Background: Dalpiciclib (SHR6390), a novel CDK4/6 inhibitor, as monotherapy has demonstrated tolerability and preliminary antitumor activity in pretreated HR+/HER2− advanced breast cancer (ABC). Here we evaluated dalpiciclib with fulvestrant in ABC. Methods: In this randomized, double-blind, phase 3 trial, patients (pts) with HR+/HER2− locally advanced or metastatic breast cancer who had relapsed or progressed on previous endocrine therapy were enrolled. Eligible pts were randomized 2:1 to receive dalpiciclib (dalp; 150 mg po qd, d1-21, q4w) or placebo (PBO) with fulvestrant (fulv; 500 mg im, cycle 1 d1, d15, then d1 q4w). The primary endpoint was investigator (INV)-assessed PFS. As of Nov. 15, 2020, 162 (71.4% of total projected) events of disease progression or death had occurred and a preplanned interim analysis was done. The corresponding superiority boundary was 1-sided P = 0.0080 (Lan-DeMets [O’Brien-Fleming] boundary). Results: Overall, 361 pts were randomized to receive dalp-fulv (n = 241) or PBO-fulv (n = 120). With a median follow-up of 10.5 mo, dalp-fulv significantly improved INV-assessed PFS versus PBO-fulv (median, 15.7 [95% CI 11.1-NR] vs 7.2 [95% CI 5.6-9.2] mo; HR, 0.42 [95% CI 0.31-0.58]; P < 0.0001). PFS per IRC were consistent with INV assessment (Table). The benefit of dalpiciclib extended beyond initial study treatment based on time to first subsequent chemotherapy (TFSCT; HR, 0.47 [95% CI 0.32-0.69]; P < 0.0001). OS data were not mature with a total of 25 deaths documented. Median duration of exposure was 9.4 (IQR, 4.3-11.4) mo with dalpiciclib and 9.9 (4.7-11.9) mo with fulvestrant in the dalp-fulv group and was 6.1 (3.7-11.0) mo with fulvestrant in the PBO-fulv group. The most common (incidence ≥3%) grade 3 or 4 AEs with dalp-fulv were neutropenia (84.2%; vs 0% with PBO-fulv) and leukopenia (62.1%; vs 0%). Treatment discontinuation due to AE was reported for 2.5% of pts with dalp-fulv vs 3.3% with PBO-fulv. The incidence of SAE was 5.8% with dalp-fulv vs 6.7% with PBO-fulv. Conclusions: The study met its primary endpoint, demonstrating that dalpiciclib plus fulvestrant significantly improved PFS versus placebo plus fulvestrant, with a manageable safety profile. Our findings support dalpiciclib plus fulvestrant as a new treatment option in pts with HR+/HER2- ABC who relapsed or progressed on endocrine therapy. Clinical trial information: NCT03927456.

*1-sided stratified