Alicia Morgans: Welcome to APCCC 2022 where I am delighted to talk to Dr. Matthew Smith, professor of medicine at Harvard Medical School and GU Medical Oncologist at Massachusetts General Hospital. And Dr. Kim Chi, who is a professor of medicine and a GU Medical Oncologist at the University of British Columbia in Vancouver. Thank you both so much for being here with me today.

Matthew Smith: Happy to join you.

Alicia Morgans: Wonderful. So I wanted to talk with you two about triplet therapy in metastatic hormone sensitive prostate cancer and all the new data that's coming out and what the implications of that data are for our clinical practices. Matthew, can you start by sharing the ARASENS data which you presented this year at GU ASCO 2022 and also published in the New England Journal?

Matthew Smith: So happy to comment. So ARASENS was designed to evaluate the addition of darolutamide, an AR pathway inhibitor, to standard therapy of ADT and docetaxel in men with mHSPC. And the data is very clear. There's a major survival benefit in favor of the triplet therapy compared to treatment with ADT and docetaxel.

Alicia Morgans: Which is really important for all those chemo fit patients that we see in our clinics, really that triplet therapy approach seems to be very, very useful. And I wonder, Kim, in your practice, are you using that on a daily basis for patients? And if you are, which patients are you choosing to really intensify on?

Kim Chi: Yeah, that's a challenging question, because when we look at the ADT docetaxel, we saw that a lot of people didn't use it. And if we look at population based databases for example, only about 10 to 15% of people were getting intensified with ADT docetaxel. And I have to admit, my practice completely switched over to ADT plus an AR pathway inhibitor, particularly around COVID trying to keep patients out of the hospital and so on.

So the question becomes, okay, do we add on an ARPI to ADT docetaxel, which we don't even really used a lot before? So my current answer is no, I don't do it, except in the rare circumstances of very aggressive disease such as patients presenting with liver metastases, and of course also young and fit to receive chemotherapy. And that's because I question what is the value of docetaxel in that triplet? We know from the studies that AR pathway inhibitor must be given if you're giving ADT. ADT alone is not sufficient. What the contribution of docetaxel is to an ADT plus AR pathway inhibitor has not really been fully defined.

Alicia Morgans: Yeah, I agree. Certainly the study that Matthew just discussed didn't ask the question of whether docetaxel was useful or not. And so I think it's an important question certainly, and we'll dig into that in just a few minutes. But would love to hear your perspective too, Dr. Smith.

Matthew Smith: Yeah, so I certainly share the opinion that ADT alone is no longer sufficient. This has now been very well established. And I'd also say ADT plus docetaxel is no longer sufficient. So the vast majority of patients with mHSPC should be receiving an AR pathway inhibitor, and I think ARASENS and the PEACE-1 data further establish that as a necessary standard of care for the vast majority of patients with mHSPC. I think the ARASENS was not designed to address the contribution of docetaxel and it's for good reason. At the time we designed that trial, ADT docetaxel was an established standard of care. It was the first drug shown to improve overall survival in mHSPC.

Further studies would be necessary to formally establish whether docetaxel is needed in patients receiving ADT and a potent AR pathway inhibitor. But we do have some information about this topic. So in the non-randomized comparison from STAMPEDE, it appears that at least for OS, abi and docetaxel are similar in their outcomes. So, it would seem that given that they confer a similar survival benefit, that's hard to imagine that docetaxel has no role in the triplet, at least for most patients. But needs to be formally established with future research.

Alicia Morgans: Absolutely, I completely agree. I would say in my clinical practice I am certainly using the triplet as you are. You mentioned this more aggressive disease in patients with liver metastases. I personally am following the data as was presented in ARASENS, and in PEACE-1 as well, and really intensifying with the triplet in patients who have high volume metastatic disease, de novo metastatic hormone-sensitive disease, and certainly having that conversation with patients about whether that's the right choice for that individual. But because I don't know the additive value, I usually err on the side of offering and discussing the data rather than removing it from my treatment paradigm upfront. However... Sorry go ahead.

Matthew Smith: I agree with that approach. So it's not really whether, but when. For patients who are candidates for chemotherapy, for docetaxel specifically, it's not a matter of whether you'll treat them with docetaxel, it's when.

Alicia Morgans: True, true.

