The Critical Intersection of Androgen Receptor Pathways and Cell Cycle Regulation in Prostate Cancer Therapy - Rana McKay

November 8, 2023

Program: Beyond Androgen Blockade – New Pathways and Novel Treatments in mHSPC and mCRPC.

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, MA

Read the Full Video Transcript

Alicia Morgans: Hi, and welcome to UroToday and our online medical education program Beyond Androgen Blockade to New Pathways and Novel Treatments in Metastatic Hormone-Sensitive Prostate Cancer and Metastatic Castration-Resistant Prostate Cancer. I have the honor to moderate today's discussion following a presentation by Dr. Rana McKay. Her topic is CDK4/6 inhibitors targeting the cell cycle. Thank you so much, Dr. McKay.

Rana McKay:
It's a pleasure to be here today. Thank you so much for having me. We are going to dive right in talking about CDK4/6 inhibition in advanced prostate cancer. We know that the cell cycle is critically important for mitosis and cell generation. Typically, cells are kind of resting in G0, and when they go to divide, they enter into the growth cycle, go into G1, then they synthesize their DNA as they enter the S phase, grow some more, and then divide into a daughter cell. And this cycle is upregulated in cancer cells. The transition from G1 to S is a highly regulated process, and the cyclin kinases, CDK4/6, CDK2, cyclin D, cyclin E, are really critical in regulating that transition from the first growth phase into the S phase where the DNA is getting synthesized. So this pathway is critically important in cancer.

We know that there is a lot of crosstalk between the cell cycle pathway and the androgen receptor pathway. Androgen receptors, like estrogen receptors, are key regulators of cell cycle and are really instrumental in the transcription of genes that allow for that G1 to S transition. Preclinical studies have demonstrated that, actually, inhibition of CDK4/6 triggers G1 arrest during the cell cycle and that inhibiting both CDK4 and CDK6 is essential to really impair that transition from G1 to S-phase. Many preclinical studies have been conducted in prostate cancer that have really honed in on this pathway and the synergy that occurs with CDK4/6 inhibition and AR targeting.

Just to kind of level set, there are multiple CDK4/6 inhibitors that are available: abemaciclib, ribociclib, palbociclib. These are all administered slightly differently with different dosing schedules. They have different pharmacokinetic profiles, their half-lives differ, their metabolism differs, and CNS penetration differs. Abemaciclib is a highly potent agent, probably the best-in-class agent when we look at ribociclib and palbociclib for its ability to actually inhibit CDK4 and CDK6, and also does have some activity at CDK9. So I think it's broadly utilized in other solid tumor malignancies, particularly breast cancer.

Let's dive into some of the data. The first study that I want to share with you is CYCLONE 1. This was a study conducted in a very refractory treatment setting of men with metastatic castration-resistant prostate cancer. It was a phase I study that was looking at abemaciclib as monotherapy for patients with advanced disease. You can see that this was a really sick patient population. Almost 47% of patients had visceral metastases, almost 28% of patients had liver metastases, and the median number of prior mCRPC therapies was three. So, a very refractory setting, and some may even argue that whether these patients have disease that's driven by the androgen receptor is questionable. The response rate in the context of this trial demonstrated a soft tissue response rate of almost 12% and an objective response rate without bone progression of 6.8%, with a stable disease rate of 40.9%. So some signal of efficacy in this very refractory patient population.

There have been other studies that have looked at other CDK4/6 inhibitors in combination with AR-targeting agents. There was a study that was presented by Dr. Kelly of ribociclib with enzalutamide. It was a standard 3+3 dose-escalation design, and then went into a phase II portion where there was a randomization to enzalutamide alone. And I think, really, what we learned from this study is that there were significant drug-drug interactions with the combination of enzalutamide and ribociclib, and enzalutamide actually resulted in decreased concentrations of palbociclib in the context of this study.

