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AR-Targeted Therapies in CRPC

Panelists: Raoul S. Concepcion, MD, FACS, Comprehensive Prostate Center; Daniel George, MD, Duke Cancer Institute; Alec Koo, MD, Skyline Urology; Phillip Koo, MD, MD Anderson Cancer Center; Neal D. Shore, MD, FACS, Carolina Urologic Research Center
Published: Tuesday, May 01, 2018



Transcript: 

Raoul S. Concepcion, MD, FACS: So, we know about this arbitrary M0. Right now, all of the newly approved agents for metastatic castration-resistant prostate cancer are not approved for M0. Therefore, there has always been that agonizing discussion of, “You’ve got this prostate-specific antigen, so we’re going to watch you.” Again, as Dan said, we can use some oral agents, some anti-androgens, that may give us a little bit of a benefit. The patient may psychologically feel better because their PSA drops. But again, there is no survival benefit. We ultimately know where they’re going to go. And, again, the choice has been clinical trial or observation. So, Neal, there have been a couple of abstracts presented. Tell us what you basically took away from a couple of these abstracts, primarily discussing the SPARTAN trial and PROSPER?

Neal D. Shore, MD, FACS: Here we are, at the ASCO Genitourinary Cancers Symposium. Arguably, the most significant things to come out of the conference in 2018 are the results that were presented by Eric J. Small, MD, on the SPARTAN trial, and Maha Hussain, MD, for the PROSPER trial. They’re very, very similar trials. They looked at this M0 CRPC population. The trials were globally performed. There were 1400 patients in the PROSPER trial and 1200 patients in the SPARTAN trial. Both had 2:1 randomization. M0 CRPC patients, 2:1, in PROSPER, got enzalutamide versus placebo. In the SPARTAN trial, they either got apalutamide, another androgen receptor–signaling inhibitor, versus placebo.

The presentations were excellent. The primary endpoint, which was a newly agreed upon endpoint called metastasis-free survival, essentially combined the first-onset demonstration of a metastasis by traditional CT scan, technetium-99m bone scan, as well as a possibility for death. In the regulatory discussions with the FDA, they had accepted this as an approvable endpoint.

Other key secondary endpoints included PSA declinations, time to next antineoplastic therapy, as well as subsequent symptomatic skeletal events. Both of these trials similarly demonstrated metastasis-free survival in the treatment arm versus the placebo-controlled arms—approximately 2 years. So, there was a dramatic change. Earlier Dan had mentioned the denosumab trial in the M0 space. We were a part of that. In the trial, we saw about a 4-month bone metastasis–free survival. And in an enriched population, in that trial of patients where the PSA doubling time was less than 6 months, it was about 7 months. It is important to recognize that in both the SPARTAN and the PROSPER trials, there was a very enriched M0 CRPC population. To get involved, you had to have a PSA doubling time of less than 10 months. In both trials, about 75% of the patients had PSA doubling times of about 4 months. So, this gets back to that idea where PSA is really a good marker of biological aggressiveness.

These are dramatically important trials that just got released. Philip Kantoff, MD, who did the review, talked about the importance of this asymptomatic patient population. Because they’re asymptomatic, it’s just a rising PSA. They already have some adverse events from the chronic ADT. How do we have the right patient/physician shared decision-making discussion about starting another therapy that delays metastasis-free survival and balancing out of the side effects?

Raoul S. Concepcion, MD, FACS: We know that enzalutamide is already approved in the pre-chemotherapy, post-chemotherapy CRPC patient with metastatic disease. Apalutamide is not approved in that setting. So, Dan, from a medical oncology standpoint, what is your take on the presentations regarding PROSPER and SPARTAN?

