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Alicia Morgans: Hi. My name is Alicia Morgans, and I am a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago, in the U.S. I'm so excited to have here with me today, Dr. Neeraj Agarwal, who is a Professor of Medicine and a GU Medical Oncologist at the Huntsman Cancer Institute at the University of Utah. Thank you so much for being here with me today, Neeraj.

Neeraj Agarwal: Thank you for having me. It's always a pleasure to be here.

Alicia Morgans: Always a pleasure to talk to you too. And I wanted to talk with you about some of the presentations that you've had at ASCO 2021, just this year. One of the most exciting, not necessarily for the drug and the treatment arm, but maybe for the message that this study really sends to patients with prostate cancer, is the SWOG study, SWOG 1216. Can you tell us a little bit about the study, the trial design, and what you were investigating?

Neeraj Agarwal: Absolutely. SWOG 1216 was a federally funded clinical trial, primarily sponsored through SWOG, and supported by all major cooperative groups. So Alliance, NCT, and all NCTN groups participated in this study. 1300 patients with newly diagnosed metastatic castration-sensitive prostate cancer were randomized to androgen deprivation therapy plus bicalutamide, versus androgen deprivation therapy plus TAK-700.

Just for your quick recollection, TAK-700 is a novel inhibitor of CYP's 17,20-lyase, and this is an enzyme that plays a pivotal role in the StAR [inaudible 00:01:42] production in the tumors, inside the prostate cancer tumors. And any extragonadal prostate testosterone production is mediated by this enzyme. Because of the higher specificity for CYP 17,20-lyase over CYP 17-hydroxylase, TAK-700 at 300 milligrams twice daily, does not require concurrent prednisone therapy. So this is the major advantage of TAK-700 over abiraterone, [inaudible 00:02:14].

So the primary endpoint of this clinical trial was overall survival and secondary endpoints were progression-free survival, defined as PSA progression, clinical progression, or radiographic progression, whichever occurs first, and PSA response rates at seven months. We also know from previous studies from SWOG and the CHAARTED studies, that PSA at seven months is a validated surrogate for overall survival. So we thought PSA at seven months as a secondary endpoint was also an important endpoint. This is about the design and the endpoints of the trial.

Alicia Morgans: Very important, thank you for setting that up for us. What did you find in that comparison of the TAK-700 versus bicalutamide plus ADT comparison?

Neeraj Agarwal: So let's talk about the primary endpoint of overall survival first. The median overall survival in the control arm with ADT plus bicalutamide was 70 months. The median overall survival in the experimental arm was 81 months. So there was an 11-month improvement in median overall survival in the experimental arm, with a p-value of 0.040 and a hazard ratio of 0.86, favoring TAK-700. However, these data did not meet the prespecified boundaries of statistical significance, so the trial is negative from the primary endpoint perspective.

I would also like to talk about the secondary endpoints of PFS and PSA responses. The progression-free survival was remarkably improved, in fact, it doubled with TAK-700. The median PFS in the control arm was 23 months and the median PFS in the experimental arm with TAK-700 was 47.6 months with a hazard ratio of 0.56 and a p-value of less than 0.001. Even PSA response rates were also significantly higher. We also know, like we just discussed, PSA at seven months is a known intermediate surrogate of overall survival and it has been validated in prospective clinical trials. So despite PFS and PSA responses being significantly positive, favoring TAK-700, and despite an 11-month improvement in overall survival with TAK-700, the primary endpoint of overall survival was not met.

Alicia Morgans: Yeah, and that makes sense. I'm sure it's actually frustrating, but what I think is one of the most striking things about this trial, is the survival duration for both of these arms, which seems actually longer than we think of them traditionally being, particularly, the ADT plus bicalutamide arm, than our historical survival for patients with the metastatic hormone-sensitive disease. Can you comment on that or compare it to other SWOG studies even that may have had a similar design and perhaps a similar patient population?

