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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and associate professor of medicine at Northwestern University in Chicago, Illinois in the United States. I am so excited to have here with me today Dr. Neeraj Agarwal who is a Professor of Medicine and the Director of the GU Oncology Program at the Huntsman Cancer Institute at the University of Utah in Salt Lake City, Utah. Thank you so much for being here with me today, Neeraj.

Neeraj Agarwal: Thank you for having me. It's always such a huge pleasure.

Alicia Morgans: Wonderful pleasure to talk to you too. And I wanted to talk to you a little bit about updated data on the TITAN study which really investigated apalutamide in the metastatic hormone-sensitive prostate cancer population. Can you tell us a little bit about the study just to set the stage as we think about this updated data?

Neeraj Agarwal: Absolutely. So TITAN as we know is a large phase III trial in patients with newly diagnosed metastatic prostate cancer, a state we also call metastatic castration-sensitive prostate cancer. So these patients are newly diagnosed to have metastatic disease. And these patients were randomized to receiving androgen deprivation therapy (ADT), which is a standard of care therapy or a backbone of therapy, plus apalutamide, a direct potent specific androgen receptor inhibitor, versus ADT plus placebo. This was a large study, more than 1,000 patients were randomized to one of these two arms. The dual primary endpoints were radiographic progression-free survival as assessed by the independent radiologist, who was not associated with the trial, and who was not an investigator, and overall survival. So these were the dual primary endpoints.

At the time of the first interim analysis, which was reported in 2019 at the ASCO Annual Meeting and was also simultaneously published in The New England Journal of Medicine, and also led to the approval of apalutamide later in the fall of 2019. After a median follow-up of 22.7 months, when the first interim analysis was conducted, the study met both primary endpoints. The median progression-free survival, as well as median overall survival, were both significantly improved with a 33% reduction in risk of that with apalutamide and approximately 48% reduction in risk of disease progression on death with apalutamide compared to placebo.

So we already know about these data. These data are already published. In this publication, which is published in the Journal of Clinical Oncology, what we did was to look.. to analyze the final overall survival after a median follow-up of 44 months. So after a much longer follow-up of approximately four years, we assessed the impact of apalutamide on overall survival, and what we found was very interesting. The risk reduction or improvement in overall survival was actually improved after a longer follow-up. The hazard ratio is now 0.65 favoring apalutamide, which translates into a 35% reduction in risk of death. So it was 33% with the first interim analysis, and now it is a 35% reduction in the risk of that.

I would also like to bring to your attention, that when the study was analyzed for the first time and apalutamide was shown to improve overall survival, the study was unblinded. And patients who were on the placebo arm were given the option of switching treatment to the experimental arm. So everybody was... any patient on the placebo arm who did not have disease progression who was still on the study was given the option of receiving apalutamide. And a large number of patients, almost 40% of patients on the control arm crossed over to the apalutamide arm.

We know, all of us know that if placebo arm patients or control arm patients received therapy with an experimental arm after crossing over, it attenuates the efficacy of the experimental arm statistically speaking. However, nowadays there are validated statistical tools like the Inverse Probability of Censoring Weighting (IPCW) sensitivity analysis that are available to adjust for the crossover. So we wanted to assess the true survival benefit associated with apalutamide after adjusting for a crossover of that 40% of patients on the placebo arm. And this was a pre-specified analysis in the protocol, so it was not something as an afterthought.

And I think this is the most interesting part of this project or paper and I think the most valuable information for the clinicians as well as patients. After adjusting for crossover using the standardized tool in a pre-specified manner, the risk reduction was further improved. The reduction of risk in death was improved now to 48%, almost a 50% reduced risk of that with apalutamide. And I think this is unprecedented. We have never seen this level of improvement in overall survival with almost a 50% reduced risk of death, precisely 48% with any agent in the context of metastatic castration-sensitive prostate cancer. And I think this is really fantastic news for our patients.

Alicia Morgans: I could not agree more. I think that certain patients are looking for these kinds of advances and this is a huge step forward and so important that this was substantiated in a longer-term analysis. And one of the things that you and I spoke about before we started recording was that quality of life (QOL) actually seemed to be maintained, and this was from an earlier analysis. I know you have not yet presented the updated quality of life analysis and that will be forthcoming, but at least in an earlier analysis, even when patients decided to take this intensified therapy, their quality of life was really maintained despite those extra pills that they took, and despite the concern that they might have more side effects because of intensified therapy. Can you comment on that?