Daniel George, MD: Raoul, as I said, this is a real unmet need. We’re anxious to see this. Historically, we had that sort of 4-month median delay in metastasis-free survival on our minds. The 2-year effect is really a pretty dramatic effect, but there were a couple of caveats associated with that. One is that the average age on these studies was 74. The range went up to almost age 90. So, we’re looking at a patient population that’s typically older than that of the castrate-resistant populations we’re used to studying in M1 castrate-resistant disease. In addition, as we talked about, we saw a rapid PSA doubling time. But because they were nonmetastatic, these patients all likely had passed through local therapy, recurrence, hormonal therapy, and probably had a longer natural history. We see this higher median age from what we’ve seen, historically, in our castrate-resistant M1 population.

I want to make clear that this isn’t necessarily a natural progression of this population into the PREVAIL or COUGAR-AA-302 populations that were studied. Those populations were more mixed, more heterogeneous, representing wider metastatic pathways to castration resistance. This is a more homogenous population. I think that’s one of the reasons why the results were so similar between these 2 studies. It’s a more well-defined biology that we’re dealing with. Nonetheless, I think it’s a clinically significant effect. I say that because this is a population, in the control arm, that we know is destined to develop metastasis in about a year. We’ve seen PSA doubling times of 4 months. The median PSA value was 8, almost 10.

These are patients who are at high risk for developing metastasis. I bet Phil would say that if you did a molecular imaging test at baseline on these patients, the majority of them are probably going to be positive. Again, they’re already metastatic. It’s just that they’re low-volume metastatic. What’s fascinating to me is this 2-year effect, which suggests that drugs like enzalutamide and apalutamide work better in that population when you use them just a year earlier than we would in the other settings of M1 castration-resistant prostate cancer.

I’m not saying that everybody has to get those drugs. But for me, if I have a younger patient than maybe that higher end, that 90-year-old, but maybe on the lower end of 74, who I think is going to live for a long time, who doesn’t necessarily have the comorbidities that these drugs are going to really exacerbate. We talk about metabolic syndrome, and we’ve talked about the up-front consequences of ADT. This is sort of ADT 2.0. This is a higher level. So, if I think there is somebody who can tolerate that, I’m going to be very motivated to treat them. But on the other hand, if I’m concerned about comorbidities and frailty and other issues, then I’m probably not going to be as proactive with this data in that population. I don’t think this is a mandate to treat everybody in M0 with these drugs. But I think it absolutely should be a therapeutic option for us.

Transcript Edited for Clarity

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Transcript: 

Raoul S. Concepcion, MD, FACS: So, we know about this arbitrary M0. Right now, all of the newly approved agents for metastatic castration-resistant prostate cancer are not approved for M0. Therefore, there has always been that agonizing discussion of, “You’ve got this prostate-specific antigen, so we’re going to watch you.” Again, as Dan said, we can use some oral agents, some anti-androgens, that may give us a little bit of a benefit. The patient may psychologically feel better because their PSA drops. But again, there is no survival benefit. We ultimately know where they’re going to go. And, again, the choice has been clinical trial or observation. So, Neal, there have been a couple of abstracts presented. Tell us what you basically took away from a couple of these abstracts, primarily discussing the SPARTAN trial and PROSPER?

Neal D. Shore, MD, FACS: Here we are, at the ASCO Genitourinary Cancers Symposium. Arguably, the most significant things to come out of the conference in 2018 are the results that were presented by Eric J. Small, MD, on the SPARTAN trial, and Maha Hussain, MD, for the PROSPER trial. They’re very, very similar trials. They looked at this M0 CRPC population. The trials were globally performed. There were 1400 patients in the PROSPER trial and 1200 patients in the SPARTAN trial. Both had 2:1 randomization. M0 CRPC patients, 2:1, in PROSPER, got enzalutamide versus placebo. In the SPARTAN trial, they either got apalutamide, another androgen receptor–signaling inhibitor, versus placebo.

The presentations were excellent. The primary endpoint, which was a newly agreed upon endpoint called metastasis-free survival, essentially combined the first-onset demonstration of a metastasis by traditional CT scan, technetium-99m bone scan, as well as a possibility for death. In the regulatory discussions with the FDA, they had accepted this as an approvable endpoint.