Matthew Smith: And I tend to err on the side of treatment, offer triplet therapy for appropriate patients. I think if I understood what you said, Kim, is that the rare presentations, say with liver metastases, that is rare, but the presentation with high volume or high risk de novo metastatic disease is not that unusual. In fact-

Kim Chi: It's the most common.

Matthew Smith: Yeah, it's the most common. Most of the patients included in ARASENS and PEACE-1 met those criteria. So for the typical patient who are enrolled in those trials, I do offer the triplet.

Alicia Morgans: Yes, and not to say that it's not common. That's the patient population where I do offer the triplet.

Kim Chi: But I guess if we look at, again, population based data, both from US, Europe, Canada, only about 10 or 15% of patients were getting ADT docetaxel when it was the only thing that we could give to intensify therapy. So should we be encouraging more ADT docetaxel or should we be encouraging the AR pathway inhibitor onto whatever you were doing? I would choose the latter route. Whatever you're doing before with ADT docetaxel or ADT alone, really the major most important to me treatment to ensure that we're adding is the AR pathway inhibitor.

Matthew Smith: We agree on that point.

Alicia Morgans: We definitely all agree. We all agree on that point. ADT alone, not the answer. We should intensify. And I think that the healthy conversation here is really around the field does not know the answer to this question and that's why we're able to debate it. And Sorry, go ahead Kim.

Kim Chi: I just want to also point out we're going to have ENZAMET data soon as well. And the initial analysis from that from the first analysis did not show a benefit of adding enzalutamide to ADT docetaxel, which is interesting. And about half the patients received ADT docetaxel. And we know that it will be presented at ASCO. The abstract titles just came out. So I think it'll be very interesting data to look at and put more into the fuel for the fire for the discussion.

Alicia Morgans: Absolutely.

Matthew Smith: Although I have to say, though, those trials are not necessary to confirm the observations of ARASENS or PEACE-1, because none of those other trials were designed to specifically evaluate that question. And the decision of docetaxel yes, no and ENZAMET was at the choice of the investigator so there could have been all sorts of unintended biases. Although I have to say I was surprised to see with the recent publication from the ARCHES data, despite the early] negative read on this issue of the docetaxel subgroup, the recent publication by Andrew Armstrong and JCO reports that the subgroup who received docetaxel also benefits from the addition.

Kim Chi: Small group of patients.

Matthew Smith: It is small, yeah.

Kim Chi: Same with TITAN. But actually, in TITAN it was the opposite. We didn't see a benefit of adding apalutamide onto ADT docetaxel, but it was only about 11% of the patients. What I do have concern about in ARCHES and TITAN is that the AR pathway inhibitors added after about six months of ADT docetaxel, so they did it after. It wasn't concurrent like in PEACE-1 or in ARASENS. And what we know is that very early on, those AR resistance mechanisms start to develop. So within six months we can start detecting AR mutations, AR amplification, within those patients. And I think the benefit of AR pathway inhibitors early on is before those resistance mechanisms are developing. So I would actually really advocate not doing ADT docetaxel and then starting AR pathway. I'd really advocate starting it right away like in ARASENS and PEACE-1. And also biologically speaking, I think that it makes more sense to do it then.

Alicia Morgans: So interesting the way that these minor changes in timing might really affect the biology. I think it's especially interesting when we think about breast cancer where there was very clearly a lack of benefit of using concurrent chemotherapy and their aromatase inhibitors. They actually have to sequence them so chemo then targeting the hormone signaling pathways, because when they used them concurrently, they were actually eliminating each other's effects. So it was really, really interesting that that's not what we see in prostate cancer.

Kim Chi: I think prostate cancer's addiction to androgens is very different, though, then breast cancer's addiction to estrogen signaling. So it's a much greater driver. If we look at the prostate cancer progression over time and the genomic alterations that occur, and we've been studying this for several years now, it all converges on androgen receptor. And so I think it's such a key driver that early treatment is better.

Alicia Morgans: Such a good message. And really that message to intensify whether we're using the triplet approach in some clinics or whether we're at least using ADT and an AR signaling inhibitor, I think that message is clear. The other message that's really clear is that if we're going to use ADT docetaxel, we should be using concurrent either darolutamide or abiraterone based on the evidence that we have today. And I'm excited that we continue to get more evidence and we'll have evidence from ENZAMET in the near future as well. So thank you both so much for having this conversation.