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Expert Point of View: Komal Jhaveri, MD


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Komal Jhaveri, MD

Komal Jhaveri, MD

“Surprisingly, the phase II PARSIFAL trial did not show a statistical superiority in progression-free survival for fulvestrant plus palbociclib over letrozole plus palbociclib in the first-line treatment of patients with endocrine-sensitive, metastatic breast cancer. The noninferiority hypothesis was also refuted,” said Komal Jhaveri, MD, an attending physician at Memorial Sloan Kettering Cancer Center, Clinical Director of the Early Drug Development Service, and Assistant Professor of Medicine at Weill Cornell Medical College, who was the study’s invited discussant.

Comparison of Trials

Unlike the FALCON trial,1 where the benefit in progression-free survival was higher in those with nonvisceral disease, in the PARSIFAL trial, there was no statistical difference in patients with or without visceral disease. Similarly, in SWOG 0226 (which found advantages for fulvestrant plus anastrozole vs anastrozole alone),2 the overall survival benefit was notable in patients without previous exposure to adjuvant endocrine therapy, but PARSIFAL found no difference in patients with de novo vs recurrent disease, Dr. Jhaveri pointed out.

In the neoadjuvant setting, data from the ALTERNATE trial, also presented during this ASCO meeting,3 showed no difference in surrogate endpoints (modified PEPI [preoperative endocrine prognostic index] score and pathologic complete response rate) among fulvestrant alone, fulvestrant plus anastrozole, and anastrozole alone.3

“Could these conflicting results be related to our lack of understanding to mechanisms of resistance? TransFAL (the translational component of PARSIFAL) will have many interesting substudies from tumor and blood samples, and these data are eagerly awaited,” Dr. Jhaveri said.

More on Fulvestrant

In addition, also reported at this ASCO meeting, the PADA-1 study is tracking the emergence of ESR1 mutations in real time in patients receiving an aromatase inhibitor plus palbociclib in the first-line metastatic setting.4 Analysis of 1,000 patients has revealed these mutations are rare within 6 months of first-line therapy but are a major mechanism of resistance after 6 months. It is not yet known whether switching endocrine therapy to fulvestrant plus palbociclib when ESR1 mutation emerges will ultimately benefit patients, noted Dr. Jhaveri.

“It is also important to highlight that fulvestrant has its limitations, including poor bioavailability,” she continued. A number of oral selective estrogen receptor degraders that may achieve higher exposure and have better activity are in development.

Remaining Questions

Finally, Dr. Jhaveri posed some relevant questions that have yet to be answered: Is a larger phase III trial, powered for a hazard ratio of 0.8, needed to show a difference? Does the particular endocrine agent even matter when it is combined with a CDK4/6 inhibitor? Would the triplet of fulvestrant/anastrozole/CDK4/6 inhibitor improve efficacy? Will oral selective estrogen receptor degraders perform better? As is the case for most breast cancer regimens, biomarkers could be informative, she noted. 

DISCLOSURE: Dr. Jhaveri has served as a consultant or advisor to AbbVie, ADC Therapeutics, AstraZeneca, Bristol-Myers Squibb, Genentech, Intellisphere, Jounce Therapeutics, Lilly, Novartis, Pfizer, Spectrum, Synthon, and Taiho Pharmaceutical and has received travel funding from AstraZeneca, Intellisphere, Jounce, Pfizer, and Tailo Pharmaceutical.

REFERENCES

1. 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.

2. Mehta RS, Barlow WE, Albain KS, et al: Overall survival with fulvestrant plus anastrozole in metastatic breast cancer. N Engl J Med 380:1226-1234, 2019.

3. Ma CX, Suman VJ, Leitch AM, et al: ALTERNATE: Neoadjuvant endocrine treatment approaches for clinical stage II or III estrogen receptor-positive HER2-negative breast cancer in postmenopausal women: Alliance A011106. ASCO20 Virtual Scientific Program. Abstract 504.

4. Bidard FC, Callens C, Dalenc F, et al: Prognostic impact of ESR1 mutations in ER+ HER2– MBC patients with prior treatment with first-line AI and palbociclib: An exploratory analysis of the PADA-1 trial. ASCO20 Virtual Scientific Program. Abstract 1010.


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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...

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