Prolonging Time to Metastatic Disease, The SPARTAN Study - Matthew Smith
Matthew R. Smith, MD, Ph.D., Professor of Medicine, Harvard Medical School, Assistant in Medicine, Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.
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, USA.
Alicia Morgans: Hi. I am delighted to have here with me today Dr. Matthew Smith, who is a Professor of Medicine at Harvard Medical School and a GU Medical Oncologist at Massachusetts General Hospital in Boston. Thank you so much for talking with me today.
Matthew Smith: Happy to be here.
Alicia Morgans: Great. One of the things that you've been discussing actually most recently are some studies that you have been actually very integrally involved with for some time. One that was presented recently at ESMO was the updated SPARTAN data, to help us understand whether there may be at this point in time a survival benefit to the treatment of men with non-metastatic castration-resistant disease with apalutamide as compared to ADT plus placebo, and certainly apalutamide was combined with ADT as well. I'd love to hear your just recap of that presentation. Let us know where the data stands now, and then we can get into the nitty-gritty of non-metastatic castration-resistant disease and your recommendations for our clinical practice.
Matthew Smith: Sure, glad to do so. At ESMO we presented the updated survival results from SPARTAN. Apalutamide is approved in men with non-metastatic castration-resistant prostate cancer. That approval was based on the results of the pivotal SPARTAN study, and the primary analysis was for metastasis-free survival. It was event-driven, and at the time of that primary analysis, apalutamide significantly improved metastasis-free survival by more than two years and reduced the risk of metastasis or death by 72%.
At the time of that primary analysis, though, the survival data were immature. There were only about 104 of the 427 events required for the final survival analysis. The purpose of this interim analysis was to better characterize the impact of apalutamide on overall survival in this disease state.
Alicia Morgans: Were you able to do that? Did you have enough events yet, or where did we find ourselves?
Matthew Smith: Yeah, so this is important to note. This was a pre-specified analysis. It, too, was event-driven. It occurred after a total of 285 events and 41 months of follow-up, so about twice the follow-up we had in the primary efficacy analysis for MFS, and the main outcome was that compared to placebo, apalutamide reduced the risk of death by about 25% with a hazard ratio of 0.75. The confidence intervals were below 1, but there's a very high statistical bar because it's this multiple testing for overall survival. So the O'Brien-Fleming boundary was 0.012, the p-value for this analysis was 0.019, so close but not quite statistically significant by that very high bar. The follow-up will continue per protocol, and we'll perform the final analysis after a total of 427 events. So, more to come.
Alicia Morgans: More to come, always. But so close, and I think we'll most likely see that we are improving survival, which I think is so critically important as we think about where this population sits in the spectrum of the lives of men with advanced prostate cancer, and the non-metastatic state really being the earliest part of castration-resistant disease for many men, and so, presumably, they've gotten multiple therapies after the time of progression. Can you comment on that?
Matthew Smith: Yeah, absolutely, and I'm glad you brought that up because this effect was seen despite a lot of subsequent treatments. When the primary analysis became positive, the study was unblinded, and patients in the placebo were allowed to cross over to apalutamide, and 76 patients, or about 19% of the placebo group, did so. Further, the study provided abiraterone acetate to encourage patients to remain on trial and to provide that drug to patients who otherwise wouldn't have access to it once they progressed.
So, a high rate of patients promptly crossed over to subsequent therapy at progression, 69% of patients in the placebo group and about 40% of patients in the apalutamide group. So, this 25% reduction risk of death was seen despite a high rate of crossover from placebo to apalutamide and an even higher rate of subsequent therapy, mostly abiraterone acetate. I think that you can think of it as generalizable in settings where there's a lot of expected subsequent therapy.
Alicia Morgans: Absolutely, which is the setting, thankfully, in which both of us practice and many of the people watching practice.
Matthew Smith: Agreed.
Alicia Morgans: It's important, I think, especially when we're looking at survival, and other trials have failed because of that crossover. So the signal, I think, is a strong one, and one that is clinically relevant when we are able to identify these patients.