Ribociclib has also been investigated in combination with docetaxel in the mCRPC setting. Here is the data of a phase Ib/II multicenter, open-label study of ribociclib with docetaxel, with a primary endpoint of 6-month radiographic progression-free survival. There was a total of 42 patients that were enrolled in this trial, 30 of whom were enrolled onto the phase II portion of the study. The phase II recommended dose was 60 milligrams of docetaxel with ribociclib at 40 milligrams daily, given days 1 through 4 and 8 through 15 of each cycle. When we looked at the primary endpoint, it was met for the trial. The 6-month rPFS rate was 65.8%, with a median rPFS of 8.1 months. So we definitely see a signal of activity, but again, it's hard to really differentiate what was the contribution of ribociclib versus docetaxel in this small single-arm, phase II trial.

Palbociclib has also been investigated in a Canadian study, a pan-solid tumor study, a pan-prostate cancer study looking at multiple agents based on biomarker selection utilizing ctDNA. There was an arm looking at palbociclib specifically for individuals that had alterations in the CDK pathway. What you can really see in the 14 patients that were presented here is minimal activity of palbociclib in this cohort analysis.

Some other trials that are currently ongoing: the UPLIFT study is being conducted in patients with PSMA PET-positive disease who had received prior ARSI and prior docetaxel. This is a two-part study looking at the combination of abemaciclib with lutetium-PSMA-617. The primary endpoint here is dosing and safety, and change in maximum SUV. This trial is currently enrolling patients.

There is also another study looking at the combination of abemaciclib with atezolizumab for patients with metastatic CRPC that are post an ARSI plus a prior taxane, based on preclinical data of this combination as well. This study is also currently accruing.

The next study that we're going to highlight is the CYCLONE 2 study. So this is moving earlier on in the mCRPC setting, where the prior studies we talked about were in the post-ARSI, post-taxane setting. This study is really looking in the first-line mCRPC setting. This was a pretty expansive study. It was a phase II/III study that actually embedded dose-finding and dose optimization of the combination of abiraterone with abemaciclib. It was a phase II/III study. In phase II, the combination of abiraterone was compared to abemaciclib versus abiraterone compared to placebo with a go/no-go decision to move into phase III. This study has completed accrual, did go on to complete full enrollment to phase III, and we're eagerly awaiting the results.

Lastly, now continuing to move on in the earlier disease setting, the CYCLONE 3 trial is looking at abemaciclib for patients with metastatic hormone-sensitive prostate cancer. This trial is particularly enrolling patients who have high-risk disease with greater than or equal to four more bone metastases based on a bone scan or the presence of visceral metastases on conventional imaging. Patients are randomized 1:1 to receive abiraterone with abemaciclib versus abiraterone with placebo, with a primary endpoint of rPFS. This is really going to be a critically important study in understanding the landscape of mHSPC and really augmenting treatment for those high-risk individuals whom we know, at the present time, the current standard of care is suboptimal. The majority of these patients go on to progress to develop castration resistance.

Moving even earlier in the treatment landscape, so for localized high-risk disease, there is a study that is looking at the combination of neoadjuvant abemaciclib with darolutamide. This is a two-part study. The first part of this study is a phase I in patients with CRPC assessing the appropriate dosing of darolutamide in combination with abemaciclib. Once the recommended phase II dose is determined, the study will move into a randomized phase II where the combination of darolutamide with abemaciclib will be compared to just ADT plus darolutamide for 6 months prior to radical prostatectomy, with a primary endpoint of post-CR minimal residual disease. I think this will be an important study that also is going to embed paired tissue analyses from baseline biopsies to the radical prostatectomy specimens to really understand mechanisms of response and resistance to abemaciclib.

In conclusion, the CDK4/6 pathway is particularly a promising therapeutic target in prostate cancer. AR is a key regulator of the cell cycle and is really instrumental in that regulation of transcription of genes that allow for that G1 to S transition, and there are multiple trials that are investigating CDK4/6 inhibitors across multiple disease spaces in advanced prostate cancer.