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Dr. Smith: Welcome to The ASCO Post Roundtable Series on Updates in Prostate Cancer. I'm Dr. Matthew Smith, director of the GU Malignancies at Massachusetts General Hospital Cancer Center in Boston. Joining me today are two of my colleagues.
Dr. Gao: Hi, my name is Xin Gao and I'm an instructor in medicine at Harvard Medical School and a medical oncologist at Massachusetts General Hospital.
Dr. Morgans: Hi, my name is Alicia Morgans, and I am a GU medical oncologist at Northwestern University, where I'm also an associate professor of medicine.
Dr. Smith: Welcome, Dr. Gao and Dr. Morgans. Today we'll be discussing recent updates in prostate cancer, including data presented at the 2021 ASCO Annual Meeting, and integrating these new developments into four patient case studies. Our first installment will focus on management of metastatic castration-sensitive prostate cancer, including data from the phase III TITAN trial. But let's begin with case 1. This is a 73-year-old man with recurrent metastatic prostate cancer. He had a prostatectomy in 2020, he is pathologic stage T3a N0, Gleason 4+4, his postoperative PSA was elevated, and then, a repeat, a year later was further elevated at 8.9. Abdominal pelvic CT scan reported a pelvic and retroperitoneal adenopathy, and bone scan showed no detectable bone metastases. Past medical history includes hypertension and elevated cholesterol. What do you recommend in this patient: ADT alone, ADT plus docetaxel, or ADT plus apalutamide, or other novel hormonal therapy? Dr. Morgans, would you like to begin?
Dr. Morgans: Sure. Thank you. So, I think in this patient, because he is clearly a patient, from my perspective, who has low-volume hormone-sensitive metastatic disease, I would really lean towards, first, combination therapy because that is the standard of care for all patients with metastatic hormone-sensitive disease. And then, I would use an intensification strategy that focuses on an AR-targeted agent rather than docetaxel. My reason for this is generally that for patients who have low-volume disease, this combination of docetaxel and ADT did not necessarily consistently seem to be really effective for patients, particularly in the start of study, even in the longer-term follow-up with that study, and for patients who really are looking for that balance between quality of life and disease control, which I think is most patients, I want to make sure that the data I have for intensification is very clearly going to help them in terms of both their disease control outcomes and their quality of life outcomes as much as possible. So that seems the best combination from my perspective.
Dr. Smith: Outstanding. Dr. Gao, you agree?
Dr. Gao: Yes, I completely agree. I think this patient has low-volume metastatic hormone-sensitive prostate cancer. He's relatively healthy overall, he doesn't seem to have too many significant comorbidities, and we know that there's good randomized phase III data now that shows that apalutamide and other novel hormone therapies added onto ADT in terms of intensifying therapy for hormone-sensitive disease is beneficial, both in terms of radiographic progression-free survival, as well as obviously, importantly, overall survival. And then, with the docetaxel, I do tend to think of that more for patients with high-volume metastatic disease as defined by the CHAARTED trial criteria, which is more for bone metastases, including at least one outside of the spine and pelvis or visceral metastases, which this patient does not have.
Dr. Smith: So, very good. Let's review some of that data. At the 2021 ASCO Genitourinary Cancer Symposium, there was a final analysis from TITAN, and that's the phase III study of apalutamide versus placebo in patients with metastatic castration-sensitive prostate cancer. The study included 1,052 patients with castration-sensitive disease and at least one bone metastases on bone scan. They randomized to apalutamide plus ADT or placebo plus ADT and followed to radiographic progression-free survival or death. And the initial analysis with 22 months of follow-up was positive, and that led to unblinding of the trial. At that point, apalutamide reduced the risk of radiographic progression or death by 52% and risk of death by 33%. And following unblinding, all the patients on placebo were allowed to receive open-label apalutamide and 40% of patients chose to do so. The update presented in 2021 with a median follow-up of 44 months showed a continued benefit for apalutamide with a reduction in risk of death by 35%.
And then, if you corrected or adjusted for that crossover, the hazard ratio improved to 0.52 or a 48% reduction in risk of death after crossover adjustment. And then, these analyses have now been published in manuscript form recently in JCO. And there's a really nice forest plot that shows a breakdown by high-volume and low-volume disease. And there's a consistent benefit in favor of apalutamide. In fact, the hazard ratio is even better in the low-volume disease than the high-volume disease. I think making a clear point that for a patient like [the one] presented in our case, apalutamide or another NHT would be the preferred form of treatment.
