a clear overall survival benefit, yes, but when we drill down, the survival benefit is clear in the patients who get testosterone suppression plus enzalutamide. But when we look at it in the patients who got docetaxel, the hazard ratio for overall survival is only 0.9 whereas it's close to 0.6, 0.5, 0.55, 0.6 for those who didn't get docetaxel.  The hazard ratio for overall survival is 0.9. Interestingly we do see a clear prolongation in time to progression of those who got ADT, testosterone suppression plus docetaxel plus enzalutamide, longer time to progression but no overall survival.

So we pre-specified this because we thought there were treatment implications and the biology would be different. Would the enzalutamide truly add to docetaxel? And so, what we found is that it would appear we need longer follow-up beyond three years to see if there's a survival benefit. But with or without docetaxel, the three overall survival is 74 and 75%. The hazard ratio is 0.9. So, we need to look beyond three years to see if there's a benefit, but right now, we can't see any evidence of a benefit (there’s a PFS benefit for the triplet but OS has not been met). So, it would suggest that patients having had ADT, docetaxel, and enzalutamide may not get the benefits, survival benefits adding to what we get from the control up front with the triplet and adding radium, cabazitaxel doesn't seem to compound upon that yet at this early data. We need a longer-term follow-up.

Alicia Morgans: Okay.

Chris Sweeney: Also we need to look at the quality of life. So hopefully that delay in that radiographic or symptomatic progression is associated with a better quality of life. So I would justify doing the triplet therapy if we showed there was an increased quality of life or prolongation of survival. We haven't seen that yet. The quality of the live analysis will hopefully be ready and presented at ESMO.

When we as physicians, Alicia, we talk to our patients, we go through the risk profile, pros, and cons. And I do think there is a degree of chemophobia out there that we need to address, but I think for patients who are high volume disease, their options are testosterone suppression with docetaxel if their chemo fit or testosterone suppression plus enzalutamide, even if they're not chemo fit or if they are chemo fit, it's an option. Now the notion of doing the triplets to having a longer time to clinical progression would make sense if there were no toxicity signals.

But we do see a bit of a signal. We actually see docetaxel related side effects are actually more pronounced when enzalutamide is added to docetaxel. We saw the same rate of neutropenic fever but we saw increase sensory neuropathy, grade two sensory neuropathy at a 9% rate with docetaxel, but it was only three with enzalutamide and docetaxel, I should say, but it was only 3% with docetaxel and the standard nonsteroidal. And that's a real side effect that would impact, I think, the clinical benefit and would count against the triplet resulting in a clinical benefit. So there is a price that we have to be aware of when we're talking. Interesting, there was more eye tearing and nail discoloration as we see with docetaxel, it was increased at a greater rate. We also have to be aware, there is the risk of seizures with enzalutamide and we saw a 1% incidence. Again, we excluded patients with a history of or predisposition but we still saw that 1% rate of seizures and we also saw with the enzalutamide alone the fatigue that comes along with that for some patients and some concentration impairment.

The study was not placebo-controlled. It was open-label so we know what patients were getting but this was ascertained by the physicians and the research teams and put into the case report form and we were able to drill out this data set. So I think the bottom line is patients who can get chemotherapy and enzalutamide or apalutamide or abiraterone should get both at some stage.

I sit with patients and I say, look, here's the side effect profile of docetaxel. You're fit for it. We'll be done in 18 weeks, six cycles, and then you don't have to be on anything. Just the testosterone suppression alone, I should say.

And that is a way of avoiding the long-term costs of daily enzalutamide, which you can be on it for three years. And also the side effects of being on enzalutamide. So there's the benefits of that docetaxel followed by enzalutamide when your PSA goes up. And we do see that the patient's on the nonsteroidal arm got a lot more life-prolonging therapy. 85% of patients got life-prolonging therapy for castration resistant disease on the standard arm.

Alicia Morgans: Very important. Yes.

Chris Sweeney: Only 4% of patients died on the nonsteroidal arm who did not get docetaxel in the hormone-sensitive or quite castration resistant and did not get a life-prolonging therapy. So only 4% of patients died with only are getting testosterone suppression on the nonsteroidal arm, the standard arm.

Alicia Morgans: So that's actually really important and for all of us to sort of think about because in many of these trials, for example, LATITUDE or in other trials, there wasn't necessarily such a high rate of getting additional therapies on disease progression and some of that we think might be where the studies were performed or perhaps the limited follow-up so that patients haven't rolled into those next therapies yet, but really important to recognize and to be aware that the investigators in these settings were actually adamantly getting patients onto their next therapy, which is so critically important when the endpoint is something like survival. That you want to make sure that you're actually understanding that these patients had those treatments.

