When Paired With Palbociclib, Fulvestrant and Letrozole Yield Comparable Results in PARSIFAL Trial

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When paired with palbociclib in the first-line treatment of metastatic breast cancer, fulvestrant and letrozole performed comparably, with no statistical superiority in progression-free or overall survival shown for either endocrine agent, in the phase II PARSIFAL study presented during the ASCO20 Virtual Scientific Program.1

“PARSIFAL was inconclusive in establishing superiority between the two endocrine backbone agents [fulvestrant and letrozole] when combined with palbociclib.”
— Antonio Llombart-Cussac, MD, PhD

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The study’s hypothesis was that fulvestrant would be the superior partner to the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, but “no major efficacy differences were observed by the two stratification factors, visceral or de novo metastatic disease,” said Antonio Llombart-Cussac, MD, PhD, of Universidad Catolica Valencia and Medica Scientia Innovation Research, Spain.

“PARSIFAL was inconclusive in establishing superiority between the two endocrine backbone agents when combined with palbociclib. The final treatment decision must balance patients’ and clinicians’ preferences as well as subsequent treatment strategies,” he added.

Erika P. Hamilton, MD

Erika P. Hamilton, MD

Breast cancer highlights speaker Erika Hamilton, MD, Director of the Breast Cancer and Gynecologic Cancer Research Program at Sarah Cannon Research Institute at Tennessee Oncology, noted that PARSIFAL’s findings differed from those of the FALCON trial, which showed progression-free survival to be superior with fulvestrant vs anastrozole.2 Dr. Hamilton noted: “How do we reconcile these findings? If we assume the results of both trials are accurate, it seems that just because SERD may be better than AI when they are given alone, this superiority doesn’t necessarily hold true when the endocrine agents are in combination with a second drug.”


In metastatic breast cancer resistant to endocrine therapy, a CDK4/6 inhibitor plus fulvestrant has improved survival in several trials. In patients with endocrine-naive metastatic breast cancer, fulvestrant conveyed a progression-free survival benefit over anastrozole in the FALCON trial,2 as previously mentioned. “PARSIFAL wanted to explore the optimal endocrine agent to combine with palbociclib in the first-line -endocrine-sensitive scenario,” Dr. Llombart-Cussac said.

PARSIFAL enrolled 486 women with endocrine-sensitive metastatic breast cancer and no prior therapy for advanced disease. The arms were well balanced in terms of baseline characteristics and prior treatment. Patients were randomly assigned to palbociclib at 125 mg daily on a 21-day schedule plus fulvestrant at 500 mg on days 1, 14, 29, and monthly thereafter or letrozole at 2.5 mg once daily, continuously.

The study assumed a 22-month median progression-free survival with letrozole plus palbociclib. The two-sided log-rank test had 80% power to detect a 0.70 hazard ratio (HR) for fulvestrant, equating to a median progression-free survival of 31.3 months. If superiority was not achieved, the plan was to switch to a noninferiority analysis whose margin was a hazard ratio of 1.21.

No Differences Observed

At a median follow-up of 32 months, in the investigator-assessed intent-to-treat analysis, median progression-free survival was 32.8 months with letrozole/palbociclib and 27.9 months with fulvestrant/palbociclib (HR = 1.13; P = .321). “At this point, we failed to see a significant difference. As the superiority of fulvestrant was not achieved, we proceeded with the noninferiority analysis. Those results were inconclusive,” Dr. Llombart-Cussac reported.

No differences were seen according to the presence of visceral disease (in both arms, nonvisceral disease was associated with notably longer remission), by disease presentation (recurrent vs de novo), or by prespecified subgroup. With 21% of deaths having occurred at the time of analysis, 3-year overall survival also did not differ: 77.1% with letrozole and 79.4% with fulvestrant (HR = 1.00; P = .986).


  • The PARSIFAL trial evaluated fulvestrant vs letrozole, both paired with palbociclib, in the first-line treatment of metastatic breast cancer.
  • The hypothesis was that fulvestrant plus palbociclib would yield superior progression-free survival, but this was not the case.
  • Median progression-free survival was 27.9 months with fulvestrant plus palbociclib and 32.8 months with letrozole plus palbociclib and (HR = 1.13; P = .321).

Objective response rate, clinical benefit rate, and relative dose intensity were also similar between the arms. Adverse events, whether related to treatment or not, were similar as well, although more patients receiving fulvestrant discontinued therapy because of toxicity or other reasons.

Focusing on toxicities of special interest, Dr. Llombart-Cussac noted that the rate of thromboembolic events was low in both arms (4.5% with letrozole, 5.8% with fulvestrant), although two grade 4 events were observed with fulvestrant. Interstitial lung disease and pneumonitis of any grade were seen in six patients in each arm; grade 3 events occurred in three patients receiving letrozole and two patients receiving fulvestrant. 

DISCLOSURE: Dr. Llombart-Cusssac disclosed financial relationships with Celgene, Eisai, Lilly, MSD, Pfizer, Roche, Initia Research, MedSIR, Genomic Health, GlaxoSmithKline, Novartis, Pierre Fabre, AstraZeneca, Agendia, Foundation Medicine, and Pierre Fabre. Dr. Hamilton has received consulting fees (paid to institution only) from Pfizer, Genentech/Roche, Lilly, Puma Biotechnology, Daiichi Sankyo, Mersana Therapeutics, Boehringer Ingelheim, AstraZeneca, Novartis, Silverback Therapeutics, Black Diamond, and NanoString; and has received institutional research support from Seattle Genetics, Puma, AstraZeneca, Hutchinson MediPharma, OncoMed, MedImmune, StemCentrx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Mersana, Millenium, TapImmune, Lilly, BerGenBio, Medivation, Pfizer, Tesaro, Boehringer Ingelheim, Eisai, H3 Biomedicine, Radius Health, Acerta, Takeda, Macrogenics, AbbVie, Immunomedics, FujiFilm, Effector, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Daiichi Sankyo, ArQule, Syros, Clovis, Cytomx, InventisBio, Deciphera, Unum Therapeutics, Sermonix Pharmaceuticals, Sutro, Aravive, Zenith Epigenetics, Arvinas, Torque, Harpoon, Fochon, Black Diamond, Orinove, Molecular Templates, Silverback Therapeutics, Compugen, G1Therapeutics, Karyopharm Therapeutics, and Torque Therapeutics.


1. Llombart-Cussac A, Perez-Garcia JM, Bellet M, et al: PARSIFAL: A randomized multicenter open-label, phase II trial to evaluate palbociclib in combination with fulvestrant or letrozole in endocrine-sensitive patients with estrogen receptor/HER2– metastatic breast cancer. ASCO20 Virtual Scientific Program. Abstract 1007.

2. Robertson JFR, Bondarenko IM, Trishkina E, et al: Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): An international, randomised, double-blind, phase 3 trial. Lancet 388:2997-3005, 2016.

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