Data from the phase II PARSIFAL trial were inconclusive in determining superior survival benefits for women with hormone-receptor–positive metastatic breast cancer (MBC) when comparing combination palbociclib with two different endocrine therapies. Findings were presented by lead study author Antonio Llombart-Cussac, MD, PhD, of Universidad Catolica Valencia and Medica Scientia Innovation Research (MedSIR), Spain, during the ASCO20 Virtual Scientific Program (Abstract 1007).
Previous clinical trials (e.g., PALOMA-3, MONALEESA-3, MONARCH-2)1-3 have shown superior survival outcomes with the addition of the CDK inhibitor palbociclib to different endocrine therapies as first-line treatment for endocrine-sensitive MBC. To better determine the optimal combination, the PARSIFAL trial assessed adding fulvestrant or letrozole to palbociclib.
Women with estrogen-/progesterone-receptor–positive and HER2-negative MBC (486 patients) were randomly assigned to either 125 mg of palbociclib plus 500 mg of fulvestrant (243 patients) or 125 mg of palbociclib plus 2.5 mg of letrozole (243 patients). Patients had no prior therapy for advanced disease and were either endocrine naive or had experienced a metastatic relapse of more than 12 months since the end of previous endocrine therapy.
Primary endpoint was progression-free survival (PFS; Figure). Secondary endpoints were PFS among select subgroups, overall survival, tumor response, clinical benefit rate, and toxicity.
“The primary objective of the study—PFS by intention-to-treat and investigators’ criteria—was achieved at 32 months median follow-up and with 256 PFS events,” Dr. Llombart-Cussac said. “At this point, we failed to see any significant differences between both arms, with a hazard ratio of 1.13 and a p-value of 0.32.”
For secondary outcomes, the prespecified subgroup analysis did not find any relevant differences between arms. The only criterion where the hazard ratio approached 1 was for previous aromatase inhibitor therapy.
“The overall survival analysis was done with 102 events and a median follow-up of 32 months, and it showed a similar behavior for both arms,” he said. “The 3-year overall survival for letrozole plus palbociclib was 77.1%, and it was 79.4% for the fulvestrant and palbociclib. The hazard ratio was 1 and a p-value of 0.99.”
No differences were found between treatment arms with respect to tumor response and clinical benefit rate.
Discontinuation for reasons other than progression—including death or adverse events—was similar, but slightly higher, with fulvestrant. Finally, safety analyses did not show any differences for incidents of adverse events related to treatment or not.
Discussant Komal L. Jhaveri, MD, of Memorial Sloan Kettering Cancer Center and Weil Cornell Medical College, contrasted PARSIFAL’s survival outcomes with those from phase III trials (e.g., FALCON and SWOG 0226)4,5 that found fulvestrant alone and in combination with anastrozole to be superior to anastrozole in endocrine-therapy–naive patients with MBC.
“Could these conflicting results be related to our lack of understanding to mechanisms of resistance?” she asked. Data from the TransFAL study, where many substudies from tumor and blood samples are planned, are “eagerly awaited,” she said, adding that the phase III PADA-1 trial has found ESR1mutations to be a major mechanism of resistance after 6 months of palbociclib therapy.6
“However, data [are] unavailable to suggest whether a change in hormone therapy to fulvestrant/palbociclib during ESR1 mutation emergence will ultimately benefit our patients.”
“However, data [are] unavailable to suggest whether a change in hormone therapy to fulvestrant/palbociclib during ESR1 mutation emergence will ultimately benefit our patients.” - Dr. Komal L. Jhaveri
Because PARSIFAL could not conclusively identify one combination treatment as more effective than the other, Dr. Jhaveri suggested several lines of future research that may help inform clinical decision-making.
“Do we need a larger phase III trial powered for a hazard ratio of 0.8? Or does the endocrine therapy really not matter when combined with a CDK4/6 inhibitor? What about the triplet of fulvestrant/ anastrozole and a CDK4/6 inhibitor?” she asked. “Ongoing and future studies will determine if oral SERDs [selective estrogen receptor degraders] will perform better. But until then, we do need better predictive biomarkers.”
— Emily A. Kuhl, PhD
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