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Alicia Morgans: Hi, I'm so excited to be with Professor Gerhardt Attard of the University College of London, where we're going to be talking about how we really think about using basic biology and our advances in that space to help us understand how to best take care of patients with advanced hormone-sensitive prostate cancer. Thank you so much for being here with me today.

Gerhardt Attard: Thank you for asking me.

Alicia Morgans: Wonderful. So, you do so much work in this space, a lot of translational investigation to help us really pin down more clearly what exactly we're dealing with and what a patient's prognosis might be in this setting. Can you share a little bit about the work that you're focusing on at this point?

Gerhardt Attard: Yeah, so we split it. The question is, how can we use biology to improve our patient outcomes? And we split it in two. The first series of large experiments we've been doing, both my group and the community, is retrieving tumor samples from the several positive phase three trials we've conducted, and then extracting molecular data from those. That gives us information on the underlying biology, what pathways are overactive, what changes are present, other immune infiltrates, etc. And then we test those for associations with outcome. And that can start to tell us which signatures are driving aggressiveness, which signatures are maybe not as relevant in the trajectory of that patient's cancer.

And the second way biology can be used is to identify new targets, and clearly the well-tested path of you taking targets validated in advanced drug-resistant disease and then taking them forward, that's been highly successful. But there are other things we need to be thinking about in terms of better understanding the biology at presentation and then looking for therapeutic opportunities.

Yeah. So broadly, those are the two areas. Now you mentioned prognostic tests, and I think we do need prognostic tests. All patients should now receive a backbone of ADT, so standard androgen deprivation therapy, plus a new-generation hormonal agent. And clearly, that's going to significantly improve outcomes. And in fact, in our recent report from the final data in the STAMPEDE trial, we showed that nearly half of the low-volume patients are in remission at eight years, but there's still a significant proportion, about 30%, who die from prostate cancer. So we need to identify those patients and give additional treatments while sparing the toxicity of further treatment intensification for the patients who are in a good prognostic category. And there's the same for the locally advanced and, to some extent, also for the high-volume metastatic patients.

Alicia Morgans: I want to explore that intensification; we'll get there in a second. But I think that one of the things that the community's been so interested in as well is whether we might be able to not just spare further intensification but even deescalate to the point of using a discrete duration of systemic therapy for our patients with that lower-risk prostate cancer and perhaps even have treatment discontinuation at some point. Do you expect that this might be something that we could hone in on as well as we do this work?

Gerhardt Attard: Yes, potentially. Although I think we have a very good biomarker in PSA and the ADerm of PSA, that gives us an accurate indication of androgen receptor activity, prostate cancer activity. And there are a number of deescalation trials being planned both in the U.S. and in Europe. And those are centered generally around stopping treatment or interrupting treatment when PSA drops below 0.2. Whether we can also integrate upfront molecular data in those sorts of designs, that's up for debate. But in my mind, for those deescalation programs, PSA is offering us, well, it could potentially be a very economical and efficient way.

Alicia Morgans: I guess we will see, but certainly an area to explore as well. So when we think about intensification, and this is an area that you really, of course, are very interested in, what are your strategies, what kind of data have really supported this sort of a direction for our patients?

Gerhardt Attard: So triplet therapy, docetaxel, NHA, ADT, there are a number of trials, PEACE1, which was the French European study, and then ARASENS, both showed survival benefits for adding NHA to a backbone of ADT docetaxel. And clearly, the numerical median survivals with triplet therapy appear longer than NHA plus ADT, but there's a cost to using docetaxel. There's a clear cost in terms of quality of life. There's a study I'm very proud that STAMPEDE produced where we looked at patients who were concurrently randomized either to abiraterone or docetaxel, and as you'd expect there's an initial drop in quality of life at six months with docetaxel, but most notably it doesn't fully recover to the same scores as with abiraterone even 18 to 24 months after treatment. And we didn't meet the pre-specified significance for saying docetaxel scores were less, but they clearly look less. I think that's a big thing for patients.

And the second important point is the effect of docetaxel is heterogeneous. So we see no benefit in high-risk localized, unlike with novel hormonal agents. And there are a number of analyses that have identified differential effects by clinical factors. And I think clinically, at least in advanced drug-resistant disease, we see that as well. So I think we really need a predictive biomarker to make the best of the triplet therapy opportunity. And we're working on that and we're working together with others, especially CHAARTED, the CHAARTED trial with Chris Sweeney because we really need to pool our data sets together to have enough events and enough power, enough robustness, to confidently address the treatment effect questions. So a predictive test is challenging to identify but I agree with you, that should clearly be our primary aim.

Alicia Morgans: Absolutely. I don't think that there is currently as heated a debate as whether or not we should add docetaxel to our treatment algorithm for patients with metastatic hormone-sensitive disease, so if you could help us with the work that you're doing to predict, even in patients who might have low-volume metastatic hormone-sensitive disease who may benefit from docetaxel, this will help all of us and especially our patients, I think, make some proper decisions and better decisions for their future treatment. So as you think about all of this work and where we go from here, where do you want to go next?

Gerhardt Attard: So we are starting a new trial, STAMPEDE2, which will have three randomizations. So that's patients will be randomized to PSMA lutetium or ADT ARASENs alone, so it's triplet therapy, but PSMA lutetium versus doublet NHADT, SABR for the oligo-met, I should say PSMA lutetium we're reserving for those patients who cannot have SABR, either because of the number of METS or the technical challenges of doing that. And all these patients will undergo next-generation sequencing and those that have a BRCA alteration will be randomized to PARP inhibitor with Niraparib plus NHADT versus ADTNHA alone. And the intention over the next few years is to integrate the tests we've been discovering into that platform to prospectively validate them. So we've discussed the prognostic test, the opportunity for predictive tests, but overall we will need prospective trials where we use the test to influence the management of patients. And that's my goal for the next decade, I guess, integrate those tests and prove that we will improve patient outcome by making a decision based on that test.

Alicia Morgans: Well, I really look forward to seeing that in the future and certainly to the quality of life data that I'm sure you'll be collecting with STAMPEDE, it's a wonderful group.

Gerhardt Attard: Which you are part of. So you'll be leading on the quality of life data, so that's excellent.

Alicia Morgans: Very excited that you're including some ex-UK folks in that analysis, and I'm so excited to participate in that work and very grateful that the team from the UK is willing to involve some folks outside of the country. So as you think about this big topic of biology, of advanced hormone-sensitive prostate cancer, where we've been, the work you're doing, and where you want to go, what would your summary be?

Gerhardt Attard: So we have a clear backbone that all patients should receive, ADT novel hormonal agents. On top of that, we have populations that should receive radiotherapy to the primary, there are opportunities for additional treatments such as docetaxel. I think we've made great progress, we're now better understanding the biology and we need to translate that improved understanding into better tests to prognosticate, and then secondly to predict which treatment will work best for a patient.

Alicia Morgans: Wonderful. Well, thank you so much for sharing all of this with us today. We appreciate your time and expertise.

Gerhardt Attard: Thank you.

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