Cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors in combination with endocrine therapy are a highly effective treatment in post-menopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer, both in the front-line and endocrine-resistant settings. However, the efficacy of CDK 4/6 inhibitors has not been established in endocrine-resistant premenopausal women with advanced breast cancer, a population with poor prognosis and high risk of relapse. In the randomized, placebo-controlled phase III PALOMA-3 trial, one cohort examined the efficacy of a combination of the CDK 4/6 inhibitor palbociclib plus fulvestrant and goserelin in 108 premenopausal women with HR-positive/HER2-negative advanced breast cancer who had received prior endocrine therapy.
Patients received 500 mg of fulvestrant intramuscularly (day 1 and 15 of cycle 1 and every 28 days thereafter) and goserelin subcutaneously (every 28 days) with either palbociclib 125 mg daily orally (3 weeks on, 1 week off) or placebo. Median progression-free survival (PFS) was significantly longer in the group receiving palbociclib (9.5 months vs 5.6 months; HR 0.50, P = .013). This is consistent with the PFS seen in postmenopausal patients treated with palbociclib plus fulvestrant (9.9 months). The objective response rate was 25.0% in the fulvestrant plus palbociclib arm, compared with 11.1% in the fulvestrant plus placebo arm. Addition of palbociclib to fulvestrant was associated with a statistically significant improvement in the clinical benefit rate compared to placebo plus fulvestrant (69.4% vs 44.4%; P = .011).
Biochemical analysis found no significant differences in concentrations of the luteinizing hormone, follicle-stimulating hormone, or plasma E2 in patients receiving palbociclib. Furthermore, pharmacokinetic data confirmed there was no clinically significant metabolic drug-drug interactions between palbociclib, goserelin, and fulvestrant when these drugs were coadministered.
The adverse event (AE) profile in premenopausal women was similar to that observed with palbociclib plus fulvestrant in postmenopausal women. Grade 3/4 AEs occurred in 83.1% of patients receiving palbociclib plus fulvestrant, compared to 25.0% in patients receiving fulvestrant plus placebo. The most common AEs in patients receiving palbociclib were neutropenia (85.9%), leukopenia (56.3%), and infections (47.9%).
In their conclusion, the investigators highlighted that this is the first registrational study of a CDK 4/6 inhibitor to include premenopausal women, and that this is the largest premenopausal cohort in an endocrine-resistant setting. The investigators indicated that the impressive PFS gain and manageable toxicity profile supports the use of palbociclib plus fulvestrant with ovarian suppression in premenopausal women with endocrine-resistant disease. This strategy may allow patients to delay chemotherapy and associated toxicity.