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Alicia Morgans: Hi, I'm so excited to be here today with Professor Matthew Smith, who is joining me from Massachusetts General Hospital in Boston, Massachusetts, as well as joining me from ASCO 2024 to talk about a wonderful oral presentation that he gave about the CYCLONE 2 trial. It was the primary analysis of this trial. Thank you so much for being here.

Matthew Smith: Happy to be here.

Alicia Morgans: Wonderful. Matthew, tell me a little bit about the CYCLONE 2 trial. What was the setup? What were the drugs used in combination here?

Matthew Smith: Yeah, happy to describe it. The background is that CDK4/6 inhibition has an established role in breast cancer, as we all know. Abemaciclib and other drugs are approved in HR-positive HER2-negative breast cancer. Given the strong biologic similarities between breast and prostate cancer, there's certainly a rationale for considering combination therapy in prostate cancer as well. Further, there was strong preclinical evidence that CDK4/6 inhibition has a role in prostate cancer and provides a rationale for combining CDK4/6 inhibitors with AR pathway inhibition. So, that led to the design of the CYCLONE program, including CYCLONE 2, which is a global randomized controlled trial of abemaciclib in combination with abiraterone acetate and prednisone in patients with mCRPC.

Alicia Morgans: Wonderful. Tell me, who was enrolled in this trial? What was the randomization? What were your primary endpoints?

Matthew Smith: Yeah. It takes a moment to describe the study design because it was intended to be efficient and seamless, but also have a rational basis for early stopping in the event of futility. It enrolled patients with mCRPC who had a good ECOG performance status and no prior treatment with either an ARPI or a CDK4/6 inhibitor. Patients who had received prior docetaxel for mCSPC were allowed, and that had some relevant stratification factors. It enrolled a total of 393 patients at 89 sites in 12 countries, so it was a global trial. The interesting part of the design is that it had this adaptive and seamless design with three parts.

Part one was a dose-finding lead-in, so 46 patients were randomized to either abemaciclib or placebo, in combination with abiraterone and prednisone, which is true of all the parts, at a dose of either 150 milligrams po bid or 200 milligrams po bid. Part one established the recommended phase two dose at 200 po bid. Part two was a randomization one to one to abemaciclib or placebo at the recommended phase two dose, and it had a pre-specified interim analysis. IDMC looked at that, and then using pre-specified criteria, recommended continuation. And then, 201 additional patients were enrolled in part three to make a total of 393 patients.

Alicia Morgans: Wonderful. I'm sure you had obviously multiple endpoints. What were those that you were looking for?

Matthew Smith: Yeah. The primary endpoint was rPFS by investigator assessment, and then we had the usual collection of secondary endpoints including overall survival.

Alicia Morgans: Okay. What did you and the other investigators find?

Matthew Smith: Yeah. Despite this early signal to move forward, the primary analysis was negative. The primary analysis for rPFS was pre-specified and event-driven. It occurred after 187 events. And compared to placebo, the addition of abemaciclib to abiraterone and prednisone did not improve rPFS. The hazard ratio was 0.83, 95% confidence interval crossed one, and the P-value was non-significant.

Alicia Morgans: Okay. It's hard and interesting to think about this because already building on quite an active control arm here and trying to build on that is always a difficult thing. What are your thoughts in terms of this particular mechanism of action in the context of metastatic prostate cancer? Is there a role for abemaciclib somewhere else? Certainly, I'm putting you on the spot, this has nothing to do with this trial, but just your thoughts.

Matthew Smith: Yeah, no, I think that's the ultimate question. Is there a path forward for CDK4/6 inhibition in prostate cancer? I would say that there were hints of activity or there's biologic activity. The hazard ratio point estimate was less than one. Some of the other endpoints directionally also supported abemaciclib including, for example, time to PSA progression, perhaps a relatively low bar, but nonetheless, that was statistically significant. OS was not statistically significant, although there was a slight trend towards better outcomes with abemaciclib. So, there's at least a hint of a biologic signal, unequivocally not clinically relevant, based on these data.

Two points about your question. I think first is that in parallel, another study was being done in mCSPC called CYCLONE 3, and it had an event-driven futility analysis that happened to coincide closely with the final analysis of CYCLONE 2. That failed to meet its pre-specified criteria, and CYCLONE 3 was discontinued. So, moving the drug earlier in combination with abiraterone and prednisone did not result in a positive outcome either.

So, the question becomes why does it appear so different than from breast cancer where there's an established role, multiple disease states, multiple different drugs? Despite the many similarities in biology, there may be differences and we hope to explore those differences in planned translational work. We have tissue collected on all the patients enrolled in parts one and two, and blood on patients enrolled in all three parts, and those analyses are ongoing. Perhaps they'll provide some clues to predict response and resistance, and perhaps then better define whether there might be a role for CDK4/6 inhibition.

Alicia Morgans: I think that's so important to know and to think about because it is certainly not unprecedented that there might be a patient population that could be selected based on your exploratory analyses with your correlatives, that might be a group to focus further work in and to move things forward. An all-comers population is not necessarily one that will always respond, so that could be a potential area of interest certainly for everyone in the future.

Matthew Smith: Yeah. We certainly do look forward to those results, particularly given some observations within this study in subgroup analyses, the estimated treatment effects were greatest in the patients with poor prognosis features. So, that'll be interesting to see whether the molecular analysis sort of bear that out.

Alicia Morgans: Yeah, absolutely. What would your message be to listeners who are curious about this particular presentation and then this approach as we move forward in prostate cancer care?

Matthew Smith: Yeah. I think this came out of the blue, so to speak. For a lot of people, they hadn't heard a lot about it, but I want to make it very clear this was a rationally-designed trial, adaptive design, seamless design. I think those attributes, because it wasn't done in an iterative way where the phase one was reported in the phase two and phase three, perhaps made it less visible. But just a reminder, stay tuned. There's a lot of interesting work going on and a lot of interesting targets. I think this is an example of a well-conducted study, which just unfortunately was a negative trial.

Alicia Morgans: Absolutely. It's important to learn what will and what won't work just the same, and it's also really important to see examples of how we can conduct these clinical trials in a condensed timeline to get our answers more quickly. Whether they're positive or negative, they're important for us to understand and the correlatives will give us more insights again, regardless of whether the study itself was positive or negative. Thank you so much for your time and your expertise, and congratulations to your team for finishing the work. And thank you to the patients, of course, for participating.

Matthew Smith: Thank you.