Clinical and Translational Oncology

, Volume 20, Issue 9, pp 1136–1144 | Cite as

Preclinical and clinical development of palbociclib and future perspectives

  • E. Martínez de Dueñas
  • J. Gavila-Gregori
  • S. Olmos-Antón
  • A. Santaballa-Bertrán
  • A. Lluch-Hernández
  • E. J. Espinal-Domínguez
  • M. Rivero-Silva
  • A. Llombart-Cussac
Review Article


Cyclin-dependent kinases (CDKs) play a key role in cell cycle regulation, which makes them a clear therapeutic target to interfere with cell division and proliferation in cancer patients. Palbociclib, a specific inhibitor of CDK4/6 with outstanding clinical efficacy data and limited toxicity, has been recently approved for the treatment of hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer, either in combination with an aromatase inhibitor or in combination with fulvestrant in women who have received prior endocrine therapy. This review describes the mechanism of action, preclinical experiences and clinical data of palbociclib, with a special focus on integrating this data with the positioning of palbociclib in the current clinical guidelines for advanced HR-positive/HER2-negative breast cancer. Aspects of the ongoing major studies are also presented, as well as future prospects in the development of palbociclib.


Cyclin Cell cycle Anti-tumor Breast cancer PI3K Palbociclib Cyclin-dependent kinases CDK4/6 



The authors wish to thank Dr. Fernando Sánchez-Barbero from HealthCo S.L. (Madrid, Spain) for his help in the preparation of the manuscript. Pfizer provided comment on the first draft of this manuscript, but thereafter authors made all the decisions about its contents.


Pfizer provided the financial support of medical writing services.

Compliance with ethical standards

Conflict of interest

The authors declare that they do not have any conflict of interest that may inappropriately influence this work.

