Palbociclib plus endocrine therapy versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (Young-PEARL): overall survival analysis of a randomised, open-label, phase 2 study.
The phase 2 randomised Young-PEARL study demonstrated that palbociclib plus exemestane with ovarian function suppression significantly prolonged progression-free survival compared with capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. Here, we report results of the protocol-specified secondary endpoint of overall survival.
Young-PEARL was a multicentre, randomised, open-label, phase 2 study conducted at 14 institutions in South Korea. Premenopausal women aged 19 years or older with histologically confirmed hormone receptor-positive, HER2-negative metastatic breast cancer that recurred or progressed during or after previous tamoxifen treatment, who were aromatase inhibitor naive, and had an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. One previous line of chemotherapy was permitted in the metastatic setting. Eligible patients were randomly assigned (1:1), using block randomisation (block size of two) stratified by previous chemotherapy for metastatic breast cancer and presence of visceral metastasis, to receive either palbociclib (orally, 125 mg per day on a 3-weeks-on, 1-week off schedule) plus exemestane (orally 25 mg daily) with leuprorelin (subcutaneously 3·75 mg on day 1 of each 28-day cycle) or capecitabine (orally, 1250 mg/m2 twice a day on a 2-weeks-on, 1-week-off schedule) until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival. Overall survival was a secondary endpoint. All analyses were done in the modified intention-to-treat population (ie, included all patients randomly assigned to treatment who had at least one post-baseline CT scan and excluded those who did not receive study medication and who had any major violation of the eligible criteria). Safety was assessed in all patients who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02592746, and is now complete.
Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled. 184 patients were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92), of whom 174 were included in the modified intention-to-treat population (n=90 in the palbociclib plus endocrine therapy group and n=84 in the capecitabine group). All patients were female and ethnicity data were not collected. As of data cutoff (Feb 29, 2024), median follow-up was 54·0 months (IQR 34·1-74·4). Median progression-free survival was 19·5 months (90% CI 14·3-22·2) for palbociclib plus endocrine therapy and 14·0 months (11·7-18·7) for capecitabine (hazard ratio 0·74 [90% CI 0·57-0·98]; one-sided log-rank p=0·036). 52 (58%) of 90 patients in the palbociclib plus endocrine therapy group and 48 (57%) of 84 in the capecitabine group died, with a median overall survival of 54·8 months (95% CI 48·9-77·1) in the palbociclib plus endocrine therapy group versus 57·8 months (46·3-89·2) in the capecitabine group (hazard ratio 1·02 [95% CI 0·69-1·51]; p=0·92). The most common grade 3 or worse adverse event was neutropenia (59 [64%] of 92 in the palbociclib plus endocrine therapy group vs 15 [18%] of 85 in the capecitabine group) . No treatment-related deaths occurred.
With extended follow-up, palbociclib plus exemestane with ovarian function suppression continued to show a significant benefit in progression-free survival compared with capecitabine in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who had been previously treated with tamoxifen; however, no improvement in overall survival was seen. Given the progression-free survival benefit, the upfront use of palbociclib plus endocrine therapy is the preferred option for premenopausal women, although a capecitabine-first strategy might be an alternative treatment strategy for maintaining overall survival in resource-limited settings.
Pfizer and Ministry of Health & Welfare, South Korea.
Ahn HK
，Kim JY
，Lee KH
，Kim GM
，Kang SY
，Lee KS
，Kim JH
，Lee KE
，Lee MH
，Kim HJ
，Kim HJ
，Koh SJ
，Park IH
，Sohn J
，Kim SB
，Ahn JS
，Kim S
，Cho H
，Jung KH
，Im SA
，Park YH
，Korean Cancer Study Group (KCSG) Breast Cancer Committee
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Efficacy and Safety of Low-Dose Oral Etoposide Combined With Capecitabine for Patients With Postoperative Metastatic Breast Cancer Resistant to Anthracycline/Taxanes.
The purpose of this study is to determine the efficacy and safety of metronomic chemotherapy with all-oral combination of low-dose etoposide/capecitabine in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and/or taxanes.
Metronomic chemotherapy, giving lower, more frequent doses of chemotherapy drugs over an extended period, often without long breaks between cycles. With oral low-dose etoposide + capecitabine was administered to patients who had postoperative MBC resistant to anthracycline/taxanes: etoposide 30 mg/m2/day, qd for 7 days + capecitabine 1400 mg/m2/day, administered in two equal dose for 14 days, with 21 days as a cycle. Patients received treatments if complete response, partial response, or stable disease was obtained until disease progressed or became intolerable. RECIST criteria were used for standard efficacy evaluation and NCI-CTC version 3.0 was used for evaluation of side effects.
From June 2008 to May 2020, 85 patients received the aforesaid treatment; 67 of these patients were eligible for efficacy and side effects evaluation. After treatment, 6 (8.96%) patients obtained partial response, 41 (61.19%) patients had stable disease, and 20 (29.85%) patients had disease progression. The overall response rate (complete response + partial response) was 8.96%, and disease control rate (complete response + partial response + stable of disease) was 70.15%. Clinical benefits (complete response + partial response + stable of disease ≥ 24 weeks) were obtained for 50% of the patients. The median and mean treatment to progression time was 5 months and 6.06 months (95% CI: 3.43~8.70), respectively. The most common grade I/II side effects were leukopenia and fatigue (15.8%).
For patients with postoperative MBC resistant to anthracycline/taxanes, oral low-dose etoposide + capecitabine was effective with tolerable safety. The patients did not need antiemetics or leukocytic drugs, and the treatment was cost-effective because the patients did not need to be hospitalized for intravenous infusion.
Chen X
，He Y
，Fan T
，Wei Y
... -
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Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): a multicentre, open-label, randomised, phase 2 trial.
Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.
This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0-2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov, NCT02592746, and is ongoing for follow-up of overall survival.
Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9-22), median progression-free survival was 20·1 months (95% CI 14·2-21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1-17·0) in the capecitabine group (hazard ratio 0·659 [95% CI 0·437-0·994], one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 [75%] of 92 vs 14 [16%] of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred.
Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen.
Pfizer, Shinpoong, and Daewoong Korea and Takeda.
Park YH
，Kim TY
，Kim GM
，Kang SY
，Park IH
，Kim JH
，Lee KE
，Ahn HK
，Lee MH
，Kim HJ
，Kim HJ
，Lee JI
，Koh SJ
，Kim JY
，Lee KH
，Sohn J
，Kim SB
，Ahn JS
，Im YH
，Jung KH
，Im SA
，Korean Cancer Study Group (KCSG)
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ResearchGate
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