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Dr. Charles Ryan: I'm delighted to be joined by Fred Saad, friend and colleague. Fred is the Professor and Chair of Urology at the University of Montreal, where he is Director of the GU-Oncology program. So, another exciting ASCO, Fred. Tell us a little bit about, you've got two things going that are important to talk about. One is quality of life for patients treated with apalutamide. And the other is some really intriguing data that we're seeing now with the combination of abiraterone and olaparib, and that's being presented here. So, why don't you summarize that data and we'll talk about its implications.

Dr. Fred Saad: So obviously, there's been a lot of excitement over the last couple of years of what to do in patients that develop resistance to first or second line therapies. PARP inhibition has been really the forefront of one of the ways of being able to tackle these patients. So, the study of abiraterone and olaparib was done in the sense of seeing if the combination would be better than the single agent approach for patients. The study that's being presented here is in the post-docetaxel setting, so patients had not gotten prior novel hormonal therapies. So, patients are randomized to abiraterone plus or minus olaparib. Obviously, we wanted to have patients with DNA repair defects involved, but there was really no selection. 

A little bit to our surprise, and something that we need to explore why, we saw the same amount of delay and progression-free survival in the patients that had repair defects, compared to those that didn't. It's intriguing as to whether we absolutely have to have a DNA repair defect and that needs to be validated.

Dr. Charles Ryan: So, to be clear, this was patients abiraterone plus olaparib compared to abiraterone alone. And you had a group who had DNA repair defects versus none. Now did those how had none have zero DNA repair defects or were they just not the most common ones or what was the sequencing result from those patients?

Dr. Fred Saad: So the difficulty we do have in the real world is that many patients don't have enough tissue to be able to analyze. So, a lot of them are either unknown, and the ones that are able to be analyzed are oftentimes negative. We have assumed that these patients are unlikely to respond to PARP inhibition. But the concept of combining, whether combining, and there is some pre-clinical data that might suggest that by giving a drug like abiraterone, you might actually help to become responsive to PARP inhibition. So this is something, it's a phase two. It's a proof of concept that needs to be validated, but it's very intriguing and presentation I think is going to generate interest.

Dr. Chuck Ryan: Well scientifically, the androgen receptor participates in DNA repair.

Dr. Fred Saad: Exactly.

Dr. Charles Ryan: And so, inhibiting the androgen receptor may cause a transient or semi-transient defect in DNA repair and thus, blocking PARP could have an enhancing effect on that. So it's very plausible. There's a scientific rationale, obviously for this to be looked at. There's a couple of prior studies that are probably worth talking about though.

One is the paper from Maha Hussain, who looked at patients with DNA repair defects, and showed that they actually had a favorable response to abiraterone, which is a bit of a surprise. It was a little bit at odds with what Kim Chi has shown using self-read DNA in the Vancouver experience. And then the other was the TOPARP study in which they clearly showed that selection of patients really did matter. 

Dr. Fred Saad: Absolutely.

Dr. Charles Ryan: For olaparib alone, right? What you're getting at, I think is something maybe to this combination that olaparib didn't have.

Dr. Fred Saad: Right. And whether it's synergistic or additive, it's interesting. Because obviously there is some response, and I don't think anyone would suggest that if you know their status, that you should never give them a drug like abiraterone or enzalutamide. But whether or not some patients that don't have the biomarker deficiency that we know of today, because we're still learning what biomarkers are most informative, I think is going to change maybe the way we view patients, - but also the way we might have to design studies.

Dr. Charles Ryan: Right, right. So really interesting data. Now just a little bit, your data's mostly in a PFS as the endpoint?

Dr. Fred Saad: That's right.

Dr. Charles Ryan: Suggesting that there's a longer PFS in the abiraterone and olaparib combination in unselected patients.

Dr. Fred Saad: Exactly. 

Dr. Charles Ryan: Differences in PSA response rates, differences in other readouts?

Dr. Fred Saad: Nope, no real significant difference. But that was the primary endpoint. It was really looking at radiographic progression, free survival, and that was attained even though it was a relatively small study. And that's why I'm cautiously optimistic that we need to confirm these things. I think we shouldn't jump the gun and start saying this is the new standard. Clearly, there are a lot of phase threes that are being done now. We need to try to see how we can answer that question.

Dr. Charles Ryan: Right. Great. So really interesting data. I'll be eager to see the presentation and review it myself. Let's switch and talk to another area that you work a lot in, which is quality of life analysis for patients with CRPC. You have taken on the task of looking at quality of life in patients on the SPARTAN study, which of course was apalutamide versus placebo in non-metastatic CRPC patients. What are the results and what do you think of them?

Dr. Fred Saad: So, in a nutshell, the results are what we had hoped. We were taking patients that are well, obviously asymptomatic, no meds, feeling perfectly fine. And what we like to do is prevent or delay the appearance of metastatic disease that clearly is related to morbidity and eventual mortality. But what we don't want to do is affect patient's quality of life because they can stay in that non-metastatic state for quite some time.

So it was very important to build in a quality of life component because we know the adverse events. And the adverse events are as expected. There are patients that will develop fatigue, hypertension, other issues. But health-related quality of life brings that all together. How impactful on their daily life were these adverse events? So sometimes people get very excited on adverse events, but how bothersome are they?

How do they affect your daily living? And we were very happy to see that really we saw no difference between the placebo arm and the apalutamide arm. And if anything, over time, the placebo arm seemed to be doing worse. Maybe the first signs of progression that we eventually document radiographically, so it was very, very interesting and the paper should be coming out very soon.