Neeraj Agarwal: Yes. So first of all, it is very heartening to see the quality of the comment from you, Alicia, who I consider as an internationally recognized expert in quality of life. And I really appreciate you bringing this point up. So as you absolutely correctly said, at the time of the first interim analysis, we also reported the quality of life data. And the most commonly used validated scales such as FACT-B, European Quality, Five Dimension, Five-Level Questionnaires, Brief Pain Inventory, Brief Fatigue Inventory, all were used throughout the study and during follow-up to assess the quality of life in these patients as reported by the patients. And we did not see any deterioration in the quality of life or fatigue in these patients when we reported the data. And these data were published in Lancet Oncology in 2019. In the upcoming ASCO, 2021, we are looking forward to reporting the quality of life data as reported by the patients after a longer follow-up of almost four years. And I am really looking forward to presenting the data.

Alicia Morgans: I am definitely looking forward to hearing that data. And thank you for letting us know, of course, and ensuring that that data will be released because I think we always look for that data in addition to efficacy data as we are actually trying to make decisions in the clinic. So very, very important. So as you consider the data that you have and the data that ultimately will be released, can you let us know please what your summary thoughts are, what your messages are to the clinicians, to the patients who are trying to integrate this data and to think about apalutamide in the metastatic hormone-sensitive or castrate-sensitive prostate cancer space.

Neeraj Agarwal: So the first message, is there any reason for us to not use these very well-tolerated, very effective treatment options backed by level one evidence known to show an overall survival in not only a statistically significant fashion but also a clinically meaningful fashion. If you look at the duration of treatment with apalutamide on the TITAN Trial, that is 39.3 months, almost 40 months, that patients do not have disease progression for 40 months. I think it's beyond that, but I think the fact that they were on apalutamide for 40 months compared to the control arm where patients were on the control arm for 20 months, I think that it still tells me how effective these options are. They are maintaining the stability of disease. They are efficacious without compromising the quality of life. And I think we have no reason any more to not use these agents which are backed by level one evidence, be it docetaxel chemotherapy, be it abiraterone with prednisone, apalutamide, enzalutamide, I think we have multiple options now.

I would like to add that novel androgen receptors blockers such as apalutamide or enzalutamide definitely have an edge over docetaxel chemotherapy or abiraterone plus prednisone in my view because they do not require frequent monitoring of electrolytes or they do not require patients to come to the hospital quite as often for an infusion in the context of docetaxel or electrolyte checks, blood pressure checks in the context of abiraterone. This makes it even more pertinent during the pandemic over the last one and a half years. I have personally prescribed apalutamide for my patients and I have told them that I will see you three months after. Did we have this luxury just two or three years ago?

So I think we have these highly well-tolerated drugs, these are oral pills that give a lot of independence to my patients as far as their own care is concerned. They can go home with some bottles of pills and then they control their lives so much better than when they were receiving chemotherapy with docetaxel or abiraterone with prednisone. So I think this would be my viewpoint. I'm not saying necessarily it should be the viewpoint of everyone, but I think these agents, novel androgen receptor blockers, allow my patients to have a much better quality of life, much better survival. And there is no reason for us to not advocate for upfront intensification of therapy in our patients with newly diagnosed metastatic castration-sensitive prostate cancer.

Alicia Morgans: I completely agree. The standard of care now for the treatment of metastatic hormone-sensitive or castrate-sensitive prostate cancer is intense by therapy. That means ADT plus something, whether that's ABI, APA, or ENZA, or even docetaxel, that is the standard of care. And you make a phenomenal point that apalutamide when started in combination with ADT does not necessarily need as intensive monitoring certainly as docetaxel or abiraterone. And this particularly in the era of a pandemic can be very, very valuable both to clinicians and patients in ensuring safety and ensuring that patients get the treatment that they need even if they can't come into the clinic every few weeks to have an assessment.

So thank you so much for sharing this updated data which really reinforces the survival benefit that is instilled by apalutamide in this metastatic hormone-sensitive setting in addition to ADT, and certainly for giving us that teaser that we will very soon hopefully have the information that we need to really confirm that the quality of life of patients in that intensified setting is actually maintained despite having to take additional therapies in addition to their ADT. Thank you so much for sharing this data with us and for your ongoing consideration of sharing your expertise and your take on the data with us Dr. Agarwal. Thank you so much.

Neeraj Agarwal: Thank you very much. It's always a pleasure.