PALOMA3 Results Show that Palbociclib in Combination With Fulvestrant Could Offer an Effective and Less Toxic Treatment Option for Endocrine-Resistant Metastatic Breast Cancer

Results of the PALOMA3 study presented at 2015 ASCO Annual Meeting

A new phase III study in patients with endocrine-resistant disease, showed that palbociclib when combined with fulvestrant, improved progression-free survival (PFS) in women with hormone-receptor (HR)-positive, HER2-negative advanced breast cancer. Benefit from palbociclib was also demonstrated across pre-specified subgroups. Palbociclib was well tolerated. The results were presented at the 2015 ASCO Annual Meeting (29 May – 2 June, Chicago, USA) by Prof. Nicholas Turner of the Royal Marsden Hospital, London, UK on behalf of the PALOMA3 study investigators and published simultaneously in the New England Journal of Medicine.

Resistance to endocrine therapy presents a major clinical challenge in patients with metastatic breast cancer. The growth of HR-positive breast cancer is dependent on Cyclin D1, a direct transcriptional target of oestrogen receptor (ER). Cyclin D1 activates CDK 4/6 resulting in G1-S phase transition and entry into the cell cycle. Cell line models of endocrine resistance remain dependent on Cyclin D1 and CDK 4/6.

Palbociclib is an orally active selective inhibitor of CDK 4/6 that inhibits cell proliferation and DNA synthesis by preventing cell-cycle progression from G1 to S phase. Palbociclib is active in cell line models of endocrine therapy resistance and is synergistic with fulvestrant.

Palbociclib was approved by the US Food and Drug Administration (FDA) on February 3rd, 2015, based on data from the PALOMA1, an open-label phase II clinical trial in postmenopausal women with newly-diagnosed ER-positive/HER2-negative breast cancer that had not received any treatment for their advanced disease. PALOMA1 showed that palbociclib in combination with letrozole, doubled progression-free survival (PFS) from a median of 10 months with letrozole plus placebo, to 20 months for palbociclib plus letrozole. The drug was approved by the FDA as a combination first-line therapy for postmenopausal women with ER-positive/HER2-negative breast cancer, as initial endocrine-based treatment for their metastatic disease.

PALOMA3 study

In PALOMA3, a double-blind phase III study, women with HR-positive/HER2-negative advanced metastatic breast cancer, whose disease had relapsed or progressed on prior endocrine therapy, were randomised 2:1 to palbociclib and fulvestrant or placebo and fulvestrant. Pre- and peri-menopausal women also received goserelin. One previous line of chemotherapy for metastatic disease was permitted.

The primary endpoint was investigator assessed PFS. Secondary endpoints included overall survival (OS), response assessment, patient-reported outcomes, and safety and tolerability.

The study experienced very rapid enrollment and at the preplanned independent data and safety monitoring review panel, the study was stopped early only 10 months after the study commenced because it met the primary endpoint of improving PFS.

From September 2013 to August 2014, 521 patients were randomised, 347 to receive palbociclib plus fulvestrant and 174 to placebo plus fulvestrant. Baseline characteristics were well balanced. The median age was 57 and 56 years, 79% were post-menopausal, 60% had visceral disease, and 79% were sensitive to prior endocrine therapy. Prior therapy included chemotherapy for advanced disease in 33% of patients.

At the time of the interim analysis the study met the primary endpoint, median PFS was 9.2 months for palbociclib plus fulvestrant and 3.8 months for placebo plus fulvestrant (hazard ratio, HR 0.422, p < 0.000001). Consistent benefit from palbociclib was seen in pre- and post-menopausal women.

The most common adverse effects in the palbociclib plus fulvestrant vs placebo plus fulvestrant arms were neutropenia (78.8% vs 3.5%), leucopenia (45.5% vs 4.1%), and fatigue (38.0% vs 26.7%). Febrile neutropenia was reported in 0.6% patients on palbociclib plus fulvestrant and 0.6% patients on placebo plus fulvestrant. The discontinuation rate due to adverse events was 2.0% on palbociclib and 1.7% on placebo.

The rates of nausea and fatigue were low and overall slightly elevated over placebo group, but the increase was not statistically significant. The drug was better tolerated than other biological therapies used in this setting. Furthermore, there was a significant difference in quality of life as measured by the rate of clinical deterioration of symptomatic disease in patients treated with the investigational combination.

The study authors concluded that palbociclib in combination with fulvestrant is an effective treatment option for patients with advanced breast cancer whose disease progressed on prior endocrine therapy. 

PALOMA3 clinical implications

Typically the first-line therapy for patients with ER-positive/HER-negative metastatic breast cancer is to administer hormone therapy. However, many tumours become resistant to endocrine therapy. Palbociclib blocks a major alternate route, the CDK 4/6 growth signal, by inhibiting cancer cell proliferation and cellular division.

"Although palbociclib has yet to be approved for this population of women, this study is likely to be practice changing," said in accompanied press release Dr Massimo Cristofanilli, Director of the Breast Care Center at Thomas Jefferson University and senior author of the study. "I don't envision a situation where single-agent endocrine therapy would be appropriate any longer for ER+/Her2- metastatic breast cancer patients."

"These are women with advanced metastatic cancer whose disease was kept in check without the use of toxic and life-disrupting chemotherapy," said Dr Cristofanilli. "Part of what was exciting about the design of this clinical trial is that we decided early on to accept women from a younger and generally sicker population than is typically enrolled in clinical trials," continued Dr Cristofanilli, who is also a researcher at the Sidney Kimmel Cancer Center at Thomas Jefferson University.

The PALOMA3 study was sponsored by Pfizer. Fulvestrant was provided by AstraZeneca.

Emerging CDK 4/6 inhibitors

Dr Joseph Sparano, who discussed the study results, said that CDK 4/6 inhibitors represent important therapeutic advance in ER-positive metastatic breast cancer. Other CDK inhibitors in phase III trials for advanced ER-positive breast cancer are ribociclib, currently under investigation in postmenopausal women with or without letrozole in the MONALEESA-2 study and with or without fulvestrant in the MONALEESA-3 study; ribociclib is also under investigation in premenopausal women in the MONALEESA-7 study in combination with tamoxifen and goserelin or a non-steroidal aromatase inhibitor and goserelin. Abemeciclib is studied in postmenopausal women with or without fulvestrant in the MONARCH 2 study, while the MONARCH 3 study tests non-steroidal aromatase inhibitor with or without abemeciclib in postmenopausal women.

The PALbociclib CoLlaborative Adjuvant Study (PALLAS) plans to randomise 1:1 in the adjuvant setting palbociclib for 2 years plus endocrine treatment for 5 years vs endocrine treatment alone for 5 years in 4,600 patients with HR-positive/HER-negative stage II or III breast cancer.


Turner N, Ro J, Andre F,et al.PALOMA3: A double-blind, phase III trial of fulvestrant with or without palbociclib in pre- and post-menopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy. Presented at 2015 ASCO Annual Meeting; J Clin Oncol 33, 2015 (suppl; abstr LBA502).

Turner N, Ro J, Andre F, et al. Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer. NEJM 2015; Online First June 1. DOI: 10.1056/NEJMoa1505270