Loibl, S., Turner, N. C., Ro, J., Cristofanilli, M., Iwata, H., Im, S. A., Masuda, N., Loi, S., Andre, F., Harbeck, N., Verma, S., Folkerd, E., Theall, K. P., Hoffman, J., Zhang, K., Bartlett, C. H., Dowsett, M. (2017) Palbociclib Combined with Fulvestrant in Premenopausal Women with Advanced Breast Cancer and Prior Progression on Endocrine Therapy: PALOMA-3 Results. ONCOLOGIST, 22 (9). pp. 1028-1038. ISSN 1083-7159

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Abstract

Background. The efficacy and safety of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, combined with fulvestrant and goserelin was assessed in premenopausal women with advanced breast cancer (ABC) who had progressed on prior endocrine therapy (ET). Patients and Methods. One hundred eight premenopausal endocrine-refractory women >= 18 years with hormone receptor-positive (HR1)/human epidermal growth factor receptor 2-negative (HER2-) ABC were among 521 women randomized 2:1 (347:174) to fulvestrant (500 mg) +/- goserelin with either palbociclib (125 mg/day orally, 3 weeks on, 1 week off) or placebo. This analysis assessed whether the overall tolerable safety profile and significant progression-free survival (PFS) improvement extended to premenopausal women. Potential drug-drug interactions (DDIs) and ovarian suppression with goserelin were assessed via plasma pharmacokinetics and biochemical analyses, respectively. (ClinicalTrials.gov identifier: NCT01942135) Results. Median PFS for premenopausal women in the palbociclib (n = 72) versus placebo arm (n = 36) was 9.5 versus 5.6 months, respectively (hazard ratio, 0.50, 95% confidence interval: 0.29-0.87), and consistent with the significant PFS improvement in the same arms for postmenopausal women. Any-grade and grade <= 3 neutropenia, leukopenia, and infections were among the most frequent adverse events reported in the palbociclib arm with concurrent goserelin administration. Hormone concentrations were similar between treatment arms and confirmed sustained ovarian suppression. Clinically relevant DDIs were not observed. Conclusion. Palbociclib combined with fulvestrant and goserelin was an effective and well-tolerated treatment for premenopausal women with prior endocrine-resistant HR+HER2- ABC. Inclusion of both premenopausal and postmenopausal women in pivotal combination ET trials facilitates access to novel drugs for young women and should be considered as a new standard for clinical trial design.

Item Type:	Article
Authors (ICR Faculty only):	Dowsett, Mitch
All Authors:	Loibl, S., Turner, N. C., Ro, J., Cristofanilli, M., Iwata, H., Im, S. A., Masuda, N., Loi, S., Andre, F., Harbeck, N., Verma, S., Folkerd, E., Theall, K. P., Hoffman, J., Zhang, K., Bartlett, C. H., Dowsett, M.
Additional Information:	ISI Document Delivery No.: FG8DD Times Cited: 0 Cited Reference Count: 39 Loibl, Sibylle Turner, Nicholas C. Ro, Jungsil Cristofanilli, Massimo Iwata, Hiroji Im, Seock-Ah Masuda, Norikazu Loi, Sherene Andre, Fabrice Harbeck, Nadia Verma, Sunil Folkerd, Elizabeth Theall, Kathy Puyana Hoffman, Justin Zhang, Ke Bartlett, Cynthia Huang Dowsett, Mitchell Pfizer We are grateful to the patients, the investigators, and the study personnel who participated in the PALOMA-3 trial. The authors would also like to acknowledge the efforts of Maria Koehler, who led the study design and collaborated with investigators performing the biochemical analyses. The FSH, LH, and E2 data in the manuscript were generated by the Centre Royal Marsden Hospital. Fulvestrant was provided by AstraZeneca. This study has been presented in part as a poster discussion at the ASCO Annual Meeting, June 3-7, 2016, Chicago, IL, USA. Editorial support was provided by Susan Reinwald, Ph.D., of Complete Healthcare Communications, LLC, and was funded by Pfizer. This study was sponsored by Pfizer. Final approval of the manuscript rested solely with the authors. 0 Wiley Hoboken 1549-490x
Uncontrolled Keywords:	Palbociclib Fulvestrant Goserelin Breast cancer Premenopausal Neoplasm metastasis phase-ii trial ovarian suppression goserelin tamoxifen efficacy anastrozole combination confidence exemestane recurrent Oncology
Research teams:	ICR divisions > Breast Cancer Research > Endocrinology ICR divisions > Molecular Pathology > Endocrinology
Depositing User:	Barry Jenkins
Date Deposited:	10 Oct 2017 15:42
Last Modified:	10 Oct 2017 15:42
URI:	http://publications.icr.ac.uk/id/eprint/16292

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