Apalutamide Improves Overall Survival and rPFS While Preserving Health-Related Quality of Life in Metastatic Castration-Sensitive Prostate Cancer (mCSPC) - Neeraj Agarwal

June 3, 2021

The TITAN Study is the pivotal phase III trial demonstrating the benefit of apalutamide in mHSPC.  At the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Neeraj Agarwal, MD, presented the health-related quality of life (HRQoL) data from this final analysis after cross-over from the phase III TITAN trial. In this conversation with Alicia Morgans, MD, MPH, he highlights this data. TITAN is a pivotal phase III trial demonstrating the benefit of apalutamide in metastatic castration-sensitive prostate cancer (mCSPC). In the primary analysis at 22.7 months median follow-up, treatment with apalutamide improved overall and radiographic progression-free survival while preserving the health-related quality of life (HRQoL). In TITAN, survival benefit with the addition of apalutamide to androgen deprivation therapy (ADT) was achieved without significant patient-reported side effect burden or reduced health-related quality of life compared with placebo in patients with mCSPC with a 48% reduction in risk of death if you account for a crossover of the placebo patients.


Neeraj Agarwal, MD, Professor in the Division of Oncology, Department of Medicine, at the Huntsman Cancer Institute (HCI) at the University of Utah School of Medicine. He is the Huntsman Cancer Institute (HCI) Presidential Endowed Chair of Cancer Research, and the Director of the Genitourinary Oncology Program, Dr. Agarwal also serves as the physician-scientist and senior director of clinical research innovation at HCI, Salt Lake City, Utah

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi. My name is Alicia Morgans and I'm a GU Medical Oncologist and an Associate Professor of Medicine at Northwestern University in Chicago in the US. I'm so excited to have here with me today, a good friend and colleague 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 to talk about your recent presentations at ASCO 2021.

Neeraj Agarwal: Thank you very much for having me. It's always such an honor.

Alicia Morgans: Great, thank you. Well, I wanted to speak with you in this video specifically about the TITAN quality of life data, which is so important as we have recently learned the updated survival data, suggesting that TITAN continues to show quite an improvement in overall survival with the combination of that ADT apalutamide intensified strategy versus ADT alone in the metastatic hormone-sensitive patient population. And when you adjusted for some crossover, some actual use of apalutamide in those patients who at the interim analysis were still on the placebo arm, really we saw that this benefit was one of the strongest that we've seen across all the studies in metastatic hormone-sensitive disease.

Despite that, what is complex, I think is that the intensification strategy in the metastatic hormone-sensitive space is not always the one that we see in practice. And multiple studies, including some that you yourself have done, have actually suggested a significant underutilization of intensification of therapy. In this abstract, I think you are giving us a reason why we don't have to be necessarily so afraid of that underutilization. Can you tell us a little bit about the quality of life data and what your thoughts are on how patients are actually faring when they're getting treatment?

Neeraj Agarwal: First of all, wonderful introduction on why we did the study. Thank you very much for doing that. As we know, TITAN was a phase three, large, really large, phase three trial with more than 1,000 patients with newly diagnosed metastatic castration sensitive prostate cancer who got randomized to ADT plus placebo versus ADT plus apalutamide. In the recent final overall survival analysis, we reported a 35% reduction in risk of death and if you account for crossover from the placebo arm to the apalutamide arm, 40% of patients did that, a 48% reduced risk of death with apalutamide. We had not seen this intensity, this magnitude of overall survival benefit with any drug until now. Still, as we presented in the ASCO 2021 meeting, multiple data sets, thousands of patients were included in those studies. ADT intensification is used in less than one-third of patients.

It's such a disconnect. We are seeing on one side, multiple trials showing a massive survival benefit. And for a medical oncologist, we are used to three months, four months of survival benefit, and we are now seeing survival benefit of two years. And then on another side, we are not seeing this ADT intensification being utilized in the vast majority of patients. And I think it is because of the concerns in the minds of doctors, as well as patients about the long-term side effects of these drugs, how deeper androgen blockade is going to affect the quality of life of our patients. And that was the topic of presentation in the context of the TITAN trial.

