ASCO 2015. News in Breast Cancer: PALOMA3 Trial

American Society of Clinical Oncology (ASCO 2015)

ASCO 2015. LBA502. 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.

Nicholas C. Turner, Jungsil Ro, Fabrice Andre, Sherene Loi, Sunil Verma, Hiroji Iwata, Nadia Harbeck, Sibylle Loibl, Cynthia Huang Bartlett, Ke Zhang, Carla Giorgetti, Sophia Randolph, Maria Koehler, Massimo Cristofanilli; Royal Marsden, London & Surrey, United Kingdom; Natl Cancer Ctr, Goyang-si, Korea South; Institut Gustave Roussy, Villejuif, France; Peter MacCallum Cancer Centre, East Melbourne, Australia; Sunnybrook Odette Cancer Centre, Toronto, ON, Canada; Aichi Cancer Center Hospital, Nagoya, Japan; University of Munich, Otterfing, Germany; German Breast Group, Neu-Isenburg, Germany; Pfizer Oncology, New York, NY; Pfizer Inc, San Diego, CA; Pfizer, Milan, Italy; Pfizer Oncology, La Jolla, CA; Pfizer Oncology, Narberth, PA; Thomas Jefferson University, Philadelphia, PA

Background: The growth of hormone receptor (HR) positive breast cancer (BC) is dependent on the cyclin dependent kinases CDK4/6, that promote G1-S phase cell cycle progression. Resistance to endocrine treatment remains a major clinical problem for patients with hormone receptor positive breast cancer. The PALOMA3 study assessed the efficacy of palbociclib and fulvestrant in endocrine-resistant advanced breast cancer. 

Methods: In this double-blind phase 3 study women with HR positive/HER2 negative advanced metastatic BC whose cancer had relapsed or progressed on prior endocrine therapy, were randomized 2:1 to palbociclib (Palbo, 125 mg/d orally for 3 wk followed by 1 wk off) and fulvestrant (F, 500 mg per standard of care) or placebo (PLB) and F. Pre- and peri-menopausal women also received goserelin. One previous line of chemotherapy for metastatic disease was permitted. The primary endpoint was investigator assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), response assessment, patient-reported outcomes, and safety and tolerability. A pre-planned interim analysis was performed after 195 PFS events by an independent data monitoring committee. 

Results: 521 pts were randomized, 347 to receive Palbo+F and 174 to PLB+F. 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 pts. At the time of the interim analysis the study met the primary endpoint, median PFS was 9.2 months for Palbo+F and 3.8 months for PLB+F (HR 0.422, 95% CI 0.318 to 0.560, P<0.000001). Consistent benefit from Palbo was seen in pre- and post-menopausal women. The most common adverse effects Palbo+F versus PLB+F 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% pts on Palbo+F and 0.6% pts on PLB+F. The discontinuation rate due to adverse events was 2.0% on Palbo and 1.7% on PLB. 

Conclusions: Palbociclib combined with fulvestrant improved progression free survival in hormone receptor positive advanced breast cancer that had progressed on prior endocrine therapy, and can be considered as a treatment option for these patients. Clinical trial information: NCT01942135


CARE Faculty Perspective:

- Since the initial excitement surrounding the randomized phase II PALOMA1/TRIO-181 trial, noting clinical benefit with the addition of palbociclib to first-line letrozole in the advanced ER+/HER2 negative postmenopausal breast cancer setting (median PFS 10·2 months letrozole group and 20·2 months for the palbociclib plus letrozole group [HR 0·488]), the breast cancer community has been eagerly awaiting larger scale confirmatory clinical trials. 

- The PALOMA3 data presented at ASCO 2015 (and subsequently published online)2, is the first Phase III study to confirm statistically and clinically significant improvements in PFS with the addition of palbociclib to endocrine therapy (fulvestrant +/- goserelin). 

- At the first pre-planned interim analysis, median PFS was reported as 9.2 months for Palbociclib + Fulvestrant and 3.8 months for placebo + Fulvestrant  [HR 0.422, 95% CI 0.318 to 0.560, P<0.000001]. The number of deaths in the PALOMA3 study at the time of the interim analysis was insufficient to assess overall survival and therefore the effect of palbociclib on overall survival is unknown.

- Apart from the trial phase, the PALOMA3 study differed from PALOMA1 in that both pre- and post-menopausal women with previously treated ER+/HER2 negative advanced breast cancer were allowed enrolment.  PALOMA3 patients were also a more heavily pre-treated group with all having prior endocrine therapy in the advanced setting (79% were sensitive to prior endocrine therapy) and 33% of patients having prior chemotherapy for advanced disease.  Despite numerous efforts to date, no other biomarker, apart from ER positivity, has predicted for a differential benefit with palbociclib addition.

- While further follow-up is ongoing, if the phase III PALOMA2/TRIO-22 trial (postmenopausal ER+ advanced breast cancer) also confirms the benefit of palbociclib to first line endocrine therapy with letrozole - CDK 4/6 inhibition with palbociclib has the potential to truly establish itself as a standard of care in the management of ER+/HER2 negative advanced breast cancer (with a role in pre- and postmenopausal, de-novo and pre-treated settings). It also has the potential to supplant the sequence of use of the current generation mTOR inhibitor treatment given the comparative risk:benefit profile. Evaluations of other competitor molecules (e.g. ribociclib and abemaciclib) are ongoing and adjuvant studies with palbociclib are also in development.

- Lastly, while the combination of palbociclib and endocrine therapy was well tolerated overall with patients (with an increase in asymptomatic neutropenia again confirmed in PALOMA3) – the estimated retail price of the drug (up to $10,000 USD/month) is not likely to be well tolerated by payers, and even less so in the Canadian health care context. 

- CARE Oncology Faculty


1.     Finn RS, Crown JP, Lang I, 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

2.     Turner NC, Ro J, André F, Loi S, Verma S et al. Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer. NEJM. June 1, 2015. DOI: 10.1056/NEJMoa1505270.  

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