Maha Hussain: I want to start first by thanking Doctors, Gillison and Omlin for organizing this fantastic conference, it's really a great effort. My discussion with you today is optimal treatment sequencing in metastatic castration resistant prostate cancer.

As you know, over the last almost 18 years, there's been a tremendous progress in the management of patients with metastatic castration resistant prostate cancer, as highlighted here by the first drug to prolong survival being docetaxel. And then we've had a series of different agents targeting different pathways that have demonstrated significant improvement in overall survival, and many of these agents have transitioned into earlier stages of the disease. I think what is really important here which is a topic of this discussion, how do we go about sequencing these agents?

There are several emerging data, and I'd like to just highlight some examples based on these data. First of all, in oncology, the basic principles are two general principles, one of them is combination treatment to better attack the cancer, and the second principle is advancing active agents into earlier stages of the disease where certainly the impact on overall survival and disease control is likely to be better. So the question is, is more always better? And there are two examples of situations whereby enzalutamide and abiraterone are being sequenced and it's, I'm sorry, being combined. And unfortunately, at least the combination of the two agents together has not proven to be better. Same situation, more does not better occurred with abiraterone and the radium therapy. Now, there are also the issue of sequencing of the agents in castration resistant disease, and I'd like to share with you three different examples that I think have a potential impact on treatment.

The first one is the issue of sequencing of enzalutamide and abiraterone + prednisone in the castration resistance space. As you know, both of these agents were demonstrated to prolong survival in end stage disease, and then were moved into the first line treatment of castration resistant disease. Dr. Khalaf and colleagues and Dr. Chi really did this great trial to try to ask the question, is sequencing of these two agents of value or not? And what was interesting, is the following, is that basically giving abiraterone first and then following it by enzalutamide did better than the reverse. The question is biologically why, I'm not sure that we really have the right answer, but certainly this highlighted, at least in the context of castration resistant disease, the potential sequence of abi first then enza. The question that I think needs to be answered is, what happens if the patients have seen abi in the context of metastatic hormone sensitive prostate cancer or enzalutamide and then now they're castration resistant disease. Are they likely to respond or not? And I'm not really sure that we have a really good set of data at this point.

The second question is the issue of third line therapy, essentially. So, in patients who have seen docetaxel and have seen an AR pathway inhibitor being abi or enza, are they better off switching to another AR targeted agent or go to chemotherapy? And the CARD trial, which was reported by Dr. de Wit about three years ago asked this important questions where patients who have seen docetaxel and an AR signaling inhibitor were basically randomized to either cabazitaxel or to an agent that they had not seen before being abi or enza, and the primary endpoint was imaging based progression, free survival, and several other endpoints were also included including overall survival.

And as you see here in the blue, cabazitaxel did better when it comes to the primary endpoint to the overall survival and to the progression free survival. Again, highlighting the point here is that, it's important for us as we are managing these patients to properly choose the drugs. Now, having said this, it is not completely wrong to consider going with an AR inhibitor in situations where the patient is not symptomatic, the progression of the disease is not significant, just to give it a try to see if it helps and if not, switch. I would say in the vast majority of times in my practice, a lot of these patients are really sick, and so, one is better off going in when there's a window of opportunity by proceeding with the cabazitaxel treatment.

The other sequencing information came from the PROfound trial, which we reported as part of the overall survival data reporting in 2020, and basically this was a post-hoc analysis. As you know, the PROfound trial took patients with metastatic castration resistant disease pre-selected for their HRR mutations, and then the patients have been mostly heavily pretreated with AR inhibitors, previously, other agents including chemotherapy and so on. Not everybody had seen chemo, so the question we tried to ask, are there differences in responses and the to [inaudible] in the context of prior therapy. And we looked at three distinct groups of patients, primarily because of the availability of a good size number of these patients. The BRCA1, BRCA2, the CDK12 and the ATM. And what was interesting is this, is that in the BRCA1, BRCA2 situation, patients responded to Olaparib irrespective of prior taxane exposure. Interestingly, the CDK12 patients responded better to Olaparib if they have not seen taxane before. As you can see here, if they have seen taxane before there's hardly any response. And then the flip side occurred in the setting of patients with ATM mutations, where basically if they have seen prior taxane, they did not do as well. With prior taxane, they seemed to respond better. Again, this is a post hoc analysis, and certainly not prospectively sort of designed to address the question. But this actually can give some information as to the sequencing of treatment potentially.

Now I should point out all of what I mentioned may or may not be of relevance as we move forward. Because as you know, there have been several now frontline castration resistant disease combination trials with a PARP inhibitor and AR targeted pathway inhibitor. Two of these trials were actually reported just recently with the PROpel trial with Olaparib and the MAGNITUDE trial with Niraparib.

And just to highlight here is that the PROpel trial was not biomarker pre-stratified. So this is [inaudible] frontline castration resistant disease with the earlier report was the radiographic progression free survival demonstrating a benefit in favor of the combination arm.

And the MAGNITUDE trial demonstrated that in fact, the combination treatment in the non HRR mutated patients did not improve outcomes. This trial was actually designed nicely and that it was biomarker pre-stratified as opposed to lump sum everybody coming in. And in the cohort of patients who have the biomarker positivity, the combination did better. So the question again here is that with these two agents, if they in fact end up getting approvals and we begin to use them, what is going to be the impact on downstream if the patients progress on one of these combinations and the effect on additional therapy downstream.

