First-line ET plus palbociclib versus standard mono-chemotherapy in high-risk HR-positive/HER2-negative metastatic breast cancer and indication for chemotherapy: primary results from the randomized phase IV PADMA study

BACKGROUND: PADMA is a prospective, randomized, open-label, multicenter phase IV study comparing palbociclib and endocrine therapy (ET) with mono-chemotherapy (CT) +/- maintenance ET (at the discretion of the treating physician) as first-line therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR-positive/HER2-negative) metastatic breast cancer (mBC). PATIENTS AND METHODS: Patients were randomly assigned 1:1 to receive first-line treatment with palbociclib + ET or investigator-selected CT (capecitabine, epirubicin, paclitaxel, or vinorelbine) +/- maintenance ET. The primary endpoint was time-to-treatment failure (TTF). Secondary endpoints were progression-free survival (PFS), overall survival (OS), safety, and treatment adherence. RESULTS: One hundred twenty patients, of whom 106 (88.3%) were postmenopausal, were randomly assigned and started treatment (palbociclib + ET, n = 61; CT, n = 59). Most patients in the CT group received capecitabine (n = 40, 67.8%) or paclitaxel (n = 17, 28.8%). In 13 patients (22%), CT was followed by maintenance ET. At a median follow-up of 36.8 months, the median TTF was 17.2 months with palbociclib + ET versus 6.1 months with CT [hazard ratio 0.46, 95% confidence interval (CI) 0.31-0.69, P < 0.001]. The TTF benefit in subgroups, including AKT signaling alterations or g/tBRCA1/2 mutations, was consistent with that in the overall population. Median PFS was 18.7 months with palbociclib + ET versus 7.8 months with CT (hazard ratio 0.45, 95% CI 0.29-0.70, P < 0.001). OS did not differ significantly between the study arms (P = 0.494). Hematologic toxicity was significantly higher in the palbociclib + ET arm than in the CT-based arm (96.8% versus 70.7%; P < 0.001), although nonhematological toxicity was comparable in both arms. CONCLUSION: PADMA is the first randomized multicenter study to show that palbociclib + ET as first-line treatment compared with CT also leads to improvements in TTF and PFS in predominantly postmenopausal patients with HR-positive/HER2-negative mBC.