Neeraj Agarwal: That's a fantastic question. First of all, we're intrigued by a much higher than expected overall survival of the control arm. The original estimate was 54 months and what we saw was 70 months. So the first [inaudible 00:05:51] that came to our mind was, is it the patient population with the low volume, low-risk disease, which is leading to higher overall survival in the control arm? So we looked back and compared the overall survival of the control arm population, where the control arm received standard ADT without intensification, in different trials. Obviously, not surprising, the SWOG 1216 trial has the highest overall survival of the control arm ever reported, ever, in the history of prostate cancer medicine.

So our next thing that we did was to look at the overall risk status, whether high volume, high risk, or extensive risk, various definitions have been used in different trials. So what we did, we compared the risk stratification, the risk status, of these patients across the trial. Of course, it is difficult because every trial has a different patient population or definition of high risk and high volume, but two trials, which came very close to risk stratification were the STAMPEDE abiraterone trial and the STAMPEDE docetaxel trial. And in both these trials, the high volume patients were 48% and 41% compared to 49% in the SWOG 1216 trial. So a very comparable overall risk profile of these patients, with the caveat, that high volume definition in STAMPEDE trials is different from the high-risk patient definition in the SWOG 1216 trial but fairly similar. But then more importantly, what you just pointed out, we went back and looked at these SWOG studies because the SWOG studies in hormone-sensitive prostate cancer settings have been using a very similar definition of extensive risk versus minimal risk.

So we decided to look at these SWOG studies and one study I would like to point out, is the SWOG 9346 trial, which was reported by Dr. Maha Hussain at the ASCO 2013 Annual Meeting. For our recollection, that study compared intermittent versus continuous ADT in our patients. So if you looked at the arm which received continuous androgen deprivation therapy, and which included the earlier population, so this SWOG 9346 study actually compared intermittent versus continuous study in those patients who were doing well after seven months of ADT. So if you just take all the patients who participated in the SWOG 9346 trial, the median overall survival of the control arm was 46 months, and if you look at the risk stratification of the patients, 48% of patients had extensive risk disease.

Now, if you look at the SWOG 1216 trial, the trial I'm talking about today, the number of patients with extensive risk of disease is 49%, that is a proportion. So the SWOG 9346 trial, which was reported in 2013, and the SWOG 1216 trial, which was reported in 2021, have exactly the same number of patients with extensive risk. And now we are seeing the difference of 24 months in the survival of the control arm, which went up from 46 months in the SWOG 9346 trial, to 70 months in the SWOG 1216 trial. That is the data I am most excited about here.

Alicia Morgans: It's so impressive and so important, I think, for us to reflect back on the approvals that have happened in that time period. I think right as Maha was reporting that study, abiraterone and enzalutamide had been recently approved and certainly, uptake was ensuing and integration into our treatment algorithms. So having access to those kinds of treatments was commonplace, most likely, by the time we got to this trial, 1216. What percentage of patients in SWOG 1216 actually had subsequent therapies after progression? Because it seems like that may be a lot of the driving force in this improvement of 24 months in that seven-year period

Neeraj Agarwal: Another fantastic question. So we did look at the receipt of life-prolonging therapy after discontinuation of protocol treatment in patients who participated in the SWOG 1216 trial, and not surprisingly, 77% of patients in the SWOG 1216 trial on the control arm received a subsequent life-prolonging therapy after discontinuation of the protocol treatment on the SWOG 1216 trial. This is also the highest number of patients receiving life-prolonging therapy after protocol treatment in a given trial, in that patient population who were treated with standard androgen deprivation therapy. So I'd like to repeat, if you look at all contemporary trials, which reported in last six, seven years, this is the highest number of patients, so SWOG 1216 has the highest number of patients who received a subsequent life-prolonging post-protocol therapy.

Alicia Morgans: It's so-

Neeraj Agarwal: Which is really remarkable and it speaks about the access of these life-prolonging therapies approved in castrate-resistant prostate cancer setting to our patients in SWOG 1216.