Dr. Chuck Ryan: We've had a couple of conversations on Urotoday and in other venues about non-metastatic disease and about how really there's shift in mentality now. It used to be that in metastatic CRPC, it was about a trade-off in that you had a progression-free survival benefit and overall survival benefit, but that would come at a cost. A cost of toxicity. Now in the non-metastatic setting, where by definition, you have an asymptomatic group of patients who generally are living well, the tolerance of a cost is much lower. In other words, we want to have therapies that control cancer and help us to live life to the fullest and not deal with side effects because it wouldn't take much for the side effects to be worse than the disease in non-metastatic disease, right? So now what you're saying is that this does appear to be happening, which is that cancer control is achieved with normal maintenance of daily living and quality of life. That's really exciting to hear.

Dr. Fred Saad: And it's key because obviously none of us want to be affecting a patient's quality of life that was good coming into. When we look at the baseline quality of life for these patients, they're actually very similar to even non-cancer patients of the same age. We've lived this with just ADT, trying to make sure that we don't over treat patients where we affect their quality of life and even sometimes their morbidity with our treatments. But these are high-risk patients. We need to stress that the apalutamide and the enzalutamide study with PROSPER and SPARTAN are in these high-risk patients that most of us, and you're doing a lot of PSMA, probably are micro-metastatic. So these patients are really destined to suffer from their disease and we need to be proactive in those patients.

Dr. Charles Ryan: The other conversation about non-metastatic disease, of course, is when do we start therapy? Yes, we can identify those patients who are at high risk. If you identify a patient with a rapid PSA doubling time, do you personally feel compelled to start them on apalutamide or do you wait, and how are you thinking through that question?

Dr. Fred Saad: It's coming back to years ago with the ADT story.  I think we have tools to help us determine who's at risk of suffering and eventually dying of the disease. PSA doubling time really is, probably, our best predictor of outcome and the patients most likely to benefit and need the treatments that we have. And it makes sense, even in the metastatic study that you led. When we look back, the patients that had the most benefit were the earlier patients.  Less metastases, lower PSAs, no symptoms.So this is just taking that logic one step back.

So in my mind, these are low volume, metastatic diseases that by conventional imaging we're not able to see and we call it MFS. But honestly, I think it's PFS that we're doing. We're preventing-

Dr. Charles Ryan: It's a subtype of PMS, yeah.

Dr. Fred Saad: We're delaying a progression of a disease that is there. High PSAs, rapid doubling time, is a reflection of the biology.

Dr. Charles Ryan: Yeah. I want to repeat something you said because I think it's really important. When we looked at the abiraterone data and we're seeing it now in other settings as well, it's not only that lower stage patients live longer, because that's intuitive, it's that they have a greater benefit of a therapy compared to the control arm. Treatments are just more likely to work. We had a nice conversation with Gert Attard about treatment mediated selection pressure and how mutations are acquired over time, AR amplification is acquired over time. So, biologically, we are treating a simpler cancer when we treat a lower stage disease. And maybe that's the argument that's going to carry the day, about whether we should start treatment earlier. Because obviously there's a cost, a financial cost, to starting therapies earlier on. But if we're treating a simpler, less biologically complex or mutated cancer, and the benefits are going to be greater by earlier starting, we should do that.

Dr. Fred Saad: Absolutely.

Dr. Charles Ryan: And we just finished a nice conversation also about adjuvant and neo-adjuvant and early relapse data in the setting. I think that this is all sort of pointing us in one direction, saying that earlier disease biology's a very targetable condition.

Dr. Fred Saad: Yeah, and like you say, the biology of the disease with lower volume, we probably have more hormone responsive... clones that are going to do well. And when you wait too long, it allows the disease to develop resistance mechanisms that hormonal therapy might just not be enough and this is where maybe the addition of PARP inhibition, other combinations, might be necessary in a higher volume disease. But in lower volume, clearly there seems to be a huge benefit in delaying. What we do here, what are we going to do when these patients progress? That is something that we'll deal with. As long as we're really improving the time without disease, improving long-term outcomes, well we'll deal with that. But this shouldn't be a reason to withhold therapy of worrying what we're going to do when they become resistant. 

Dr. Charles Ryan: That's a really important point. We have evidence that heavily pre-treated disease results in worse biology. But that is not the same thing as saying that earlier treatment results in earlier aggressive disease.

Dr. Fred Saad: Absolutely.

Dr. Charles Ryan: Two very different points. People conflate that two issues all the time. It's a good question, but we have no data to show that early apalutamide or early abiraterone results in worse outcome. In fact, we continue to show that results in better outcome.

Dr. Fred Saad: And that's PFS 2.

Dr. Charles Ryan: Exactly.

Dr. Fred Saad: That was the intent of PFS 2, that even though you introduce early abiraterone in the placebo arm, you never come close to catching up to those who started early. And so we'll deal with that. That is going to be a whole area of research that'll keep us all busy, is what is the best approach? And that's where people like Gert, yourself, others that are working on trying to understand the disease that we're creating, to better personalize what we need to do for those patients.

Dr. Charles Ryan: Yeah. Well, it's always a pleasure talking to you. I always learn something new or get a new perspective on new data. So thank you so much for joining me today, Fred.

Dr. Fred Saad: Thanks for having me Chuck.