Other key secondary endpoints included PSA declinations, time to next antineoplastic therapy, as well as subsequent symptomatic skeletal events. Both of these trials similarly demonstrated metastasis-free survival in the treatment arm versus the placebo-controlled arms—approximately 2 years. So, there was a dramatic change. Earlier Dan had mentioned the denosumab trial in the M0 space. We were a part of that. In the trial, we saw about a 4-month bone metastasis–free survival. And in an enriched population, in that trial of patients where the PSA doubling time was less than 6 months, it was about 7 months. It is important to recognize that in both the SPARTAN and the PROSPER trials, there was a very enriched M0 CRPC population. To get involved, you had to have a PSA doubling time of less than 10 months. In both trials, about 75% of the patients had PSA doubling times of about 4 months. So, this gets back to that idea where PSA is really a good marker of biological aggressiveness.

These are dramatically important trials that just got released. Philip Kantoff, MD, who did the review, talked about the importance of this asymptomatic patient population. Because they’re asymptomatic, it’s just a rising PSA. They already have some adverse events from the chronic ADT. How do we have the right patient/physician shared decision-making discussion about starting another therapy that delays metastasis-free survival and balancing out of the side effects?

Raoul S. Concepcion, MD, FACS: We know that enzalutamide is already approved in the pre-chemotherapy, post-chemotherapy CRPC patient with metastatic disease. Apalutamide is not approved in that setting. So, Dan, from a medical oncology standpoint, what is your take on the presentations regarding PROSPER and SPARTAN?

Daniel George, MD: Raoul, as I said, this is a real unmet need. We’re anxious to see this. Historically, we had that sort of 4-month median delay in metastasis-free survival on our minds. The 2-year effect is really a pretty dramatic effect, but there were a couple of caveats associated with that. One is that the average age on these studies was 74. The range went up to almost age 90. So, we’re looking at a patient population that’s typically older than that of the castrate-resistant populations we’re used to studying in M1 castrate-resistant disease. In addition, as we talked about, we saw a rapid PSA doubling time. But because they were nonmetastatic, these patients all likely had passed through local therapy, recurrence, hormonal therapy, and probably had a longer natural history. We see this higher median age from what we’ve seen, historically, in our castrate-resistant M1 population.

I want to make clear that this isn’t necessarily a natural progression of this population into the PREVAIL or COUGAR-AA-302 populations that were studied. Those populations were more mixed, more heterogeneous, representing wider metastatic pathways to castration resistance. This is a more homogenous population. I think that’s one of the reasons why the results were so similar between these 2 studies. It’s a more well-defined biology that we’re dealing with. Nonetheless, I think it’s a clinically significant effect. I say that because this is a population, in the control arm, that we know is destined to develop metastasis in about a year. We’ve seen PSA doubling times of 4 months. The median PSA value was 8, almost 10.

These are patients who are at high risk for developing metastasis. I bet Phil would say that if you did a molecular imaging test at baseline on these patients, the majority of them are probably going to be positive. Again, they’re already metastatic. It’s just that they’re low-volume metastatic. What’s fascinating to me is this 2-year effect, which suggests that drugs like enzalutamide and apalutamide work better in that population when you use them just a year earlier than we would in the other settings of M1 castration-resistant prostate cancer.

I’m not saying that everybody has to get those drugs. But for me, if I have a younger patient than maybe that higher end, that 90-year-old, but maybe on the lower end of 74, who I think is going to live for a long time, who doesn’t necessarily have the comorbidities that these drugs are going to really exacerbate. We talk about metabolic syndrome, and we’ve talked about the up-front consequences of ADT. This is sort of ADT 2.0. This is a higher level. So, if I think there is somebody who can tolerate that, I’m going to be very motivated to treat them. But on the other hand, if I’m concerned about comorbidities and frailty and other issues, then I’m probably not going to be as proactive with this data in that population. I don’t think this is a mandate to treat everybody in M0 with these drugs. But I think it absolutely should be a therapeutic option for us.

Transcript Edited for Clarity
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