From the Desk of Evan Yu: "What Works for Breast Cancer Should Work for Prostate Cancer, Right?"

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

References:

  1. Schettini, Francesco, Irene De Santo, Carmen Giusy Rea, Pietro De Placido, Luigi Formisano, Mario Giuliano, Grazia Arpino et al. "CDK 4/6 inhibitors as single agent in advanced solid tumors." Frontiers in oncology 8 (2018): 608.
  2. Batra, Anupam, and Eric Winquist. "Emerging cell cycle inhibitors for treating metastatic castration-resistant prostate cancer." Expert opinion on emerging drugs 23, no. 4 (2018): 271-282.
  3. De Bono, Johann S., Christopher J. Logothetis, Arturo Molina, Karim Fizazi, Scott North, Luis Chu, Kim N. Chi et al. "Abiraterone and increased survival in metastatic prostate cancer." New England Journal of Medicine 364, no. 21 (2011): 1995-2005.
  4. Ryan, Charles J., Matthew R. Smith, Johann S. De Bono, Arturo Molina, Christopher J. Logothetis, Paul De Souza, Karim Fizazi et al. "Abiraterone in metastatic prostate cancer without previous chemotherapy." New England Journal of Medicine 368, no. 2 (2013): 138-148.
  5. Fizazi, Karim, NamPhuong Tran, Luis Fein, Nobuaki Matsubara, Alfredo Rodriguez-Antolin, Boris Y. Alekseev, Mustafa Özgüroğlu et al. "Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer." New England Journal of Medicine 377, no. 4 (2017): 352-360.
  6. James, Nicholas D., Johann S. de Bono, Melissa R. Spears, Noel W. Clarke, Malcolm D. Mason, David P. Dearnaley, Alastair WS Ritchie et al. "Abiraterone for prostate cancer not previously treated with hormone therapy." New England Journal of Medicine 377, no. 4 (2017): 338-351.
  7. Scher, Howard I., Karim Fizazi, Fred Saad, Mary-Ellen Taplin, Cora N. Sternberg, Kurt Miller, Ronald de Wit et al. "Increased survival with enzalutamide in prostate cancer after chemotherapy." New England Journal of Medicine 367, no. 13 (2012): 1187-1197.
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  11. Smith, Matthew R., Fred Saad, Simon Chowdhury, Stéphane Oudard, Boris A. Hadaschik, Julie N. Graff, David Olmos et al. "Apalutamide treatment and metastasis-free survival in prostate cancer." New England Journal of Medicine 378, no. 15 (2018): 1408-1418.
  12. Chi, Kim N., Neeraj Agarwal, Anders Bjartell, Byung Ha Chung, Andrea J. Pereira de Santana Gomes, Robert Given, Álvaro Juárez Soto et al. "Apalutamide for metastatic, castration-sensitive prostate cancer." New England Journal of Medicine 381, no. 1 (2019): 13-24.
  13. Fizazi, Karim, Neal Shore, Teuvo L. Tammela, Albertas Ulys, Egils Vjaters, Sergey Polyakov, Mindaugas Jievaltas et al. "Darolutamide in nonmetastatic, castration-resistant prostate cancer." New England Journal of Medicine 380, no. 13 (2019): 1235-1246.
  14. Musgrove, Elizabeth A., C. Elizabeth Caldon, Jane Barraclough, Andrew Stone, and Robert L. Sutherland. "Cyclin D as a therapeutic target in cancer." Nature Reviews Cancer 11, no. 8 (2011): 558.
  15. Hamilton, Erika, and Jeffrey R. Infante. "Targeting CDK4/6 in patients with cancer." Cancer treatment reviews 45 (2016): 129-138.
  16. Choudhury, Atish D., and Himisha Beltran. "Retinoblastoma loss in cancer: casting a wider net." Clinical Cancer Research (2019): clincanres-1292.
  17. Palmbos, Phillip Lee, Scott A. Tomlins, Neeraj Agarwal, Przemyslaw Twardowski, Alicia K. Morgans, William Kevin Kelly, Vivek Arora et al. "Cotargeting AR signaling and cell cycle: A randomized phase II study of androgen deprivation therapy with or without palbociclib in RB-positive metastatic hormone sensitive prostate cancer (mHSPC)." (2018): 251-251.
  18. Hussain, Maha, Catherine M. Tangen, Celestia Higano, Paul F. Schelhammer, James Faulkner, E. David Crawford, George Wilding et al. "Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162)." Journal of clinical oncology 24, no. 24 (2006): 3984-3990.
  19. Harshman, Lauren C., Yu-Hui Chen, Glenn Liu, Michael A. Carducci, David Jarrard, Robert Dreicer, Noah Hahn et al. "Seven-month prostate-specific antigen is prognostic in metastatic hormone-sensitive prostate cancer treated with androgen deprivation with or without docetaxel." Journal of Clinical Oncology 36, no. 4 (2018): 376.
  20. Sharma, Ankur, Wen-Shuz Yeow, Adam Ertel, Ilsa Coleman, Nigel Clegg, Chellappagounder Thangavel, Colm Morrissey et al. "The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression." The Journal of clinical investigation 120, no. 12 (2010): 4478-4492.
  21. Wang, Qianben, Wei Li, Yong Zhang, Xin Yuan, Kexin Xu, Jindan Yu, Zhong Chen et al. "Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer." Cell 138, no. 2 (2009): 245-256.
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