pionERA Breast Cancer (BC): Phase III study of first-line (1L) giredestrant vs. fulvestrant, both combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), in patients (pts) with estrogen receptor-positive (ER+), HER2– locally advanced/metastatic BC (LA/mBC) with resistance to prior adjuvant (adj) endocrine therapy (ET).

TPS1130 Background: Pts with ER+, HER2– LA/mBC who relapse on/after adj ET and who have endocrine resistance represent a population with a high unmet need; for pts who relapse on or <12 months of adj aromatase inhibitors, fulvestrant + a CDK4/6i is 1L standard of care. However, fulvestrant has limited efficacy in pts with ESR1-mutated ( ESR1m) tumors and requires monthly intramuscular (IM) injections that negatively impact quality of life (QoL). New treatment (tx) options, such as combinations of an oral selective ER degrader (SERD) + a CDK4/6i (beyond palbociclib), are needed to improve survival, QoL, tolerability, and adherence. Giredestrant is a highly potent, nonsteroidal, oral selective ER antagonist and degrader that achieves robust ER occupancy and is active regardless of ESR1m status. Giredestrant was well tolerated with promising activity, as monotherapy and in combination with any approved CDK4/6i, in Phase I/II studies in ER+, HER2– BC. pionERA BC is the first study to investigate an oral SERD (giredestrant) + investigator’s (inv’s) choice of CDK4/6i in pts with 1L ET-resistant ER+, HER2– LA/mBC. Methods: pionERA BC (NCT06065748) is a Phase III, global, randomized, open-label, multicenter study in pts with ER+, HER2– LA/mBC with resistance to prior adj ET. Pts will be randomized 1:1 to oral daily 30 mg giredestrant or IM 500 mg fulvestrant (Days 1 and 15 of Cycle 1, then once monthly), both in combination with inv’s choice of CDK4/6i (palbociclib, abemaciclib, or ribociclib), stratified by: prior adj CDK4/6i (yes vs. no); choice of CDK4/6i; ESR1m status by central testing ( ESR1m vs. no ESR1 mutation detected [ ESR1nmd]); disease site (visceral vs. non-visceral). Pts will receive tx until disease progression, limiting toxicity, death, or consent withdrawal. Eligibility: Female/male pts with ER+, HER2– LA/mBC; resistance to prior adj ET (± CDK4/6i); no prior systemic tx for LA/mBC; documented ESR1m status by circulating tumor DNA. Enrollment of pts with ESR1nmd tumors will be capped at 60% of the total study population. Co-primary endpoints (EPs): Inv-assessed progression-free survival (PFS) in the ESR1m subgroup and in the full analysis set. Secondary EPs: PFS ( ESR1nmd subgroup); overall survival (OS); inv-assessed confirmed overall response rate; duration of response; clinical benefit rate; time to chemotherapy; safety; pt-reported outcomes. The co-primary EPs will be compared between tx arms using a stratified log-rank test at an overall 0.05 significance level (two-sided). An interim OS analysis is planned at the time of the primary PFS analysis; an independent data monitoring committee will be in place for safety. Target enrollment: 1050 pts; recruitment ongoing. Clinical trial information: NCT06065748 .