nmCRPC: Clinical Trial Data on AR Inhibitors


Shared insight on the SPARTAN, PROSPER, and ARAMIS studies with androgen receptor (AR) inhibitors in non-metastatic castration-resistant prostate cancer.


Alan Bryce, MD: Dr Zhang, can you give the audience the background on the 3 key studies we have in NMCRPC [nonmetastatic castration-resistant prostate cancer]? Just in terms of the study design, the endpoint, and what we learned from these studies?

Tian Zhang, MD, MHS: Tall order Dr Bryce, I'll try my best. [There are] 3 very important phase 3 studies in nonmetastatic castration-resistant prostate cancer, and they include SPARTAN, which was the trial comparing apalutamide versus placebo; PROSPER, which was the trial comparing enzalutamide with placebo; and ARAMIS, [which was] darolutamide versus placebo. When these trials started, we were in a space where we were asking the question, is metastasis-free survival [MFS] a surrogate for overall survival? I think it was the primary endpoint for all 3 of these trials, and it certainly was met across the board. I think that is clear, and yet now many years later, we've also learned that metastasis-free survival is a good surrogate endpoint for overall survival. Not only are we delaying time until metastasis for these patients, we're also getting them to live longer. Subsequently, multiple analyses of these trials post hoc have added to our knowledge of this space.

Alan Bryce, MD: Absolutely, and I think that overall survival message is important, that the people realize even though these were designed around MFS, we now have this overall survival data. I wonder how the rest of you feel, but I look at these 3 studies, and I tell patients [that] the results are essentially the same; there are fairly minor differences, but I don't think there's meaningful differences between these 3 studies. In terms of their results, they're all good, they're all positive. When we talk about the question, how does imaging change the expectation? If you have a patient that's conventional imaging negative, qualifies for this study, but has a ditzel, a retroperitoneal node, a pelvic node on PSMA scan, what do you say to them, Dr Zhang? Is this NMCRPC, or [is] that MCRPC?

Tian Zhang, MD, MHS: Again, I think it's accurate in terms of localizing disease, and sometimes it allows an area to be treated with metastasis-directed radiation, for example. I think of it as a way that we could potentially keep patients on their treatment for nonmetastatic CRPC longer. I don't think of it as true disease progression on their AR-targeted therapies during nonmetastatic CRPC setting. We can go into a little bit of the post hoc analysis if you'd like?

Alan Bryce, MD: Yes, absolutely.

Tian Zhang, MD, MHS: We saw some of the PSA changes associated with patient-reported outcomes on SPARTAN at GU ASCO last year. There was an abstract presented by Eric Small, [MD], and his colleagues, that showed that PSA undetectable less than 0.2 at 3 months on trial was associated with better quality of life, so I think that's easy to grasp. Better disease control is also meaningful for improving quality of life. There was also a subsequent post hoc analysis that was presented at GU ASCO in February of 2023, that showed that there were subsequent treatments for patients who are treated with apalutamide. Three hundred and eleven of those patients received subsequent treatments, the vast majority of whom had abiraterone as a next treatment, and we can debate whether that's effective, but 9% had docetaxel, 6% on enzalutamide, and then 7% on other treatments, and I think that helps us inform our treatment selection in the postapalutamide setting. Overall, these patients did very well. The patients who had subsequent overall survival generally ranged from 17 to 21 months. On enzalutamide, there was also a survival subgroup analysis that was published about a year ago now, and this one has me scratching my head a little bit, but on multivariate analysis, ECOG performance status, the log of PSA, and subsequent treatments are also associated with better survival outcomes. Finally, we also recently saw a subsequent analysis of the ARAMIS study, which was darolutamide compared against placebo, in this nonmetastatic space, and 30% of patients were able to stay on darolutamide for a long period of time; over 4 years on treatment, in this nonmetastatic CRPC space. There was an open label portion, and then a rollover portion of the study, and that’s what's impressive to me, is that we're able to keep patients on treatment for prolonged periods of time, 4 years or more.

Alan Bryce, MD: Absolutely. It's wonderful to see that, and it's encouraging for the patients to understand that up front, that yes, they have metastatic cancer, but we're going to keep them going for years, and realistically can hope for that.

Transcript edited for clarity.

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