GU Cancers 2021 | Apalutamide in combination with abiraterone acetate, docetaxel and prednisone for mCRPC

So many years ago, we had designed a trial that was primarily designed for safety, but we also had an expansion cohort that was the combination for patients with metastatic CRPC, combination of abiraterone acetate with prednisone plus apalutamide plus docetaxel. That initial Phase I part included a dose escalation, so we considered that docetaxel and abiraterone were the standard drugs. A trial before that, a Phase I trial that was published in European Neurology showed that that combination was safe at the standard doses. So, we added in apalutamide at a slightly lower dose, initially, 120 milligrams. And then, if that was safe, we were going to escalate to 160 milligrams. And in fact, we did that with that initial dose escalation data presented at AACR in the past.

This presentation at the 2021 Genitourinary Symposium included the dose escalation portion in addition to the expansion cohort. So, that’s now a completed trial. And the bottom line is that a total of 16 men were enrolled, the dose escalation plus expansion. They had metastatic CRPC and, generally speaking, were untreated. The regimen was tolerated overall. So, there was a couple of cases of grade three hypertension, one of whom did qualify as a DLT, but two had grade three and two had grade two hypertension, which we know is an overlapping risk for abiraterone and apalutamide. Patients did have neutropenia, one of whom had febrile neutropenia that we know is a risk with docetaxel. But overall, we did not see a lot of overlapping toxicity. So, we called the regimen overall well-tolerated, I would say.

Not surprisingly with, in a way, three drugs that target the AR axis. I didn’t mention this at the beginning in terms of rationale, but clearly, AR signalling inhibitors like apalutamide, CYP17 inhibitors and taxanes which microtubules can inhibit the translocation of the AR into the nucleus. So, a vertical blockade of that in addition to other mechanisms of docetaxel, it’s not so surprising that we see PSA declines, but it was really quite impressive where essentially only one did not have a PSA 50% decline. I think the one that didn’t was 40-something percent and 12 out of the 16 or 3/4 had at least a 90% PSA decline. This did not look to be just transient.

We did not reach a median radiographic progression-free survival, but the two year radiographic progression-free survival percentage was about 70%. So, it looked like there was reasonable long-term disease control from the triplets. I should mention that docetaxel was only given at the beginning, once patients completed whatever course was appropriate per their treating physician, they continued what I would consider maintenance abiraterone and apalutamide. We also looked at circulating tumor cell counts before and 12 weeks with the CellSearch methodology. Five of 10 that had a valuable pre-treatment and post-treatment started undetectable and remained undetectable. Five that were detectable at baseline, all five of those converted to undetectable at 12 weeks. So just another prognostic biomarker that we have there.

This overall dataset was designed several years ago when kind of simultaneously or slowly after the design of two Phase III trials, one was the NCI Alliance led a study by Michael Morris that looked at enzalutamides with or without abiraterone. And then the ACIS trial, which was presented at this meeting by Dana Rathkopf looking at abiraterone with or without apalutamide. So, the thought process was, you know, more potent inhibition of the AR pathway as a frontline treatment for metastatic CRPC was going to lead to better outcomes. They both showed basically the same thing, an rPFS benefit without an overall survival benefit.

So, the design of this was primed, if those trials were positive and the standard of care changed to dual inhibition, then the idea is that we would have safety data to test a triplet, i.e. the addition of docetaxel to the doublets. Those Phase IIIs were like I said, only partly positive in terms of one of the end points, so the secondary end point for the Alliance study the primary end point of rPFS for the ACIS study. But because of the lack of an overall survival benefit, I don’t think that we’re going to test the triplets, but in a small non-randomized study, it does look like there is a disease control that appears to be longer than either doublet in terms of the rPFS endpoint. So that’s just an observation, hypothesis-generating, so if we ever have a disease state where we are combining those two, we do now have at least safety data that docetaxel could be added.