Overall Survival Data Presented at ASCO 2020 for nmCRPC

Daniel J. George, MD: Chuck, do want to update us on some of the data that have come up this year regarding OS ?

Charles Ryan, MD: The data from our most recent presentation essentially confirm that all these studies that had met their primary end point for MFS also met an end point for overall survival. The question of whether MFS is a surrogate end point for an improvement in survival is something that is continuing to be thought through. It’s fair to say that we’ve now demonstrated that improving MFS in the nonmetastatic setting is both a provability end point and is clearly associated with a long-term outcome benefit for the patient in terms of overall survival.

My interpretation of this also is that MFS—apropos of what I said previously—is really PFS [progression-free survival]. It’s just going from a radiographically invisible metastasis to radiographically visible metastasis. It’s not a wholesale qualitative change in the state of the cancer. How these data will integrate into further studies in the nonmetastatic space will be curious to see. I’m wondering if the nonmetastatic CRPC [castration-resistant prostate cancer] space itself may go away with a lot of the newer imaging modalities that we’re seeing tested and presented, as we did at ASCO this year. It’s going to be an interesting area, and I also think we won’t be able to see any more placebo-controlled studies in this setting, either.

Daniel J. George, MD: That’s interesting. Some of these studies actually allowed pelvic lymphadenopathy, so the reality is that what we called nonmetastatic was low-volume metastatic disease. In many respects, maybe our novel imaging is just going to reinforce it. Maybe it’s not as low volume as we thought when we do this novel imaging, but at least by these standards, it’s still relatively responsive. That will be 1 of the questions.

Tanya, what do you think about that? How is some of the novel imaging going to influence your thinking? You mentioned earlier in the castration-resistant setting that imaging probably isn’t going to change how you think about that disease biology. Will it influence it here in this castration-resistant setting if the novel imaging is showing perhaps a higher volume of disease than what our standard imaging is showing?

Tanya Dorff, MD: I’m not sure it would, given that we would already intensify treatment either way once we get to castration resistance. Now we have these approved drugs that have proved metastasis-free survival and overall survival benefit. I’ll add that quality of life was preserved in these trials, which is quite remarkable for that amount of difference between metastasis-free survival of 40 months versus 15. That’s a huge difference, and for people to be feeling well during that is really important.

If you have a well-tolerated agent that’s highly effective in castration-resistant nonmetastatic disease that’s also available for metastatic disease, I don’t think the imaging adds much. Just because we see more spots, do we treat it differently? Some differences that it could impact are whether you might add bone support if you saw something in the bone that you didn’t see on traditional imaging, but that’s a huge gray area. There is no research on that yet. Maybe we need to look to our European and Australian colleagues, as Eleni mentioned earlier, and learn from how they’re handling that type of situation.

Daniel J. George, MD: It’s a great point. It’s another setting where I think this novel imaging isn’t necessarily going to drive a change in our therapy. What it might point to is another class of therapy that’s evolving, and we’re going to get to that subject later. It may be more useful as a biomarker for preparing for future therapy than it is for changing the current therapy in these patients, so I think that’s reasonable.

Eleni Efstathiou, MD, PhD: Can I make a comment on that? It’s very interesting. We are a bit trapped in this administrative term nonmetastatic CRPC. We have the data from the Hadassah Medical Center group, where if you took patients who would be accrued on this trial and did the PSMA [prostate-specific membrane antigen] PET, 75% of these men would have findings, whether localized or metastatic. For the purpose of the FDA approvals and the like, we use these terms. But as physicians, we know well that it’s earlier CRPC versus later.

Even though we can’t compare trials, we even have Chuck, who was the lead in the COU-AA-302 trial. If you look at those survival benefits, even in absolute terms in this later chemotherapy-naïve disease versus earlier disease, as Tanya brought up, the difference in what you get is quite big as long as you’re good at monitoring these patients and taking care of them. That’s our duty.

I think it’s a no-brainer. I’m saying that because people will then be saying, “Of the 3 drugs, only 1 has approval in metastatic CRPC.” These are agents in the same class, and then you go into the safety and tolerability, and adapt it to your patients. That’s where you make the decision. You don’t go by just the sheer administrative label. That’s my take, and I’d like to know your thoughts.

Daniel J. George, MD: I like that thinking. I think back to what Chuck said earlier about disease heterogeneity and how these agents are going to work so much better in that castration-sensitive setting, when we knock down the tumor burden with ADT [androgen deprivation therapy] and then wait for the castration-resistant setting. This is like that, because here, we’ve got a low-volume, chronic development of castration-resistant disease. It’s unlikely to be as heterogeneous as our patients who have high-volume metastatic castrate-resistant disease.

We see that a 30% survival benefit in this setting, when patients are going to live for 5 years or more, is way more impactful than a survival benefit of 30% when a patient has 1 year to live. Recognizing that hazard ratio in the context of the overall natural history is really important, and in recognizing that, it makes sense that these drugs would have a more lasting, more durable, and greater benefit in this setting.

Benjamin H. Lowentritt, MD, FACS: I’m curious for the group to comment, because of this question of using hazard ratios or time in how we communicate with one another or with patients. As you’ve said, we can’t compare trial to trial. But you do now have these overall survival benefits of 11 months with enzalutamide and 14 months with apalutamide, compared with 4 months with enzalutamide in the metastatic castration-resistant space. That tells the story as dramatically as anything. I’m curious if that is something you find to be a differentiator in explaining it to colleagues and patients. I’m curious how you’re finding these data are helping you.

Charles Ryan, MD: Can I make a quick point on that? It’s a really interesting point. One of the things I’ve been reflecting on in looking at the survival data and thinking about the more aggressive treatment of low-volume disease is that we are beginning to see the other causes of death competing with prostate cancer as a cause of death in these patients. That was unimaginable when we were treating postdocetaxel patients with enzalutamide and everyone was dying of prostate cancer. Not only that, but they were suffering a lot before they did.

Now we have taken these drugs into a much earlier phase, where we’re beginning to see that the risk of dying of prostate cancer is going down and is being almost eclipsed in many cases by the risk of death from cardiovascular disease. I think there was a slide and Neal Shore’s presentation, which showed that for a man diagnosed with prostate cancer, the risk of dying of cardiovascular disease actually exceeds the risk of dying of prostate cancer.

That has huge implications for how we would talk to a patient in that we can actually say, “Not only are we going to delay the progression of your cancer, but this may be your chronic therapy moving forward, and prostate cancer may not threaten your life.” It’s a long way before we can say that to every patient, but I see that beginning to creep its way into the conversation.

Daniel J. George, MD: It’s a great point, and these nonmetastatic castration-resistant prostate cancer patient populations were generally older than the populations of patients we’re studying in these castration-sensitive and even metastatic castration-resistant settings. Again, it speaks to the natural history of this biology, but probably 20% or 30% of these patients are 80 years old, and average age is about 75 years old. We’re dealing with a population of patients in which cardiovascular risk is only increasing with time.

Charles Ryan, MD: Ironically, this is what statins and beta-blockers did to cardiovascular death a couple of decades ago.

Transcript Edited for Clarity