But one of the challenges that I've heard from clinicians is how do I identify these patients when I get imaging, the standard imaging, which is really the imaging that was used to define the patient population for this trial, so CT scans of abdomen and pelvis, and bone scans, technetium bone scans. When I have that and then if I have a PSMA-PET or some other Axumin PET and I see metastatic disease, aren't those patients then metastatic, and how do I think through this conundrum of imaging? What would you say to people that are facing that issue?
Matthew Smith: Absolutely. I think it's important to begin by acknowledging that we, in a way, have a terminology challenge or problem in that all of the drugs approved for mCRPC, metastatic castration-resistant prostate cancer, included patients who had detectable metastases by conventional imaging, so technetium bone scan, CT, MRI. So, all of what we know in the approved drugs of mCRPC really comes from evidence in patients with metastases detectable by conventional imaging.
So, when looking at this somewhat earlier disease state, we had to choose a name.
Alicia Morgans: Yes, yes.
Matthew Smith: So we chose the corollary, which is non-metastatic CRPC, which seems to antagonize some, but it simply was an acknowledgment that the other disease state was already named. And biologically we, of course, expect that those patients would have microscopic metastases at a very high rate and that more sensitive imaging might in fact detect that disease, so we chose the term non-metastatic CRPC. We could have chosen some more complicated terminology, like no detectable metastases by CT, MRI, or bone scan, but that becomes a bit awkward or uncomfortable.
Alicia Morgans: A mouthful.
Matthew Smith: A mouthful, agreed, so nmCRPC seems to be a better fit. In sort of parallel work, there's been work done looking at SPARTAN-like patients by retrospective studies of PSMA PET, collaboration of multiple universities largely led by investigators in Germany, and that very nicely showed, and this data's now been published, that SPARTAN-like patients or ARAMIS-like patients or PROSPER-like patients, in fact, have a high rate of PSMA-positive disease even though it's not detectable by bone scan or CT, which is kind of what we believed to be the case all along.
So, to my way of thinking, this newly defined group of patients, bone scan negative, CT negative, but PSMA PET positive, we now really have good data to support intervening in those patients, and that data comes from SPARTAN, PROSPER, and ARAMIS.
Alicia Morgans: Yes, which is really important. I love the way you set it up that way, because we actually don't have data that treating those patients in the context of mCRPC, the trials that defined how we treat mCRPC would not have included those patients. So they are this patient population that, if we look only at metastatic CRPC trials, they are excluded, but because of that crossover imaging data that brings everything together, we know that they can benefit, I think, in this population now. There were patients, I think, that those patients that are included in the trials, in other words, would be patients who, if we had performed this more intensive molecular imaging, would be positive, and we know that they could benefit.
Matthew Smith: Yeah, we now know that most of them would have been PSMA PET positive.
Alicia Morgans: Yes.
Matthew Smith: That, I guess, comes as no surprise.
Alicia Morgans: Yes. Well, as you're trying to advise people in the community to use these medications, do you have any guidance? Any thoughts on how to best counsel patients, how to use the medications? Are there things that you think about or just messages that you want clinicians to think about?
Matthew Smith: Yeah, I take the approach as I do in many other studies, which is to follow the evidence. We now have strong evidence from three trials that intervening in this disease state, nmCRPC, has a meaningful impact on patients. There is a marked improvement in time to detectable metastases by conventional imaging, and there's strong supportive evidence from late secondary endpoints, strong trend for overall survival in more than just SPARTAN but the other trials as well, and improvements in other endpoints, like time to symptomatic progression, delay in time to chemotherapy. So, I think we really are providing clinical benefit to this group of patients.
I also say one size does not fit all. The patients enrolled in all three of these trials were truly high risk. They had to have a PSA doubling time of less than 10 months, but all three trials accrued patients with doubling times of closer to four or five months. So, probably not the right thing for certainly older, frailer patients and/or those with much more delayed PSA kinetics who would be at lower risk for prostate cancer progression.
Alicia Morgans: Absolutely. So, patient selection is really going to be critical, but we can make a meaningful difference in patients who look like those patients who were included in these trials, and important to think about using these treatments to prolong the time to metastatic disease by traditional imaging, I think, is going to be really an important part of our treatment paradigm moving forward, so thank you for sharing these updates and your guidance. It is always appreciated.
Matthew Smith: Thank you. Glad to be here.