Petros Grivas: Hello. I'm Dr. Petros Grivas. I'm a Medical Oncologist at the Seattle Cancer Care Alliance and Associate Professor at University of Washington and Associate Member in the Fred Hutchinson Cancer Research Center. I'm very honored today to have Dr. Neeraj Agarwal, who is a Professor of Oncology at the University of Utah Huntsman Cancer Institute. He's also a Director of the Clinical Genitourinary Cancer Program there. He also has a leadership role in the cancer center overseeing clinical research operations there. Dr. Agarwal, we're very honored to have you. Welcome.

Neeraj Agarwal: Always a pleasure. Thank you so much for having me.

Petros Grivas: Dr. Agarwal, recently we had data from a very important clinical trial that you participated in leading, which is the TITAN trial, evaluating the addition of apalutamide, a novel androgen receptor inhibitor, to standard androgen deprivation therapy in patients with metastatic castration-sensitive prostate cancer. Could you tell us a few words about the design and the takehome message, the clinical implications, of the findings of this important landmark Phase III trial.

Neeraj Agarwal: Yes, absolutely. Before I talk about the TITAN trial, I would like to highlight apalutamide first because that was the drug of interest in this trial. So, apalutamide is a potent oral next-generation androgen receptor inhibitor. The TITAN clinical study was designed to test the addition of apalutamide or placebo to standard androgen deprivation therapy for patients with newly diagnosed metastatic castration-sensitive prostate cancer. So TITAN was a Phase III randomized double-blind study where 1,052 patients, or more than 1,000 patients, were randomized to receive apalutamide versus placebo in addition to the backbone of androgen deprivation therapy. The dose of apalutamide was 240 mg per day. The primary endpoints, rather dual primary endpoints, were radiographic progression-free survival and overall survival. Remarkably, both were met at the first blind interim analysis at 24 months of followup when the trial had barely been in 24 months of the start. The rates of both radiographic progression-free survival and overall survival were significantly higher in the apalutamide group than the placebo group, a result that led to the unblinding of the study to allow the patients in the placebo group to cross over to treatment with apalutamide.

So just to highlight that there was a 33% reduction in the risk of death, that is, overall survival, and a 52% decrease in the risk of progression or death. And both primary endpoints were met at the first interim analysis. So that's how I think the results are so impressive. Because I cannot recall a trial with a novel androgen receptor-targeted therapy in the recent past, which where both primary endpoints were met at the first interim analysis.

Petros Grivas: That's a pretty exciting study, and it's impressive we have now a number of agents that have demonstrated overall survival benefit when they're added to androgen deprivation therapy alone, and the other studies including the ENZAMET trial, the LATITUDE trial, STAMPEDE trial, the CHAARTED trial that have shown overall survival benefit in this setting with other agents like enzalutamide, of course tied in with apalutamide and then abiraterone as well as docetaxel, but I think that there was some analysis in the ENZAMET study, but we should probably not combine the docetaxel with one of those agents for now but to wait for the future. What's your take on that? Would you just choose one of those agents in that setting?

Neeraj Agarwal: That's a great question. So with these trials reporting and CHAARTED trial data out there for four years now, the first question which comes to my mind and a frequently asked question by my colleagues, especially from the community, why don't we combine or offer our patients triplet therapy, which is combination of androgen deprivation therapy with docetaxel and with either enzalutamide, apalutamide, or other drugs. And the question's answer is this is not the right time yet. Because if you look at, as you rightly pointed out, in the ENZAMET trial, almost half of the patients received docetaxel while they were receiving the trial treatment, so ENZAMET trial had this unique design where the accruing physicians had to determine whether patients are going to be treated with docetaxel or not. And once they had determined that, patients were registered, and half of the patients actually received docetaxel while they were receiving trial treatment whether on enzalutamide or bicalutamide. That was another difference in the trial, that enzalutamide was compared with bicalutamide. And results were interesting. Overall survival was met, which was the only primary endpoint of this trial. However, if you look at those patients who received docetaxel chemotherapy with enzalutamide, there was no improvement in overall survival, the primary endpoint of the study at the time of the report of the study. Is it possible that we may see some survival improvement down the line with longer follow-up? It's possible, but at least based on what we have seen and looking at the Kaplan-Meier curves, at least for now, we do not see any role of triple therapy, which is chemotherapy and a newer androgen access inhibitor at least for now.

Petros Grivas: So let me ask you this bit, Dr. Agarwal regarding your recent publication. Very impressive in the Lancet Oncology, in which you are the lead author, regarding the patient report outcomes that were generated, this very important quality of life and patient report outcomes data from the TITAN trial, tell us a little bit about the methodology used as well as the main findings and how you think they could potentially impact or not clinical practice.