I was struck by one of the comments you made, Dr. Morgans, that I think you said, "All patients with metastatic castration-sensitive disease warrant intensification," but can you clarify that? Are there patients who you would treat with ADT alone? And what type of patient would that be?
Dr. Morgans: So, thanks for the opportunity to clarify, because I think there are nuances in nearly everything we do in medicine.
Dr. Smith: Sure.
Dr. Morgans: It's so difficult to make blanket statements, but the way that I phrased it really reflects the way I think about it, which is that every patient that I meet, I want to understand whether that patient can get something that I think is standard of care, which is intensification of ADT at the time of metastatic hormone-sensitive disease. There are many patients – not many, I guess I should say a subset of patients who don't meet that criteria, who do not warrant the intensification. But if you face every patient by saying, "Everyone should get this therapy, except those that I should exclude for clear clinical reasons or comorbidity reasons or for life expectancy reasons," then I think it sheds a different light so that everybody has the opportunity to get the intensification.
The patients that I typically do not intensify on are patients who are really very ill or frail, who have a life expectancy of maybe 1.5 to 2 years, or really have other competing comorbid illnesses that would make intensification perhaps worthless, because they have other heart failure issues or limited life expectancy from neurologic disorders or other reasons why they have these competing issues that would make it such that we couldn't treat them for a long enough period of time, but an intensification of their systemic therapy would actually benefit them in the long run.
There are also patients who are, for example, not chemo fit and who have such financial toxicities that they can't actually access androgen receptor–targeted therapies to intensify. And those patients sometimes choose not to intensify because of that financial toxicity. And I think we all have to make decisions for ourselves. And if you understand your options and you can't access something, that's also your choice, and there is a reasonable decision to maintain whatever it is that you need to do to continue your life. So, it's relatively few patients that I don't intensify. And facing patients by saying, "Who shouldn't I do this in?" I think is a better way than saying, "Well, who should I intensify in?"
Dr. Smith: I appreciate that clarification. I think it's a really important pivot in the field and we need to think about this differently. And I think the field has a lot of catching up to do because certainly claims-based data are saying that many patients with metastatic castration-sensitive prostate cancer are still receiving ADT alone, and we can do better. Dr. Gao, do you have anything to add about either this case or this general topic of low-volume metastatic castration-sensitive disease?
Dr. Gao: I think Dr. Morgans has covered it quite well. I completely agree with her comments about facing the patient. For the vast majority of patients, I think they would benefit from early intensification of therapy. And obviously, looking at low-volume versus high-volume disease and thinking about the question of docetaxel versus an NHT. And then, thinking about the potential toxicities that are involved with each of these therapies, they do come with different side effect profiles, and thinking about, "Is this patient fit for intensification of therapy?" Are there certain risk factors in terms of more frail patients or elderly patients who might be more prone to falls or the fatigue issues associated with certain therapies, like the antiandrogens for example, or patients with more concerning cardiac issues or hypertension, where I think more about concerns with abiraterone.
But I do look at every patient with a diagnosis of metastatic hormone-sensitive prostate cancer. And I think about intensification as the default. And then, if I have certain concerns about comorbidities, frailty, those kinds of things, and, certainly, financial toxicities that do come up from time to time, then we make that call.
Dr. Smith: Very good. I agree. So, thanks to both of you for those comments. And with that, I'll conclude with a few clinical takeaways that are derived from this case and the faculty comments, for most patients with metastatic castration-sensitive prostate cancer, ADT alone is no longer the standard of care. And as you've heard from both of our faculty members, really it's intensification of systemic treatment that should be the starting point for our patients. The addition of docetaxel or a novel hormonal therapy, either abiraterone acetate, enzalutamide, or apalutamide, improves progression-free and overall survival compared to ADT alone, these are compelling and consistent data. And for those patients with low-volume or low-risk mCSPC, there is strong evidence, level one evidence, that the addition of an NHT to ADT improves progression-free and overall survival.
This brings us to the end of the case. Please see the other segments for further discussion about the latest data in prostate cancer or visit ascopost.com.