Alicia Morgans: Hi, I'm so excited to be at ASCO 2022, where I'm speaking with Professor Fred Saad about a presentation that he gave at the meeting. Thank you so much, Dr. Saad.

Fred Saad: Always a pleasure.

Alicia Morgans: Well, always a pleasure to talk with you, too. And I'm really excited to hear some of the work that you and the team did on the ARASENS data, which of course was the really nicely positive data in metastatic hormone-sensitive disease, looking at the triplet of ADT, docetaxel and darolutamide versus ADT and docetaxel, finding a survival benefit. You and the team actually did some post hoc analysis to understand which patients may have the longest disease control benefits. And I'd love to hear a little bit about your work.

Fred Saad: So obviously when we're trying to figure out prognosis and outcomes, what we usually look at is PSA response, right? I mean, I think we're all very comfortable that PSA response is a good reflection of how well or how unwell patients are going to do over time. And what doesn't really available, and this is 1300 patient study. We had the opportunity to look at how low PSA can go with docetaxel and ADT, which is, a life prolonging doublet, but looking in comparison to the triplet and seeing how many patients can we get to undetectable PSA? Which is really, I think now one of our surrogates to really achieving what we want to do.

And so what was nice is that in this analysis, we saw that patients who go on to docetaxel and ADT will get to undetectable PSA below 0.2 in only about 25% of patients. And when you add darolutamide to ADT and docetaxel, which is clearly what we want to be doing for these patients, we get up to about 67% undetectable PSA. And how does this reflect outcome? Because clearly ADT and docetaxel is one of the therapeutic options when we looked at patients who went to undetectable versus not. And this is in patients who could have gotten subsequent therapy after, when they started with only docetaxel. There was about a two third reduction in the risk of death, about a 65% reduction in the risk of death in patients who were achieved a below 0.2 versus those that did not. So really this needs to be our objective when we're treating patients with mHSPC.

Alicia Morgans: Well, and I think this is something in general is a concept that we've thought about for years. Early data suggesting, even by Maha Hussain, I think suggesting that the lower our PSA nadir was the better we would find those patients would do. And what's really striking is that 67% or so if patients with the triplet are reaching this undetectable nadir whereas we're only talking about 20% or so with ADT and docetaxel. It doesn't necessarily surprise me because chemotherapy isn't necessarily going to lower our PSA as dramatically as a targeted androgen receptor antagonist, of course. But still that difference is dramatic. And in this study, at least there was a very clear association with disease control, which is so important.

Fred Saad: Yeah. And it tells us that we don't catch up.

Alicia Morgans: Yeah.

Fred Saad: We didn't look for rPFS in this study. Our only objective was overall survival. So when patients became castration-resistant, there was no pressure on the investigator not to add another line of treatment. So really we weren't telling patients, "Stay on until you get rPFS." If PSA was rising, they had progression of disease, they were encouraged to get whatever the investigator felt was the best treatment. And even though they got early subsequent treatment in the study, the survival differences are striking. So you really need to do the very best upfront, is really the message. You don't catch up by delaying therapy. And even worse, ADT alone, we now know it's only about 11, 12% that reach undetectable PSA in those metastatic patients.

Alicia Morgans: And I think that's such an important point too, that ADT alone is not the standard of care for these patients. We really need to use intensified therapy. And clearly the ARASENS data suggests for any chemo fit patient that triplet is really going to be the way to go. Does that affect the way that you practice in clinic?

Fred Saad: Absolutely. And we're anxiously waiting for Health Canada approval for this triplet that we hope we're going to get very quickly, because when you think about it, the standard is ADT and a novel hormonal therapy or an ARSi. And so what we're actually adding is six cycles of docetaxel, which is really cheap. And so we're adding these six cycles to really make a big difference over what many would consider the standard of care. Even though chemotherapy and ADT did show very significant improvements in overall survival, the combination only makes biological sense.

And I wouldn't limit it only to the very worst patients, because a lot of these patients, even that don't have visceral metastases, or aren't the worst, what we commonly call high volume disease, need this therapy, because we know when we do just novel hormonal plus ADT, when they fail and we introduce chemotherapy at that point, the results are really not very impressive. It's very disappointing actually, when we're introducing the chemotherapy later. And I think our best approach in those patients that will eventually need it is to give it as early as possible.

Alicia Morgans: I think I've heard you say it's not whether chemotherapy ever it's now versus later, it's when.

Fred Saad: Exactly.

Alicia Morgans: And I think that message is really important for us to hear as a field, if we're not giving chemotherapy up front in the metastatic hormone-sensitive setting, it should really only be in those patients who are not going to be fit at all. And that's of course the ever never, but this is not ever never, this is when. And your data suggests that this needs to be early. And that's so important for our patients. So if you had to sum this up, what would your message be to listeners?

Fred Saad: The message is, it's a really exciting and encouraging time to be. Nobody wants to have metastatic hormone-sensitive, but I think we're able to do what we've been hoping to do for a long time, maximize the chances of very long term remissions by hitting hard, as early as possible. And I think these results are telling us that this actually works and we're mimicking what other tumor models have shown, where they give even quintuple therapy and then they can actually cure patients that are judged to be incurable. And hopefully we're getting to that state.

Alicia Morgans: I think that's a great goal, using every mechanism that we can safely put together to try to eradicate every clone we possibly can until they're all gone. That is a goal for sure. Thank you so much for your time and for your expertise today.

Fred Saad: Thanks.