Alicia Morgans: Absolutely, and though it did not meet statistical significance, TAK-700 did seem to improve progression-free survival, and had this trend towards this improvement in overall survival. I can only imagine, would love to hear your thoughts, if we had a more powerful agent, perhaps, in that early phase, that these numbers could be even bigger, perhaps, for that intervention arm? You are the PI who also has presented some of the updated results of TITAN, which of course integrates apalutamide into that early setting. Certainly, we can't know the answer for sure, but one might imagine, that improvement could be even greater as we've seen every time we move these really effective treatments earlier and earlier into the intensification program for patients that we might do even better when we use these novel agents in the metastatic hormone-sensitive setting when they are more active. What are your thoughts on that?

Neeraj Agarwal: Great point. So I have, as an investigator in this trial, working with patients in the SWOG 1216 and finally seeing the results after eight years of work, I have learned two lessons here. Number one, we did see an 11-month improvement in overall survival with TAK-700, and as you just said, if it was a more potent androgen receptor targeting drug, such as apalutamide for example, and just take an example of TITAN, because I had the privilege of being involved in that study as well. If we used those agents upfront, I think the survival rate will further go up, from 11 months to an even higher median absolute improvement in survival. We have not seen the data from TITAN yet because the study has not matured that much. We just presented the overall survival data in terms of hazard ratios, but patients are very interested in absolute numbers, and based on these numbers I'm seeing here with 1216, I think if we had used apalutamide in this context, I wouldn't be surprised to see even higher absolute overall survival benefit with apalutamide.

So I think there is no excuse for us to not offer any eligible patient ADT intensification today. There is no excuse out there. If a patient is eligible for ADT intensification, they should be offered it and they should receive ADT intensification. Unfortunately, that is not happening. Based on our three other abstracts we are presenting, less than one-third of patients in the United States, regardless of whether they are in the Medicare population, have commercial insurance, have Medicare Advantage, we are talking about thousands of patients of these studies. One study has 35,000 patients, being presented by Stephen Freedland and Dan George, who is the last author, and I'm involved in that study as well, we are seeing less than one-third of patients receiving ADT intensification.

So I think this is the number one message, that no one with metastatic castration-sensitive prostate cancer should not be offered ADT intensification, as long as they are healthy to receive the drug and they do not have any contraindication.

The second lesson I've learned, looking at the absolute overall survival of these patients in the control arm, which is the highest ever reported, is the importance of access to life-prolonging therapy in the castrate-resistant prostate cancer setting. There is no point having these drugs approved in the castrate-resistant setting and patients not receiving them. When we see the absolute overall survival benefit of the control arm, going up to 70 months without receiving upfront intensification, I think this is happening because these patients had access to approved drugs in a castrate-resistant prostate cancer setting. So I think we have to do two things on an urgent basis. Number one, make our colleagues, our patients. Patients are equally important because they are the ones who are making decisions in our clinic. So patients have to know about these data, about how these ADT intensification therapies are improving survival. And second, the onus is on us to make these drugs accessible to our patients.

Alicia Morgans: Absolutely. I could not agree more. So two main messages; intensification early, even with an agent that did not quite meet statistical significance can, in this case, having a trend towards improvement in overall survival. But when we use some more potent agents, our hope is that this is going to be an even more significant prolongation. Such an important piece of information from SWOG 1216 is that we are making a difference in the lives of men with prostate cancer and the survival, even in the control arm here, has prolonged to 70 months, which means that utilization of those therapies in the metastatic CRPC setting and continuing to give patients access to these treatments throughout the course of their disease can absolutely change their lives by making them longer. And according to the data, actually helping them feel better as well.

So thank you so much for taking the time and digging into this a little more deeply than maybe you knew at the beginning we were going to get into, but I do appreciate you lending your expertise, your thoughts, and congratulations to you, the team, and all of the patients for participating in this massive effort, which is really another success for the [inaudible 00:18:00] program here, the National Cancer Institute Supported Cooperative group. This one was SWOG, but with the support of all of the others, fantastic work. Thank you very much, Dr. Agarwal.

Neeraj Agarwal: I cannot agree with you more, that the role of NCI was extremely important. This was a taxpayer's funded trial. So very thankful to all patients, their family members, and of course, NCI, National Cancer Institute, for the funding.