Prostate Cancer - Episode 3

Case 1: Initiating Patients on AR-Targeted Therapy in nmCRPC

November 19, 2019


Neal Shore, MD, FACS: Here we have these 3 trials—the SPARTAN, the PROSPER, and the ARAMIS trials—which had endpoints of metastasis-free survival [MFS] and effectively showed similar trial designs. These were patients who had to have nmCRPC [nonmetastatic castration-resistant prostate cancer] with PSAs [prostate-specific antigen levels] greater than 2 [ng/mL]. They had doubling times of less than 10 months, showed this MFS endpoint of about 2 years, and had hazard ratios of about 0.3, 0.4. And so, with the near 2-year delay to metastasis-free survival—survival data, still we’re waiting to get that—I guess the next question I would have for you to all weigh in on is: You have this patient. The doubling time clearly fits the trial inclusion/exclusion criteria for these 3 global trials that were all published in theNew England Journal of Medicine. So, obviously really well done, great data. Is there ever an indication to now not start a patient who has an ECOG [Eastern Cooperative Oncology Group] performance status of 0, assuming accessibility, on 1 of these 3 drugs? And if yes/no, how do you make your decisions?

Jorge Garcia, MD:I think that one of the challenges that we’re facing with this patient population, Neal, is the fact that when we made the decision to initiate ADT [androgen deprivation therapy] by virtue of his rising PSA, automatically that actually allows you to keep following the patient and allows you to make treatment decisions in the future. It is very hard for you to tell a patient, right now, when they are developing M0 CRPC, to wait, because you already made that decision to put them on ADT. If the question before was, the timing of ADT is controversial, but I’m going to do it because of the features of the disease, the doubling time for after surgery, how can you justify telling that patient that you’re going to wait until they develop metastatic disease? That is not possible, in my opinion, in this context.

But more importantly than that, you brought up a great point. One has to wonder what the denosumab data would have been today if the data were actually published and presented today? Because the primary endpoint of that data was MFS, or time to progression. I think there is a bigger question. You may recall that Matthew R. Smith, MD, PhD’s, data were actually looking at zoledronic acid. We shut down that trial because we would never have met that endpoint because most people were progressing early on. That’s where we captured the doubling time and importance of doubling time.

I think the bigger question for me right now is, we have 3 oral agents that have met the primary endpoint, and the bar has changed for FDA approval right now in the United States with MFS. But I always argue that if you look at the MFS data, the MFS data as a surrogacy came from the ICECaP [Intermediate Clinical Endpoints in Cancer of the Prostate working group] data, which are the adjuvant data. So that’s what we still hear in the community. People actually say, “I want to see the survival data before I can commit to an oral agent that is financially challenging for some patients, also has quality of life issues, and has adverse effects.” All these agents have adverse effects, and yet we don’t see that sort of “gold standard” for survival.

I think the MFS, for me, and I have changed a lot over the last 10 years… I think that before, we used to believe in survival. Survival was the most important one. But the reality of it is maintaining someone free of symptoms, maintaining someone free of progression; and delaying time to pain, delaying time to skeletal-related events, and delaying time to chemotherapy. This is super important in our patient population. If you look at the mortality of men with bone metastases within 5 years, less than 20%, 30% of patients are alive. That means that these people do die from prostate cancer, and they do die from castration-resistant disease. So I don’t think today, at least in my opinion, you can support not treating a patient like that in the context of their disease.

Alicia Morgans, MD:I completely agree. I think it’s not just that you need to prevent metastases, but you really have the opportunity to maintain quality of life, which, interestingly, in all 3 trials, the patients actually maintained quality of life. In the ARAMIS trial, the quality of life data presented at ASCO [the American Society of Clinical Oncology annual meeting] this past year by Karim Fizazi, MD, PhD, suggested that they actually may do better in terms of their urinary and bowel symptoms, which is surprising to me. Because these patients have had local treatment, for the most part, although some of those patients perhaps did not have extensive local treatment. These were international patients on that trial. But if you can maintain or potentially improve quality of life, in addition to reducing anxiety, I think that’s worth it. And I think there’s absolutely no way you’re going to convince these patients, who we’ve already engaged in this partnership to start ADT in the first place, to say, “We won’t do something else when we have these options.”

Kenneth Kernen, MD:That’s what I was going to say, because we always joke that PSA stands for patient stimulating anxiety. So now you’ve committed, like Jorge said, to treating them with ADT. Their PSA is going up. They know what metastatic disease means. That resonates with them. If you offer them something to delay that, they know what that means. So I think that’s compelling to them. But I do think, like you said about the ARAMIS trial, one of the other concerns is you’re taking someone who’s asymptomatic and potentially making them symptomatic. And so, that’s why that ARAMIS data were quite compelling about how well they did on the trial.

Neal Shore, MD, FACS:Let me echo that. We don’t have OS [overall survival] data yet. I think we’re pretty confident that we’re going to probably see OS data for all 3 trials sometime in 2020. I think we’re all very cautiously optimistic. It’s been trending to look like it will be real. But you’re right. Is it lead time bias? Are we changing the pathophysiology of the disease by starting AR [androgen receptor] inhibitor therapy earlier? That waits to be seen. But the thing about the PSA going down so dramatically, and you look at the hazard ratios, and it’s 0.06…

Jorge Garcia, MD:That’s pretty impressive.

Neal Shore, MD, FACS:And that anxiety, and seeing the PSA plummet, the delay to antineoplastic therapies, usually chemotherapy-based, I think goes back to the patient-reported outcomes that really help patients note a sense of benefit until we get further OS data. The MFS is clearly there.

Transcript edited for clarity.