Broadening Treatment Horizons with CDK4/6 Inhibitors from Breast to Prostate Cancer - Rana McKay
November 8, 2023
Part of an Independent Medical Education Initiative Supported by LOXO@Lilly
Rana R. McKay, Medical Oncologist, Associate Professor, University of California, San Diego, San Diego, CA
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
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Alicia Morgans: Hi, I'm so excited to be here today with Dr. Rana McKay of UCSD, but we are talking about CDK4/6 inhibitors. Thank you so much for being here with me today.
Rana McKay: Oh, it's a pleasure to be here. Thank you for having me.
Alicia Morgans: Wonderful. Well, it's always exciting to talk to you. This is a specific topic that I know is near and dear to your heart. So tell me about these inhibitors. What are we inhibiting? How does it work?
Rana McKay: So I think stepping back, the cell cycle is an incredibly regulated process inside the cell. Basically, a cell going to divide and make a daughter cell is highly, highly regulated. Usually, cells are just hanging out in G0, but a lot of cancer cells are actually in the state of active cell division. There's a growth phase, then they synthesize their DNA, then they grow a little bit more, and then finally they divide into a daughter cell. And that process is incredibly regulated. Especially, that transition of going from G1 to S where you're synthesizing the DNA.
And that checkpoint is regulated by cyclin-dependent kinases, predominantly, CDK4/6. And there have been, historically, attempts to try to block this pathway. Initial drugs were pan-CDK inhibitors. They failed in the clinic because they were just too toxic, actually. And then as the science advanced and drug development advanced, drugs got better at specifically targeting CDK4/6 that were less toxic and actually were associated with efficacy in the clinic. And so it makes perfect rational sense to think about utilizing these drugs. Building off of what we know in breast cancer, there's a lot of synergy between the CDK4/6 pathway and the AR pathway and a lot of crosstalk between that pathway. So it actually makes sense to use these drugs in combination with hormonal agents, drugs like abiraterone and others.
Alicia Morgans: Really important and very interesting. So as you mentioned, breast cancer, there are actually approved drugs in this setting, right?
Rana McKay: That's correct. There are three CDK4/6 inhibitors that are approved in breast cancer: abemaciclib, ribociclib, and palbociclib. Abemaciclib has actually received approvals across the spectrum as monotherapy in the refractory setting, for patients with metastatic disease, earlier on, combined with hormonal therapy and actually even in the localized disease setting. So it really has pan indications for patients with localized and advanced breast cancer. And so building off of what we've learned in breast cancer and also from the preclinical studies that have been conducted in prostate cancer, there does appear to be the potential for a positive effect with the CDK4/6 inhibitors, particularly, in men with prostate cancer.
Alicia Morgans: Great. And I think we've already had some data to suggest that there's a signal there, right?
Rana McKay: That's correct. I think where there is data... A lot of the data has come from older agents, if you will, ribociclib and palbociclib. The CYCLONE 1 study looked at abemaciclib, but in a very refractory treatment population where we did see very modest activity. But again, it was a pretty refractory setting. I think the role is probably more in AR-driven tumors where we can expect to see that potential synergy with hormonal therapy.
Alicia Morgans: So definitely important to move it up earlier in the disease pathway.
Rana McKay: Yep. Yeah.
Alicia Morgans: And I think there are ongoing trials that are investigating in the mCRPC and metastatic hormone-sensitive prostate cancer populations as well.
Rana McKay: Yeah, that's correct. So the CYCLONE 2 study is looking at the frontline mCRPC setting in combination with abiraterone. That was a phase 2/3 study where they actually did do some dose-finding, went on to phase 2 with a go-no-go to move into phase 3 and actually went on to move into phase 3. That study has completed enrollment, and we're eagerly awaiting the results. And the CYCLONE 3 study is now nearing the end of accrual. That study is being conducted in the mHSPC setting, particularly in individuals with high-risk prostate cancer. Patients who are randomized to abemaciclib plus abiraterone versus placebo plus abiraterone. We know that individuals with high-risk disease with mHSPC high-risk disease continue to present an unmet need. The majority of those patients go on to develop castration resistance. So developing alternative treatment options for them is really needed, clinically.
Alicia Morgans: Absolutely. I think as we imagine that these trials hopefully will be positive and we'll move into our clinics, what do we have to think about in terms of side effects?
Rana McKay: Very good question. So I think it's exciting because abemaciclib presents a novel mechanism of action compared to all of the other agents that are right now being utilized for patients with advanced disease. But I think with that novel mechanism of action comes a learning curve of utilizing the CDK4/6 inhibitors. I think one of the biggest side effects with abemaciclib is diarrhea. So I think there needs to be prophylaxis against that and education for the clinical team and also the patient around what to do should somebody develop diarrhea. Usually, it's pretty modifiable with antidiarrheal agents. There can also be fatigue and sometimes cytopenias can occur that require monitoring. So I think there is a learning curve, but it's not anything that cannot be well-managed with great education.
Alicia Morgans: Wonderful. So one thing I wanted to ask about, because I know abemaciclib is certainly moving into all these settings and we're really excited about these clinical trials. There were clinical trials with other agents, including palbociclib, that didn't seem to go as far. Now, these were not in combination with AR signal inhibitors and certainly the CYCLONE program was in combination here with abiraterone. Can you tell me, does that have anything to do with it, that combination, or are these just different drugs and how should we or why should we expect something different?
Rana McKay: I do think that the drugs are different. So abemaciclib has very potent activity on CDK4 and CDK6 with some activity at CDK9, which is lacking with the other agents. Additionally, the other agents, I think, paired with docetaxel, paired with enzalutamide, there were a lot of drug interactions with the enzalutamide pairing. And then where we've seen the most robust data is in pairing with hormonal agents. So the docetaxel study, there were some limitations there. So I think using earlier on with hormonally targeting agents that allow for combination is going to be critical.
Alicia Morgans: Wonderful. So as you think about where we go, not just where we go in terms of impending results, but where we go in the future, where do you think we're going?
Rana McKay: So there are a lot of studies that are currently ongoing in the mHSPC setting. There are studies of PSMA radioligand therapy with PSMA addition. There are two studies currently ongoing, AMPLITUDE and TALAPRO-3, of PARP inhibitors in this setting. There's the CAPItello study looking at capivasertib, which is an AKT inhibitor. I think what's unique about abemaciclib is that it is specifically in the cohort of patients that have clinical high-risk disease as opposed to a biomarker PARP or a PSMA-based disease with imaging. So I think it's going to be really exciting to see how this agent is going to end up fitting into the landscape of other mHSPC studies.
Alicia Morgans: Wonderful. So how would you sum it up? Where should we look for abemaciclib in the future?
Rana McKay: So I think I'm eagerly awaiting the results of CYCLONE 2. Hopefully, those should be presented sometime in the next year or so and we'll see what role abemaciclib is going to have in the mCRPC setting frontline. And then I think the mHSPC study, obviously, is a little bit behind that. So I think we should certainly be on the lookout, but time will tell once the data gets reported and how this agent is going to impact the treatment landscape in mHSPC. I think, additionally, the agent is being explored in earlier disease settings. There's currently a trial ongoing combining abemaciclib with darolutamide. There's an mCRPC cohort that's currently ongoing just to figure out dose-finding and actually a study integrating that therapy in the neoadjuvant setting for patients with high-risk disease. So there are other disease settings beyond metastatic disease where this drug is being investigated.
Alicia Morgans: Well, certainly lots of opportunities and lots for us to be on the lookout for. I really appreciate you taking the time to share all of this with me today.
Rana McKay: Well, thanks for having me.