SAN ANTONIO – For postmenopausal women with hormone receptor–positive, HER2-negative breast cancer that has progressed on aromatase inhibitor therapy, the combination of palbociclib with either exemestane or fulvestrant was not better than capecitabine at delaying progression or inducing clinical responses, results of the phase 3 showed.
At a median follow-up of 13.45 months there was no significant difference in progression-free survival (PFS) for patients treated with either fulvestrant (Faslodex) or exemestane (Aromasin) plus palbociclib (Ibrance) or with capecitabine (Xeloda) alone, nor was there a difference in PFS between patients with mutated or wild-type ESR1, reported, from the Gregorio Marañón Health Research Institute in Madrid.
“Palbociclib plus endocrine therapy is one of the standards of care today for patients with prior aromatase inhibitor [therapy] in the metastatic setting, and capecitabine as well is another option for this population, since it produces significant activity and a significant proportion of responses in patients with metastatic breast cancer. But we don’t know actually the relative efficacy of each therapy versus the other,” he said at the San Antonio Breast Cancer Symposium.
The phase 3 PEARL study was a head-to-head comparison of the two regimens in women with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer that had progressed on aromatase inhibitors (AIs).
The study was originally designed to test the combination of palbociclib and exemestane versus capecitabine, and 296 patients were enrolled (cohort 1).
The study was modified in 2016, however, following evidence that mutations in ESR1 are a major mechanism of resistance to AIs in patients with metastatic disease, and that fulvestrant, a selective estrogen receptor down-regulator, did not appear to have cross-resistance to either tamoxifen or AIs, and may be active against tumors with ESR1 mutations. Therefore, a second cohort of 305 patients was enrolled to test palbociclib plus fulvestrant versus capecitabine.
Each cohort included patients with HR-positive, HER2-negative metastatic breast cancer that had recurred within 1 year of completed adjuvant therapy with nonsteroidal AIs, or progression within 1 month of completing adjuvant AIs for advanced disease. Patients could have received one prior line of chemotherapy for metastatic disease, but no prior capecitabine, exemestane (in cohort 1), or fulvestrant (in cohort 2)
In each cohort, patients were stratified by visceral or nonvisceral metastases, prior sensitivity to hormonal therapy (yes or no), and prior chemotherapy for metastatic breast cancer, and then randomized on a 1:1 basis to capecitabine 1,250 mg/m2 (1,000 mg/m2 for patients older than 70 years) twice daily 2 weeks on, 1 week off every 21 days; to palbociclib 125 mg 3 weeks on, 1 week off every 28 days plus exemestane 25 mg daily in cohort 1; or to fulvestrant 500 mg on days 1 and 15 of cycle 1 and then once every 28 days.
The trial did not meet its coprimary endpoints of superior PFS with palbociclib/fulvestrant regardless of ESR1 mutational status, or superior PFS with palbociclib and either partners in patients with ESR1 wild-type tumors.
In cohort 2, after a median follow-up of 13.47 months, the median PFS with palbociclib/fulvestrant was 7.5 months versus 10 months with capecitabine, with a nonsignificant hazard ratio.
Similarly, in cohort 1 (patients with wild-type ESR1), the median PFS at a median follow-up of 18.89 months was 8.0 months with palbociclib plus endocrine therapy versus 10.6 months with capecitabine.
For the secondary endpoint of PFS in the combined cohorts, the median overall PFS after a median 17.64 months of follow-up was 7.4 versus 9.4 months, respectively.
There were no significant differences by intrinsic breast cancer subtypes expect for nonluminal breast cancer, for which capecitabine had a significantly better benefit (P = .008 in cohort 2, and .002 for patients with ESR1 wild type).
Objective response rates in both cohorts trended in favor of capecitabine, but neither trend was statistically significant.
The palbociclib-containing regimens were, however, generally better tolerated than capecitabine, with a lower frequency of treatment discontinuations (3.7% with palbociclib plus endocrine therapy vs. 12.8% with capecitabine) and a smaller proportion of patients with serious adverse events (3.7% vs. 10.4%, respectively).
In the question and response following his presentation, perennial SABCS provocateur Steven “Vogl New York” Vogl, MD, of Montefiore Medical Center asked Dr. Martin: “Did you really give the capecitabine for a median of 18 months because that was the time to progression?”
Dr. Vogl commented that 18 months “is a very long time to keep a patient on drugs that make their palms sore, give them diarrhea, give them rashes, and sore mouths. So were the Spanish doctors particularly smart about reducing the doses?”
Dr. Martin replied that in his experience patients could be maintained on capecitabine for more than 4 years, with dose adjustments for those who develop palmar or plantar problems or other side effects, but “many patients prefer that to alopecia, to vomiting, to IV injections, so in my view capecitabine is a great drug for luminal metastatic breast cancer cases, and we can keep the drug going for many, many months in most patients.”
The study was funded by Pfizer. Dr. Martin disclosed speaker honoraria and consulting fees from Pfizer and others.
SOURCE: Martin M et al. SABCS 2019.