Alicia Morgans: Hi. I'm so excited to be here at ESMO 2022, where I have the opportunity to speak with Dr. Rana McKay from UCSD about a trial in progress, CYCLONE 3. Thank you so much for talking with me today.

Rana McKay: Of course. Thanks for having me.

Alicia Morgans: Wonderful.

Rana McKay: Great to be here.

Alicia Morgans: Wonderful, wonderful. It is great to be here. It's a beautiful place and a beautiful meeting and so exciting to hear data on this trial in progress that's really featuring and focusing on abemaciclib. Tell us a little bit about it.

Rana McKay: This is really an amazing trial. It's really built on the CYCLONE program in advanced CRPC. The whole CYCLONE program initially started with CYCLONE 1, with abemaciclib as monotherapy for patients with advanced disease, moved into CYCLONE 2 for first-line CRPC in combination with abiraterone. CYCLONE 2 was a phase II/III trial that's still ongoing. And now moving into the hormone-sensitive space with CYCLONE 3, really mirroring what's been done with the MONARCH program in metastatic breast cancer. We know that the CDK4/6 pathway is upregulated in prostate cancer, we know that that pathway is amplified through the androgen receptor, and this is a strategy to basically target that pathway for men with metastatic disease.

Alicia Morgans: Fantastic. tell us a little bit about the study design.

Rana McKay: This is a double-blind, randomized study, multi-center, international trial for patients with metastatic hormone-sensitive disease that's high risk, meaning patients have to have four or more bone metastases to go on, or they have to have visceral metastases. Patients are randomized 1:1 to receive abiraterone with abemaciclib or abiraterone plus placebo. The primary endpoint is radiographic progression-free survival as determined by RECIST and Prostate Cancer Working Group 3 criteria. So it's really designed to target that unmet need of those patients that have high-risk disease. While we've made tremendous progress in the field regarding overall survival for these individuals, we know that the large majority of them go on to develop castration-resistant disease and lethal prostate cancer.

Alicia Morgans: Absolutely, and some of them even very quickly. So really such an important patient population and really, I also wanted to mention, a very active control arm. So it's quite a high bar.

Rana McKay: Yeah, yeah. No, it absolutely is. But I think that's where the field is going. It's no longer a standard of care to have ADT alone. For any metastatic hormone-sensitive trial, the standard is NHT doublets with ADT, and even as we think about chemotherapy as well, it's no longer standard of care to do chemotherapy alone with ADT based off of data from PEACE and ARASENS that have demonstrated that triplet therapy is better than ADT-docetaxel. So I think it's building on that paradigm of how can we escalate therapy, and abemaciclib has demonstrated activity certainly in the preclinical setting and will be tested, as I stated, clinically in the CYCLONE 1/2 program.

Alicia Morgans: Tell me a little bit about the endpoints in this trial. What are you looking to improve?

Rana McKay: The primary endpoint of the trial, as I stated, was radiographic progression-free survival, which is definitely a clinically meaningful endpoint. It's a surrogate for overall survival, particularly for patients with metastatic disease, and it's a very cleanly defined endpoint because it's radiographic progression-free survival. As we think about some of the other hormone sensitive trials, they integrated PSA progression, integrated clinical progression. In the context of the study, it's really clean and basically defined radiographically. The key secondary endpoint, of course, is going to be overall survival, time to castration resistance, which will also integrate PSA as well, safety, quality of life, SSEs, and hopefully integrating correlatives as well.

Alicia Morgans: Wonderful. Where are you in terms of enrollment? Where does the trial stand currently?

Rana McKay: The trial is opening up internationally at multiple sites. We're still waiting to get several sites activated. It'll be open at US, Europe, Asia, Australia. So really an international study. Accrual is currently ongoing and we're hoping that that continues to ramp up by the end of next year and beginning of the year thereafter.

Alicia Morgans: That's fantastic. Well, I really wish you, the team, and of course the patients, all the luck. It's really exciting. We do need something more for these high-risk patients with metastatic hormone-sensitive disease and I look forward to seeing where CYCLONE 3 takes us. Thank you so much for your time and for your expertise.

Rana McKay: Thank you.