Neeraj Agarwal: Absolutely. So as you mentioned, patient reported outcome has gained a lot more recognition in the recent past compared to how we perceive that just like a decade ago, because what we have realized now that with these newer therapies, it is great to improve survival, but it is also very important to maintain quality of life. As these patients are living longer, it is extremely important to make sure that they don't lose their quality of life. So the patient reported outcomes were pre-specified exploratory endpoints in TITAN. Pain, fatigue, and other aspects of patient's health-related quality of life were evaluated using wide range of questionnaires, which are very standardized, such as brief pain inventory short form, brief fatigue inventory, and functional assessment of cancer therapy for prostate cancer, also known as FACT-P. And there are some other questionnaires also, but I would like to highlight these ones for now.

And then, next important aspect was that patient-reported outcome assessments were administered frequently throughout the trial to allow regular monitoring of patient wellbeing. So assessment of pain and fatigue were offered or were administered for seven consecutive days leading up to and including the first day of each cycle during the study, and patients were coming on a monthly basis. And they were also administered at months four, eight, and 12 after treatment discontinuation. So I think I have a lot to highlight that even after patients discontinue the trial treatment for any reason, they still were undergoing assessment of patient-reported outcomes periodically. And this basically tells you how comprehensive the overall assessment of patient-reported outcomes were obtained or were done.

And I will summarize basically what we found. So when we talk about this deeper androgen blockade on top of standard androgen deprivation therapy, the first thing which comes to my mind as a clinician is fatigue. I think that ... If you asked me what is the most important side effect I'm worried about in my patients who are going to be on this deeper androgen blockade therapy for years, fatigue is the number one thing which comes to my mind and then everything else. Nothing is less important, but fatigue is most important. So I was really concerned and curious to see what is impact on fatigue of treatment with apalutamide. And the most important finding in my view from these extensive PRO assessments were there was no deterioration in fatigue in the apalutamide arm, and that's what we reported in the Lancet Oncology publication, compared to the standard therapy are no deterioration of fatigue.

So basically, while apalutamide was delaying disease progression, controlling the disease for much longer, and improving overall survival, it was also not leading to worsening of fatigue. That's number one. Number two is patient-reported health-related quality of life, and that is a more extensive assessment of pretty much every other aspect of care, and again, there was no deterioration in the health-related quality of life as reported by the patient. The scores were very similar in both arms despite these patients on apalutamide living much longer and having their disease controlled for much longer by apalutamide. Again, there was no deterioration in health-related quality of life. I think those are the two most important messages I would like to give from our quality of life patient-reported outcome assessments.

Now, there was a very interesting question by your colleague, Dr. Evan Yu, during the ESMO presentation that rashes, which are recognized side effects, although pretty rare ... We rarely see significant rashes impacting our patients when they're treated with apalutamide, but there's still a pretty discussed side effect of apalutamide. And doctor, you asked me this question, how you are assessing the rash because none of these questionnaires are really looking for or asking for rash. So first of all, my answer was rashes were extremely uncommon and grade III or IV, which basically is defined as the area of the skin, how much area is involved ... So if you look at these quality of life questionnaires, they basically ... Well, there's one question, which is how much your side effects are bothering you, so side effect bother. And it's sufficed to say that if rashes are bothering you or bothering my patients, they would be picked up, they would have it picked up by these quality of life assessment scores even though there is no direct way to ask how much area is involved in your body, but what is really interesting to me is, is my patient being bothered by the rash, and is this quality of life being affected by the rash? And answer was no.

So overall, I want to summarize, fatigue and health-related quality of life as reported by the patients were maintained in the TITAN study while patients were living longer and their disease were being controlled for longer on apalutamide. So to summarize the TITAN findings, especially with the emphasis on quality of life as reported by the patient, there was no deterioration in the fatigue and health-related quality of life as reported by the patient on treatment with apalutamide while they were living longer and their disease was being controlled for longer. And I think this is a great message overall from the study.

Petros Grivas: That's pretty remarkable, and I think you did a great job placing these findings in context. I think we need to capture more and more patient-reported outcomes, so that's a very reasonable and relevant clinically endpoint in clinical trials, so I would like to congratulate you on all your effort with your clinical research team to capture and report this data. And in that context, I would like to also thank you for being available to us today, giving us your experience and putting this data in the broader context for our audience. Thank you so much for joining us today, Dr. Agarwal.

Neeraj Agarwal: Thank you very much.