We looked at health-related quality of life as reported by the patients without interference by doctors and the medical provider teams. We used brief pain inventory, brief fatigue inventory, and FACT-P, functional assessment of cancer therapy, prostate, which are all very validated scales to measure this quality of life. And I must tell you, I feel a little nervous about talking about the quality of life in front of an internationally recognized quality of life expert, you Alicia. Pardon me if I misspeak something here, but these are very validated scales. Wouldn't you agree, to the assessment of the quality of life?

Alicia Morgans: Absolutely. And used in multiple studies and really actually quite good at capturing I think quality of life, particularly in the metastatic patient population. I completely agree.

Neeraj Agarwal: Okay. Thank you. I feel better. So what we did was we looked at a longer follow-up now, the follow-up on TITAN was 44 months. We are getting close to four years of follow-up. And when we saw this significantly improved overall survival benefit, we looked at the quality of life as assessed by these scales with a longer follow-up. And we did not see any deterioration in the quality of life. In fact, 86% of patients on the apalutamide arm reported, not bothered, not a bit bothered or only a little bit bothered by the side effect of apalutamide. The fatigue was not worse in the apalutamide arm versus the placebo arm. So I think these data are so telling, we are seeing a very dramatic improvement in overall survival benefits and we are not seeing a deterioration in the quality of life or fatigue. Very good news overall, in my view.

Alicia Morgans: Absolutely it is. And I agree with you that this is one of the barriers I think, to intensifying therapy in our clinical practices. And as I tell patients, the majority of side effects that they experience are actually related to the backbone of treatment, the backbone of androgen deprivation therapy, and thankfully the addition of these oral agents, like apalutamide on top of that does not seem to necessarily add to their burden substantially. From your perspective outside of the trial perhaps, but even in your clinical practice, is apalutamide well tolerated in patients that you see? And how about things like rash and thyroid? Are those things that seem to impact patient's lives or in accordance with the quality of life data reported here today, does it seem to be actually pretty manageable from your perspective?

Neeraj Agarwal: Very good point. I'm so glad you asked this question. First of all, the side effect bother includes rash.  These questionnaires are automatically very spontaneously capturing every single side effect, including rash. If we look at the rash, which is grade three and four, which are happening in a very small number of patients, we are talking about single-digit numbers, depending upon how you look at the rash and intensity of rash. Less than, you're talking about around 5% or fewer patients experiencing that kind of symptoms. And more importantly, I would like to emphasize that half of the time, I'd say more than 90% of the time in my personal experience, and I've used apalutamide for five years now, all we have to do is to discontinue the drug for seven days, to hold the drug not discontinue, hold the drug apalutamide for seven days and restart at the same dose and patients don't have any rash or recurrence of the rash.

In a very small number of patients, we have used topical steroidal ointments, which are so commonly used in the context of tyrosine kinase inhibitors. If you look at the kidney cancer, the bladder cancer patient population, we use the steroidal ointment so commonly in the context of TKIs, compared to that, I think we do not use, we don't need topical steroids in these patients. So overall, not bad at all.

Alicia Morgans: Well, thank you for sharing that experience and that guidance, it is very, very useful. So as you think about this presentation and certainly the importance of the patient-reported data in supporting the intensification strategy that we have for metastatic hormone-sensitive disease, what would your take-home message be to the audience after presenting this year at ASCO?

Neeraj Agarwal: The final message from me from the TITAN data is that apalutamide significantly improves overall survival with a 48% reduction in risk of death if you account for a crossover of the placebo patients, placebo arm patients, without compromising the quality of life, without worsening fatigue. And I think this is great news for our patients.

Alicia Morgans: Well, thank you so much again for sharing your expertise. And of course, congratulations on another fantastic presentation and a wonderfully done trial. Thank you to you, your patients, and to all of the investigators. We appreciate your time and your efforts.

Neeraj Agarwal: Thank you, again.