Now, with all of that, of course, as I mentioned, the basic principles in oncology is advancing effective treatment into earlier stages of the disease where the potential for better impact is there. And as you can see here, this is a list of several clinical trials starting with charted and stamped and latitude, and so on. Evaluating combination treatments of either AR inhibitor or docetaxel in the metastatic hormone sensitive space, all of them demonstrating an advantage with regard to overall survival in that space. And now I want to just highlight a couple of other trials, which were recently reported. The PEACE-1 trial, which was focused on De Novo metastatic hormone sensitive disease, where it's evaluated triplet therapy. And the ARASENS which also evaluated triplet therapy.

This is the PEACE-1 data which was recently reported in Lancet and led by Dr. Fizazi and colleagues. And this is again, De Novo metastatic hormones sensitive prostate cancer, which by default, prognostically, it's a high risk group of patients who were randomized one to one to standard of care being androgen, I'm sorry, being androgen deprivation plus docetaxel. And then the patients were randomized with or without abiraterone. And then radiation therapy was another randomization. And when you look at the overall population, the radiographic progression free survival was actually significantly better with the addition of Abiratone. And this is the overall survival definitely was also better with the addition of Abiratone. So triplet therapy was better than doubled therapy.

What was interesting is this is looking at it by volume of disease, the high volume, low volume, while the radiographic progression-free survival and the low volume was better. The median has not been reached and that does not mean it has no advantage. As you know, these patients tend to do better and certainly longer follow up is needed. Clearly, there was an improvement in the overall survival in the high volume disease. Now, one of the issues, of course, that all this data will highlight together with the data I will share with you from the ARASENS trial which evaluated again, triplet therapy of androgen deprivation, docetaxel, and darolutamide versus placebo. Again, demonstrating that the triplet added advantage with regard to overall survival and other efficacy endpoint. The question comes up is what is the impact of this at the time of progression on the ability to use other agents targeting similar pathways and the setting of castration resistant prostate cancer.

Clearly additional examples are moving forward. This is just an example from a presentation I did recently looking at the fact that PARP inhibitors are also moving into the earlier stages of the disease. And specifically there are several phase two and phase three clinical trials in the clinical metastatic hormone sensitive prostate cancer. And it would be really interesting to see what the data looks like. Certainly there's a lot of science that supports the potential of benefit with these combinations.

Now, one of the things that I think is important is this. This is a slide from a presentation that Dr. Agarwal shared with me. This is from his presentation at ASCO last year. And I want to highlight one thing. I specifically selected two clinical trials that were conducted in the United States only from a consistency perspective, because they were conducted in one country and within the mechanisms of our cooperative groups. And what you'll see here, CHAARTED was one of the first trials to demonstrate that docetaxel had impact in hormone sensitive disease. This is the control arm from the CHAARTED trial with a median survival of 44 months. What's interesting is this SWOG 1216, which is a trial that combined androgen deprivation with androgen deprivation plus [inaudible] which is another CYP17 inhibitor. And what was interesting is this, is if you look at the control arm, the control arm patients have lit significantly longer, even though we're talking, they have just received basic androgen deprivation type treatment. Again, highlighting the fact that the downstream therapies that are occurring in the castration resistant disease is really impacting in a positive way on the outcome. And the question comes up is obviously as we move these agents into the earlier phases of the disease, how will the outcomes be and what are the impact of sequencing of treatment?

So the question comes back is how do we go decide and on how to best use these treatments? And I want to say revisiting clinical decision regarding castration resistant, prostate cancer in terms of treatment options in 2022. Clearly, we have several drugs that have demonstrated in overall survival benefit. And I highlighted also in read several of the drugs that actually have demonstrated an overall survival benefit either in the metastatic hormone sensitive prostate cancer or the non-metastatic castration resistant disease. So the question is, how does one go about deciding what to do? And I think there are several clinical considerations. As patients are evaluated for metastatic castration resistant disease, I think clearly the prior therapy and the hormone sensitive space and the non-metastatic castration resistance space is important to be taken into consideration. The performance status of the patient is important. Comorbidities, symptoms and how acute are the symptoms, the availability of the agents, the cost of the agents, the logistics of administration. Clearly, I think genomics have entered the space of prostate cancer, and we have to be very mindful of them because there are certainly PARP inhibitors. The use of immune therapy and so on. And additional agents hopefully will, will come. And clearly patient's preference is very important and a shared decision has to be made with regard to how best to proceed.

So in conclusion, there's really clearly tremendous progress that has occurred in the management of different advanced prostate cancer disease settings with several life prolonging therapies since 2004 and significant improvement in overall survival. The current data indicate that sequential AR targeted therapy specifically as it relates to abi and enza is not very impactful in metastatic castration resistant disease. And certainly if you have to do it and a patient has seen abi nothing wrong with using enza and seeing how that works. But the question is what about the sequence of the same end class agents and sequence in different disease settings? For example, patients might have received abi in the setting of a node positive disease or metastatic hormone sensitive prostate cancer then is enza going to work or apa or daro going to work in the castration resistance space.

Now in previously treated metastatic castration resistant prostate cancer, clearly several drugs highlighted here have demonstrated an overall survival advantage in these disease settings. Several of these drugs, as I showed you are being moved into the earlier disease setting. And the question is going to be the effect downstream on a response to same in class agents. Now moving therapy to earlier disease states has better return on investment for sure, in terms of clinical benefit. The question is how will this impact, again, response to the same in class agent or different agents downstream resistance mechanisms. And clearly what we need is well designed clinical trials to address selected focused questions regarding optimal therapy sequencing in this regard. And this is going to require actually partnership and collaboration between the academic teams, between pharma, and between the cooperative groups.

And with that, I want to thank you very much and thank actually our patients for volunteering to be part of these trials to try to impact prostate cancer. Thank you.