Giredestrant for Estrogen Receptor-Positive, HER2-Negative, Previously Treated Advanced Breast Cancer: Results From the Randomized, Phase II acelERA Breast Cancer Study.

PURPOSE: To compare giredestrant and physician's choice of endocrine monotherapy (PCET) for estrogen receptor-positive, HER2-negative, advanced breast cancer (BC) in the phase II acelERA BC study (ClinicalTrials.gov identifier: NCT04576455). METHODS: Post-/pre-/perimenopausal women, or men, age 18 years or older with measurable disease/evaluable bone lesions, whose disease progressed after 1-2 lines of systemic therapy (≤1 targeted, ≤1 chemotherapy regimen, prior fulvestrant allowed) were randomly assigned 1:1 to giredestrant (30 mg oral once daily) or fulvestrant/aromatase inhibitor per local guidelines (+luteinizing hormone-releasing hormone agonist in pre-/perimenopausal women, and men) until disease progression/unacceptable toxicity. Stratification was by visceral versus nonvisceral disease, prior cyclin-dependent kinase 4/6 inhibitor, and prior fulvestrant. The primary end point was investigator-assessed progression-free survival (INV-PFS). RESULTS: At clinical cutoff (February 18, 2022; median follow-up: 7.9 months; N = 303), the INV-PFS hazard ratio (HR) was 0.81 (95% CI, 0.60 to 1.10; P = .1757). In the prespecified secondary end point analysis of INV-PFS by ESR1 mutation (m) status in circulating tumor DNA-evaluable patients (n = 232), the HR in patients with a detectable ESR1m (n = 90) was 0.60 (95% CI, 0.35 to 1.03) versus 0.88 (95% CI, 0.54 to 1.42) in patients with no ESR1m detected (n = 142). Related grade 3-4 adverse events (AEs), serious AEs, and discontinuations due to AEs were balanced across arms. CONCLUSION: Although the acelERA BC study did not reach statistical significance for its primary INV-PFS end point, there was a consistent treatment effect with giredestrant across most key subgroups and a trend toward favorable benefit among patients with ESR1-mutated tumors. Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known endocrine therapy risks. Overall, these data support the continued investigation of giredestrant in other studies.

Partitioning RS domain phosphorylation in an SR protein through the CLK and SRPK protein kinases.

SR proteins are essential splicing factors whose biological function is regulated through phosphorylation of their C-terminal RS domains. Prior studies have shown that cytoplasmic-nuclear translocalization of the SR protein SRSF1 is regulated by multisite phosphorylation of a long Arg-Ser repeat in the N-terminus of the RS domain while subnuclear localization is controlled by phosphorylation of a shorter Arg-Ser repeat along with several Ser-Pro dipeptides in the C-terminus of the RS domain. To better understand how these two kinases partition Arg-Ser versus Ser-Pro specificities, we monitored the phosphorylation of SRSF1 by CLK1 and SRPK1. Although SRPK1 initially binds at the center of the RS domain phosphorylating in an orderly, N-terminal direction, CLK1 makes widespread contacts in the RS domain and generates multiple enzyme-substrate complexes that induce a random addition mechanism. While SRPK1 rapidly phosphorylates N-terminal serines, SRPK1 and CLK1 display similar activities toward Arg-Ser repeats in the C-terminus, suggesting that these kinases may not separate function in a strict linear manner along the RS domain. CLK1 induces a unique gel shift in SRSF1 that is not the result of enhanced Arg-Ser phosphorylation but rather is the direct result of the phosphorylation of several Ser-Pro dipeptides. These prolines are important for binding and phosphorylation of the SR protein by CLK1 but not for the SRPK1-dependent reaction. The data establish a new view of SR protein regulation in which SRPK1 and CLK1 partition activities based on Ser-Pro versus Arg-Ser placement rather than on N- and C-terminal preferences along the RS domain.