The Future of CDK4/6 Inhibitors for Prostate Cancer May Need to Draw Inspiration from Goldilocks and the Three Bears — Cyclin dependent kinases (CDKs) and D-type cyclins (CCND) have a critical role in cell cycle progression from G1 to S phase.1 Several tumors have been shown to have alterations of proteins involved in the activity and regulation of this complex. Multiple small molecule inhibitors have been developed to target CDK 4/6, including ribociclib, palbociclib and abemaciclib.2 These agents are now regulatory approved in combination with aromatase inhibitors or fulvestrant for patients with metastatic breast cancer.

It is rather easy to draw analogies between many of the treatments utilized for breast cancer to prostate cancer, as both are hormonally-driven tumors. For example, aromatase inhibitors inhibit production of estrogen, resulting in successful metastatic and adjuvant treatment of hormone receptor positive breast cancer. Similarly, abiraterone acetate inhibits synthesis of testosterone, and improves survival for men with both metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC).3-6 Fulvestrant is a selective estrogen receptor degrader also utilized for hormone-receptor positive metastatic breast cancer. In a similar manner, enzalutamide, apalutamide, and darolutamide are all irreversible androgen receptor inhibitors that offer benefit for men with multiple prostate cancer disease states.7-13

Theoretically, the use of CDK 4/6 inhibitors in prostate cancer also makes sense, however, it is important to consider the mechanism of action for optimal patient selection. CDK 4/6 inhibitors lead to inactivation of CCND-CDK 4/6 complexes, resulting in increased activity of the phosphorylated Rb protein. This results in G1 arrest and eventual apoptosis.14, 15 Importantly, we are detecting an increase in Rb inactivation in treatment-resistant prostate cancer,16 so it makes sense to evaluate that molecular pathway to select patients with an intact Rb pathway for treatment on CDK 4/6 inhibitor trials.

A trial was presented at the 2018 Genitourinary Cancers Symposium that co-targeted the androgen receptor and the cell cycle with androgen deprivation therapy (ADT) and palbociclib, respectively, in men with mCSPC.17 Given the generally long duration of response to ADT for men with new mCSPC, a previously identified prognostic intermediate endpoint of PSA <4 ng/mL at 28 weeks,18, 19 was utilized as the primary endpoint in the above trial, to gather early inklings of potential efficacy.  The patients were randomized 2:1 to ADT + palbociclib 125 mg po 3 weeks on, 1 week off versus ADT alone. Accrual was completed with 72 eligible patients, 64/72 (90%) patients with adequate tissue for Rb analysis, and 62/64 (97%) with retained Rb expression by immunohistochemistry. This high rate of retained Rb expression is not surprising given the earlier disease state evaluated, since Rb loss tends to occur later in CRPC.20 In the palbociclib arm, 32/40 (80%) achieved a PSA <4 ng/mL at 28 weeks, compared with an identical 16/20 (80%) rate in the ADT alone arm (p=0.87). Data on progression-free survival and biomarker analyses are pending.

Although the initial results with palbociclib may seem disappointing, we have to recognize that these cell cycle inhibitors may yield the greatest promise in treatment-resistant mCRPC and not in earlier disease states. This is because CRPC cells generally harbor more alterations in the cell cycle that may predispose to greater susceptibility to CDK 4/6 inhibitors.21 Combining CDK 4/6 inhibitors with androgen biosynthesis inhibitors and pure androgen receptor antagonists, like abiraterone and enzalutamide, respectively, may also produce more promising results.

The above concepts are already being tested in ongoing clinical trials, highlighted below. As more efforts focus in on this area, it will be important to recognize that the development of these agents may need to draw inspiration from Goldilocks and the Three Bears. Non-sequitur? Not quite.  The challenge with administering a CDK 4/6 inhibitor too early in the evolution of disease is that we may not capture a population of patients with enough cell cycle abnormalities for optimal effect. Additionally, any effect may be blanketed by the very potent, sustained biological and clinical effects of ADT; potential biological efficacy may not be easy to detect. Administering these agents too late also runs significant risks of missing the optimal patient population. As Rb inactivation seems to evolve in later disease states, treating these patients with CDK 4/6 inhibitors offers little promise for success, given the mechanism of action of these agents. Therefore, like Goldilocks, finding the “just right” situation is crucial for success in the developmental strategy of this class of promising drugs.  It is likely important to ensure Rb expression is maintained in target study populations for CDK 4/6 inhibitor treatment. Fortunately, we will continue to learn more as the results of the below trials will further shape this field.

Highlighted trials for prostate cancer patients using CDK 4/6 inhibitors

  • Randomized phase 2 trial of abiraterone +/- abemaciclib for mCRPC (NCT03706365)
  • Phase 2 trial of palbociclib for mCRPC (NCT02905318)
  • Randomized phase 1/2 trial of enzalutamide +/- ribociclib for mCRPC with retained Rb expression (NCT02555189)
  • Phase 1/2 trial of ribociclib + docetaxel/prednisone for mCRPC (NCT02494921)

Written by: Evan Yu, MD, Professor, Department of Medical Oncology, University of Washington School of Medicine,  Member, Fred Hutchinson Cancer Research Center and Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center


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