Palbociclib-Endocrine Therapy Combo Outperforms Standard Chemotherapy in HR+/HER2− Metastatic Breast Cancer
The phase 3 PADMA trial demonstrated that first-line treatment with palbociclib plus endocrine therapy (ET) significantly improves outcomes compared with standard mono chemotherapy in patients with high-risk hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) metastatic breast cancer.
The findings, presented at San Antonio Breast Cancer Symposium (SABCS) 2024, provide evidence supporting current international guidelines recommending ET plus cyclin-dependent kinase (CDK) 4/6 inhibitors as the standard first-line therapy in this setting.
“Many patients still received first-line chemotherapy when we started the study,” noted lead investigator Sibylle Loibl, MD, of the German Breast Group, during her presentation. “PADMA is one of the first prospective randomized trials to compare first-line therapy with palbociclib plus endocrine treatment vs mono chemotherapy as treatment of physician’s choice.”
Study Design and Patient Population
This open-label, multicenter, phase 3 trial enrolled 130 patients across 28 German sites between April 2018 and December 2023. Patients with previously untreated HR+/HER2− metastatic breast cancer who had an indication for chemotherapy were randomized 1:1 to receive either palbociclib (125 mg on days 1-21 of a 28-day cycle) plus ET or the physician’s choice mono chemotherapy with optional maintenance ET.
The study population represented a high-risk cohort, with 75% of patients having metastases in two or more organ systems, and 43.3% presenting with symptomatic disease. Liver metastases were present in 42% of patients, and approximately one third had endocrine resistance. The median age of the participants was 62 years (range, 31-85 years), and 90% of the participants were postmenopausal. Molecular analysis revealed PIK3CA mutations in 22.5% of patients, BRCA mutations in 5.8% of patients, and ESR1 mutations in 1.7% of patients.
In the chemotherapy group, treatment choices included capecitabine (69%), paclitaxel (29.3%), and vinorelbine (1.7%). Among patients receiving chemotherapy, 22.4% subsequently switched to maintenance ET. In the palbociclib/ET group, 77% of patients received an aromatase inhibitor as their ET partner.
When asked about the relatively low rate of patients in the chemotherapy group who transitioned to maintenance ET, Kari B. Wisinski, MD, endowed professor at the University of Wisconsin-Madison and associate director for Clinical Research at the UW Carbone Cancer Center, Madison, Wisconsin, said: “I think this implies that many of the patients in the chemotherapy arm were continuously on chemotherapy until disease progression rather than switched to maintenance. One key question is whether patients went on to next-line therapy with endocrine therapy with a CDK4/6 inhibitor. This would be interesting data to help understand the overall survival endpoint.”
Palbociclib-ET Combination Significantly Delays Treatment Failure
After a median follow-up of 36.8 months, the trial met its primary endpoint of time to treatment failure (TTF). The median TTF was significantly longer with palbociclib/ET group at 17.2 months than with chemotherapy group at 6.1 months, producing a hazard ratio (HR) of 0.46 (80% CI, 0.35-0.60; P = .0002). Disease progression was the leading cause of treatment failure in both groups but was lower in the palbociclib/ET group (52.5%) than in the chemotherapy group (76.3%).
In an interview, Wisinski, who was not involved in the study, emphasized the significance of these findings. “This study supports the current standard of care, which is to use endocrine therapy plus a CDK4/6 inhibitor as first-line therapy for those with newly diagnosed metastatic HR+/HER2− breast cancer,” she noted. “It should only be rare situations where chemotherapy is used in the first line.”
Palbociclib-ET Combination Significantly Delays Disease Progression
Progression-free survival (PFS) was improved with palbociclib-ET combination therapy, with a median PFS of 18.7 months in the palbociclib/ET group vs 7.8 months in the chemotherapy group (HR, 0.45; 95% CI, 0.29-0.70; P = .0002). The time to first subsequent treatment was also significantly prolonged with palbociclib/ET group (19.9 vs 8.0 months; HR, 0.52; 95% CI, 0.34-0.80; P = .0028).