Ethical statement

The study has been performed in accordance with the ethical standards of the Declaration of Helsinki and its later amendments. This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–66.CrossRefPubMedGoogle Scholar
  2. 2.
    (FDA) USFDAUS. Palbociclib (IBRANCE). 2017. Accessed 30 June 2017.
  3. 3.
  4. 4.
    Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.CrossRefGoogle Scholar
  5. 5.
    Witkiewicz AK, Knudsen ES. Retinoblastoma tumor suppressor pathway in breast cancer: prognosis, precision medicine, and therapeutic interventions. Breast Cancer Res. 2014;16:207.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Fornier MN, Rathkopf D, Shah M, Patil S, O’Reilly E, Tse AN, et al. Phase I dose-finding study of weekly docetaxel followed by flavopiridol for patients with advanced solid tumors. Clin Cancer Res. 2007;13:5841–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Toogood PL, Harvey PJ, Repine JT, Sheehan DJ, VanderWel SN, Zhou H, et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J Med Chem. 2005;48:2388–406.CrossRefPubMedGoogle Scholar
  8. 8.
    Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004;3:1427–38.PubMedGoogle Scholar
  9. 9.
    Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16:25–35.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Dean JL, Thangavel C, McClendon AK, Reed CA, Knudsen ES. Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene. 2010;29:4018–32.CrossRefPubMedGoogle Scholar
  11. 11.
    Hu W, Sung T, Jessen BA, Thibault S, Finkelstein MB, Khan NK, et al. Mechanistic investigation of bone marrow suppression associated with palbociclib and its differentiation from cytotoxic chemotherapies. Clin Cancer Res. 2016;22:2000–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11:R77.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Caldon CE, Sergio CM, Kang J, Muthukaruppan A, Boersma MN, Stone A, et al. Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells. Mol Cancer Ther. 2012;11:1488–99.CrossRefPubMedGoogle Scholar
  14. 14.
    Skildum AJ, Mukherjee S, Conrad SE. The cyclin-dependent kinase inhibitor p21WAF1/Cip1 is an antiestrogen-regulated inhibitor of Cdk4 in human breast cancer cells. J Biol Chem. 2002;277:5145–52.CrossRefPubMedGoogle Scholar
  15. 15.
    Wardell SE, Ellis MJ, Alley HM, Eisele K, VanArsdale T, Dann SG, et al. Efficacy of SERD/SERM hybrid-CDK4/6 inhibitor combinations in models of endocrine therapy-resistant breast cancer. Clin Cancer Res. 2015;21:5121–30.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Qin G, Xu F, Qin T, Zheng Q, Shi D, Xia W, et al. Palbociclib inhibits epithelial-mesenchymal transition and metastasis in breast cancer via c-Jun/COX-2 signaling pathway. Oncotarget. 2015;6:41794–808.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Dean JL, McClendon AK, Knudsen ES. Modification of the DNA damage response by therapeutic CDK4/6 inhibition. J Biol Chem. 2012;287:29075–87.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Roberts PJ, Bisi JE, Strum JC, Combest AJ, Darr DB, Usary JE, et al. Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy. J Natl Cancer Inst. 2012;104:476–87.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Clark A, O’Dwyer P, Troxel A, Lal P, Feldman M, Gallagher M, et al. Abstract P6-13-08: palbociclib and paclitaxel on an alternating schedule for advanced breast cancer: results of a phase Ib trial. Cancer Res. 2016;76:P6-13-08-P6-13-08.Google Scholar
  20. 20.
    Schwartz GK, LoRusso PM, Dickson MA, Randolph SS, Shaik MN, Wilner KD, et al. Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (schedule 2/1). Br J Cancer. 2011;104:1862–8.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Flaherty KT, Lorusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS, et al. Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res. 2012;18:568–76.CrossRefPubMedGoogle Scholar
  22. 22.
    DeMichele A, Clark AS, Tan KS, Heitjan DF, Gramlich K, Gallagher M, et al. CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res. 2015;21:995–1001.CrossRefPubMedGoogle Scholar
  23. 23.
    Finn RS, Hurvitz S, Allison M, Applebaum S, Glaspy J, DiCarlo B et al. Phase I study of PD 0332991, a novel, oral, cyclin-D kinase (CDK) 4/6 inhibitor in combination with letrozole, for first-line treatment of metastatic post-menopausal, estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Cancer Res. 2009;69(24 Suppl):5069.Google Scholar
  24. 24.
    Finn RS, Dieras V, Rugo HS, Joy AA, Moulder SL, Walshe JM, Mukai H, Shparyk YV. Palbociclib (PAL) + letrozole (L) as first-line (1L) therapy (tx) in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC): efficacy and safety across patient (pt) subgroups. J Clin Oncol. 2017;35(suppl; abstr 1039).
  25. 25.
    Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17:425–39.CrossRefPubMedGoogle Scholar
  26. 26.
    Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373:209–19.CrossRefPubMedGoogle Scholar
  27. 27.
    Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375:1925–36.CrossRefPubMedGoogle Scholar
  28. 28.
    Rugo HS, Rumble RB, Macrae E, Barton DL, Connolly HK, Dickler MN, et al. Endocrine therapy for hormone receptor-positive metastatic breast cancer: American society of clinical oncology guideline. J Clin Oncol. 2016;34:3069–103.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Wilcken N, Hornbuckle J, Ghersi D. Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer. Cochrane Database Syst Rev. 2003;CD002747.
  30. 30.
    Robertson JFR, Paridaens R, Bogaerts J, Rukazenkov Y, Campbell C, Bradbury I. Visceral metastases from hormone receptor positive breast cancer are as sensitive to endocrine therapy as non-visceral metastases. Cancer Res. 2015;75(9):P1-13-02.Google Scholar
  31. 31.
    Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520–9.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2018

Authors and Affiliations

  • E. Martínez de Dueñas
    • 1
  • J. Gavila-Gregori
    • 2
  • S. Olmos-Antón
    • 1
  • A. Santaballa-Bertrán
    • 3
  • A. Lluch-Hernández
    • 4
  • E. J. Espinal-Domínguez
    • 5
  • M. Rivero-Silva
    • 5
  • A. Llombart-Cussac
    • 6
  1. 1.Medical Oncology DepartmentProvincial Hospital of CastellónCastellón de la PlanaSpain
  2. 2.Medical Oncology DepartmentValencian Institute of OncologyValenciaSpain
  3. 3.La Fe University HospitalValenciaSpain
  4. 4.Clinic University Hospital of ValenciaValenciaSpain
  5. 5.Oncology UnitPfizer Inc.MadridSpain
  6. 6.Medical Oncology DepartmentArnau de Vilanova University HospitalValenciaSpain

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