Maha Hussain: So thank you very much for the opportunity and I want to actually thank Dr. Gillessen and Dr. Omlin for the opportunity here. I want to point out I wore blue so just notice I was a good girl so there. My topic is going to be dealing with the non-metastatic castration-resistant prostate cancer and I want to just highlight that this is not going to be a debate about "is it really non-metastatic?" because we all know they have micro-metastatic disease. So that's really the point. Here's my disclosure. They were asked us to do the pro and con and this is, I'm going to be the pro. Tia will do the con and this is from a birthday celebration from about a hundred years ago.

Let me begin with the general background and I know some of this stuff might be duplication of what Howard just presented, but I would say up until early 2018 the non-metastatic castration-resistant prostate cancer was an area of unmet need and there were really no approved therapies and all of us in clinic used different types of drugs, none of which really had an impact.

In 2011, the FDA convened an oncologic drug advisory committee, ODAC, panel. Some of us, myself, Howard, I think, were on that panel to look at endpoints in different settings of prostate cancer and one of the areas that actually was discussed was the non-metastatic castration-resistant prostate cancer and the feeling of ODAC was that the transition from non-metastatic, so clinically non-metastatic to clinically metastatic is a very relevant event and that metastasis-free survival is a reasonable endpoint to consider in clinical trials. ODAC also basically stressed the importance that we really need to see substantial magnitude of improvement with regard to the metastasis-free survival with a favorable benefit to risk ratio and then following that as a reference to another ODAC session that I happened to be on also, reviewing the denosumab data from Dr. Smith and colleagues in the non-metastatic castration-resistant disease and the overall verdict of the ODAC meeting. The vote was not to approve the drug primarily because it was felt that a median of four months of only metastasis, bone metastasis-free survival, is not a favorable thing balancing benefits of risk.

Howard, also Dr. Scher, I'm sorry, mentioned some of the critical prognostic factors that we were aware of and we are aware of right now and that is in this population development of clinically positive metastases by conventional imaging is something that happens with time, if the patient lives long enough, and it is associated with increasing baseline PSA and a doubling time of less than 10 months, and the median bone metastasis-free survival is roughly about two to two and a half years. Mind you, this is bone metastasis. It doesn't reflect on other soft tissue disease and I think you could see this very clearly highlighted in here. One of the critical issues, of course, is the PSA doubling time and that's not really a surprise. It's essentially a reflection on the aggressiveness of the disease.

So why focus on non-metastatic castration-resistant disease? I would argue that this is a window of opportunity. Lower tumor burden may portend for better and more durable responses. I would say the basic principles in oncology is advancing effective treatments from end-stage disease all the way to even the adjuvant setting. So this is really not like an unusual sort of approach in terms of investigating in clinical trials. I would say specifically in prostate cancer, what is very clear is that advancing systemic therapy earlier has a greater return on investment, so to speak. If you think about it, of any of the drugs, and I just for sake of time did not include abiraterone, but if you look at enzalutamide in post-Taxotere®, pre-Taxotere® metastatic hormone-sensitive disease and as we'll show the data for it and it's other drugs. In the non-metastatic castration-resistant disease, the magnitude of benefit gets bigger and bigger and that's really not a huge surprise in here. I would argue that having metastatic castration-resistant disease is not a good thing. It's a deadly disease. So delaying time to all metastasis is clinically relevant with potential to delay cancer-related morbidity and prolong overall survival.

So these are the three drugs and I am for sake of time not speaking about abiraterone and I know Dr. Scher made a reference to it. So, enza, apa, and daro, but all of these are second-generation anti-androgens. They target the androgen receptor at three key points. The difference, if you look at sort of the chemical structure of enza and apa, they're very comparable to each other. Darolutamide looks different. It's structurally distinct from apa and enza and it's characterized at least by the low blood-brain barrier penetration, which may be a positive thing or it may not be because you could think of dural disease and meningeal disease and is that a plus or not? But certainly in terms of the side effects.

Now again, for the sake of time I am not going to put the designs of every trial. I'm just going to give you a brief summary of these trials (SPARTAN, PROSPER, ARAMIS). So three randomized placebo-controlled blinded Phase III trials were conducted. They were specifically with conducted in patients who have M0 disease. Some of the trials allowed pelvic lymph nodes and this is a topic for discussion I think in terms of how we move forward. Essentially there was a central radiologic review of the baseline scans and then evaluation also by independent blinded radiologic reviewers. The trials were designed similarly. They're two to one design and they focused on a higher risk patient population, which is the patients with PSA doubling time of 10 months or less.

I just, I don't know if you could see it here, but I wanted to just highlight few things which is that even though the criteria was a doubling time of 10 months or less, the medians actually were a lot shorter. So it's about just under five months in the apa trial and the daro trial and it's under four months actually in the enzalutamide trial. So you're talking about picking up patients who have really serious disease, rapidly progressing disease. The other part is this, is while we talk about non-metastatic, in reality, some of the trials actually allowed patients with pelvic lymph nodes, again to highlight that these patients were actually sick and had significant disease.

So this is the outcomes and I guess if you don't read the top and the bottom, this looks almost comparable to each other. In reality, both apa and enza resulted in a 70% reduction in the distant metastasis or death, somewhere about 60% for the darolutamide. Really, what I would call an unprecedented impact with regard to development of metastasis in there.

One of the biggest issues is what about other endpoints? Just for the sake of time, I'll go through this quickly and I will refer you to the original publications basically on just about every front of a secondary endpoint. These endpoints were met and there was a benefit in favor of the treatment. And the other thing I want to highlight is really at the end of the day you also worry about overall survival and what you see here is that the curves actually are beginning to separate and this is the data here for also for the ARAMIS trial. This data I should point out are not mature yet and it will be interesting to see the follow-up.

I will not go into details with regard to the side effects. I'm almost there. With regard to the side effect, I would say there is no treatment that has no side effect. So at the end of the day when you look at the profile of the side effects, they're really overall reasonably safe to administer minding that you have to really carefully select your patients with regard to certain concerns. But I would say overall the treatment was very well tolerated and at the end of the day in situations where you're worried about quality of life and someone who's asymptomatic, especially if you cannot make them live longer, the least you can do is actually not make them live worse.

So the quality of life, and this is data that was published by Dr. Tombal recently, highlighting again that it relates to FACT-P and then health-related quality of life. If anything, and this is blinded, actually the benefit was in the treatment arm. In this case it was the enzalutamide and quality of life did not go down and downstream effect with regard to health-related quality of life, if anything actually was getting better.

So in conclusion, in men with non-metastatic castration-resistant prostate cancer and a rapid PSA doubling time, enza, apa, and daro resulted in a clinically meaningful and statistically significant reduction in the risk of developing metastatic castration-resistant disease. I'd say the treatment was overall very well tolerated. The FDA approval for all three drugs, by the way, is not restricted by doubling time. I would say the basic principle behind this, I think similar to the abiraterone situation from LATITUDE is that absence of proof is not a proof of absence and therefore at the end of the day, it's a shared decision between physician and patient with regard to risk-benefit that must be really taken into account when prescribing treatments. I would say future directions is, again, we talked quite a bit about the role of better imaging, but I would say really the future direction. This is a window of opportunity to build on this treatment and novel multi-targeted combination therapy with the intent of intensifying therapy, then de-intensifying and possibly stopping treatment is certainly an option and I would love for clinical trials to be pursued there. Thank you very much and welcome to Chicago in the summer. Thank you.