Overall survival (OS) analysis showed a numerical advantage for the palbociclib/ET group with a median OS of 46.1 months compared with that of 36.8 months for the chemotherapy group; however, this difference did not reach statistical significance (HR, 0.81; 95% CI, 0.46-1.43; P = .4630).
In an interview, Wisinski provided a potential explanation about the lack of statistical significance in OS despite the TTF and PFS benefits: “This study was not powered for an OS endpoint and due to multiple subsequent lines of therapy, which likely include CDK4/6 inhibitors and chemotherapies in the respective arms, an OS benefit would likely require a large sample size. I think the TTF and PFS are notable and strongly support the use of endocrine therapy with CDK4/6 inhibitors in the first line.”
Safety and Tolerability of Palbociclib-ET Combination
According to Loibl, the safety profile of the treatment “was consistent with previous studies of CDK4/6 inhibitors, showing expected differences between the treatment arms.” Hematologic toxicity was significantly higher in the palbociclib/ET group (any grade: 96.8% vs 70.7%; P < .001; high grade: 56.5% vs 10.3%; P < .001), whereas nonhematologic toxicity was comparable between the two groups. Serious treatment-related adverse events were relatively low in both groups (6.5% with palbociclib/ET vs 10.3% with chemotherapy), with one treatment-related death reported in the palbociclib/ET group.
“Although hematologic toxicity, in particular high-grade neutropenia, is common with palbociclib, this is associated with low risks of serious infections and is managed with dose holds and reductions,” Wisinski said, in an interview with Medscape Medical News. “Studies have demonstrated no significant risk of infection-related deaths and no difference in time to deterioration in quality of life.”
Clinical Implications and Future Directions
Wisinski pointed out that the PADMA findings build upon previous evidence, including the RIGHT Choice trial.
“There was a previous randomized phase 2 study, RIGHT Choice, which also compared these approaches as first-line treatment, which also supported the use of the CDK4/6i as first-line therapy over chemotherapy.”
According to Loibl, the PADMA trial results provide compelling evidence supporting the use of CDK4/6 inhibitors plus ET as first-line therapy, even in patients traditionally considered for upfront chemotherapy.
“The PADMA trial contributed to the data that endocrine-based therapy with a CDK4/6 inhibitor is the preferred standard of care as first-line treatment,” she said.
During the discussion session, Loibl addressed important clinical considerations, including the management of patients with visceral crisis.
She noted that “visceral crisis is very badly defined” and that “42% of the patients at least had liver metastasis, but there were no patients enrolled with very high liver metastases, if you consider those as visceral crisis.”
She further explained that patients with visceral crisis are typically excluded from clinical trials because of safety concerns and that the efficacy of this combination therapy in patients with visceral crisis remains unknown.
In an interview, Wisinski echoed unanswered questions about the applicability of clinical trial findings to real-world practice.
“The definition of ‘high-risk’ disease in metastatic HR+/HER2− breast cancer is not clearly defined in any guidelines, but involvement of multiple organ sites and, in particular, visceral disease has traditionally been of enough concern to oncologists that chemotherapy has been considered in the first line,” she said.
She added, “Recently, we have seen data and approval for inavolisib with fulvestrant and palbociclib in patients with a PI3K mutation in the tumor and early disease recurrence on adjuvant endocrine therapy. A key question is whether this approach is better than sequencing an aromatase inhibitor plus a CDK4/6 inhibitor and then a second-line endocrine therapy with a PI3K/AKT pathway inhibitor, as well as whether the triplet would be better in the first-line setting for all patients whose tumors harbor PI3K pathway alterations.”
Wisinski concluded, “In practice, we see a heterogeneous population, some with very limited metastatic disease burden with oligometastatic disease, others with bone-only disease, and some with multi-organ involvement and high symptom burden. Currently, it appears that first-line CDK4/6 inhibitors plus endocrine therapy is the best approach in all of these settings.”
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