Farooki, Azeez

TPS1107 Background: ALP (α-selective PI3K inhibitor and degrader) is approved with FUL for pts with PIK3CA-mut HR+, HER2− ABC. HG is a known on-target effect of PI3K inhibition, manageable with oral anti-HG agents such as MET and dose interruptions/modifications of ALP and reversible upon discontinuation of ALP. Although HG management guidelines were refined throughout the SOLAR-1 and BYLieve studies evaluating ALP + FUL/letrozole, there remains a need for optimized strategies beyond initial MET therapy that offers earlier and more sustained improvement of HG, particularly for pts at an increased risk for severe HG. In preclinical models, the addition of a SGLT2 inhibitor to ALP (+/− MET) reduced HG while maintaining ALP efficacy. The aim of this study is to evaluate the safety and efficacy of prophylactic MET XR +/− the SGLT2 inhibitor DAPA in reducing severe HG in pts with PIK3CA-mut HR+, HER2− ABC on ALP + FUL with an increased risk for severe HG (grade ≥ 3) on ALP. Methods: EPIK-B4 is a Phase II, randomized (1:1), open-label, active-controlled study assessing the efficacy and safety of MET XR +/− DAPA (starting at Cycle 1 Day 1 [C1D1]) with ALP (300 mg orally [PO], once daily [QD], starting at C1D8) + FUL (500 mg intramuscularly on C1D1, C1D15, and D1 of subsequent cycles) in pts (N ≈ 132) with HR+, HER2–, PIK3CA-mut ABC after progression on/after endocrine-based treatment (Tx). MET XR is administered PO starting at 500 mg QD (titrated up to 2 g QD) and MET XR + DAPA starting at 500 mg and 5 mg QD (titrated up to 2 g and 10 mg QD), respectively. Eligible pts include adult men or postmenopausal women with confirmed HR+, HER2–, PIK3CA-mut ABC and ≥ 1 risk factor for severe HG (diabetes [fasting plasma glucose (FPG) ≥ 126 mg/dL and/or HbA1c ≥ 6.5%], prediabetes [FPG ≥ 100 to < 126 mg/dL and/or HbA1c 5.7% to < 6.5%], obesity [BMI ≥ 30], age ≥ 75 years); prior endocrine-based Tx (eg, FUL or oral SERD) was permitted. Randomization is stratified by baseline diabetes status. Key exclusion criteria include > 1 line of Tx in the metastatic setting; prior chemotherapy (metastatic setting) or PI3K, mTOR, or AKT inhibitor; type I or II diabetes requiring Tx; or antecedent of pancreatitis or severe cutaneous reaction. The primary endpoint is the occurrence of severe HG (grade ≥ 3 [glucose > 250 mg/dL] based on laboratory assessments) over the first 8 weeks of ALP + FUL. Secondary endpoints include progression-free survival, overall response and clinical benefit rates with confirmed response, safety, and tolerability. A biomarker analysis is planned as an exploratory objective. Recruitment is ongoing with enrollment planned in 56 sites across 8 countries; completion of primary data collection is anticipated in 2023. Clinical trial information: NCT04899349; EUDRACT#2021-001908-15.

Objective: The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPG). Methods: Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. Results: The Executive Summary of this 2020 updated guideline contains 52 recommendations: 21 Grade A (40%), 24 Grade B (46%), 7 Grade C (14%), and no Grade D (0%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 368 citations: 123 (33.5%) EL 1 (highest), 132 (36%) EL 2 (intermediate), 20 (5.5%) EL 3 (weak), and 93 (25%) EL 4 (lowest). New or updated topics in this CPG include: clarification of the diagnosis of osteoporosis, stratification of the patient according to high-risk and very high-risk features, a new dual action therapy option, and transitions from therapeutic options. Conclusion: This guideline is a practical tool for endocrinologists, physicians in general, regulatory bodies, health-related organizations, and interested laypersons regarding the diagnosis, evaluation, and treatment of postmenopausal osteoporosis.