The other thing that I think is really important is that this is the metastatic hormone-sensitive setting and your control arm actually was some form of ADT plus this additional nonsteroidal like bicalutamide or flutamide versus ADT plus your enzalutamide and both of these arms with or without docetaxel, but that control arm was more powerfully androgen suppressed than in other studies that used only standard either bilateral orchiectomy or GnRH agonists or antagonists.

So really pitting yourself against a stronger comparator, which is important. And then, of course, we added in docetaxel as well as you know, even harder to sort of meet that bar. And you found that there was an advantage to adding enzalutamide in that setting with the bar so high.

Chris Sweeney: Exactly.

Alicia Morgans: And that is really important and impressive and something that I want everyone to take away. What's not as clear from what I understand is whether the docetaxel and enzalutamide is actually an additive combination or like you said, perhaps with further follow-up, we'll find that it is, but or, like you said, perhaps it's just the sequencing of having access to both of these therapies at some point in the course of your treatment may provide similar benefit.

Chris Sweeney: And highlighting for the chemo fit patient and high volume.

Alicia Morgans: Yes.

Chris Sweeney: Not for the low volume. We don't see any evidence of benefit. Again, just want to drill that home. And also, the side effect profile has to be weighed in. So are they chemo fit?

Alicia Morgans: So can you speak a little bit more to that? So, you know we've had this high volume, low volume conversation regarding CHAARTED. There is an expected analysis in STAMPEDE using the charted definitions on the stampede data to help us again understand high volume, low volume. Is there a benefit to chemotherapy in the metastatic hormone-sensitive setting in the low volume patients? We hope and expect that analysis from stampede sometime later this year. And then this-

Chris Sweeney: They will absolutely do that-

Alicia Morgans: At ESMO.

Chris Sweeney: At ESMO, exactly. Yep.

Alicia Morgans: And so in this study, can you clarify this high volume, low volume benefit just once more.

Chris Sweeney: So, patients with high volume disease, those we prespecified and designed in CHAARTED and we use the exact same definition in ENZAMET.

Alicia Morgans: Okay.

Chris Sweeney: We find that is very prognostic for a poor outcome on testosterone suppression alone, 50% of high volume patients were alive at three years with testosterone suppression alone. We get up to about 65, 70% when we add docetaxel to those patients.

Alicia Morgans: With high volume.

Chris Sweeney: In the high volume of patients. We don't see any evidence from the study so far of docetaxel improving the survival of the low volume patients.

Alicia Morgans: The same definition as CHAARTED.

Chris Sweeney: The same definition, three or less bony metastases, lymph node only disease. So I think in the absence of genomic profiling telling us or biomarkers, old school conventional scan radiography is still a very powerful prognostic tool and it's definitely in our tool chest of how we think about what patients should get which therapies and we should use that information, I think when we're deciding which treatments to bring in. But hopefully, we'll get more advances with more advanced imaging, PSMA PET, whole body MRI. These things have to be compared until shown to be better than what we have.

I would also like to say and reiterate again, there's a really big need to get both the chemotherapy and the hormone therapy or the hormone and the chemotherapy if you're chemo fit at some stage. And it's not saying that the low volume patients shouldn't get chemotherapy for advanced disease, castration resistant. Absolutely. If they’re chemo fit, they should get it, but there is no evidence of benefits upfront.

Alicia Morgans: I sincerely appreciate you sharing the ENZAMET data with us and if you had one final message, what would it be, to clinicians who are trying to understand, now that the landscape is a little bit more complicated again. What do you do with these metastatic hormone sensitive patients?

Chris Sweeney: Sit down and have a conversation. Say to them, I see you as being fit for chemotherapy or not fit for chemotherapy. That's the first question. I see your volume of disease is high or low. Here are your treatment options. Chemo fit, high volume, testosterone suppression, and docetaxel or testosterone suppression plus abiraterone, enzalutamide or apalutamide. There's the two options. For the low volume patients, I think it's testosterone suppression plus enzalutamide, abiraterone or apalutamide. We'd have to see all the data sets laid out. That's how I think. Are you chemo fit and what's the volume of disease.

Alicia Morgans: Absolutely. So if we can break it down in those pretty simple terms for now, before we have that sequencing data, that really helps to direct us more clearly, we can have those conversations and we can hopefully get these good outcomes and that everyone over time needs to have access to all of these treatments that we..

Chris Sweeney: All the tools in the tool chest.

Alicia Morgans: All the tools in the tool chest, and I appreciate you driving that message home as well. So thank you for your time, Chris.

Chris Sweeney: You're very welcome. Thank you very much for the opportunity.