PIK3CA-mutant Breast Cancer Research Articles

PLK1 Inhibitor Onvansertib Enhances the Efficacy of Alpelisib in PIK3CA-Mutated HR-Positive Breast Cancer Resistant to Palbociclib and Endocrine Therapy: Preclinical Insights.

Endocrine therapy (ET) combined with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) is the preferred first-line treatment for hormone receptor-positive (HR+)/HER2- metastatic breast cancer. Although this is beneficial, acquired resistance leads to disease progression, and patients harboring PIK3CA mutations are treated with targeted therapies such as the PI3Kα inhibitor, alpelisib, alongside ET. Drug-associated resistance mechanisms limit the efficacy of alpelisib, highlighting the need for better combination therapies. This study aimed to evaluate the efficacy of combining alpelisib with a highly specific PLK1 inhibitor, onvansertib, in PIK3CA-mutant HR+ breast cancer preclinical models. We assessed the effect of the alpelisib and onvansertib combination on cell viability, PI3K signaling pathway, cell cycle phase distribution and apoptosis in PI3K-activated HR+ breast cancer cell lines. The antitumor activity of the combination was evaluated in three PIK3CA-mutant HR+ breast cancer patient-derived xenograft (PDX) models, resistant to ET and CDK4/6 inhibitor palbociclib. Pharmacodynamics studies were performed using immunohistochemistry and Simple Western analyses in tumor tissues. The combination synergistically inhibited cell viability, suppressed PI3K signaling, induced G2/M arrest and apoptosis in PI3K-activated cell lines. In the three PDX models, the combination demonstrated superior anti-tumor activity compared to the single agents. Pharmacodynamic studies confirmed the inhibition of both PLK1 and PI3K activity and pronounced apoptosis in the combination-treated tumors. Our findings support that targeting PLK1 and PI3Kα with onvansertib and alpelisib, respectively, may be a promising strategy for patients with PIK3CA-mutant HR+ breast cancer failing ET + CDK4/6i therapies and warrant clinical evaluation.

PI3K PROTAC overcomes the lapatinib resistance in PIK3CA-mutant HER2 positive breast cancer

Although anti-HER2 therapy has made significant strides in reducing metastasis and relapse in HER2-positive breast cancer, resistance to agents like trastuzumab, pertuzumab, and lapatinib frequently develops in patients undergoing treatment. Previous studies suggest that the hyperactivation of the PI3K-AKT signaling pathway by PIK3CA/PTEN gene mutations is implicated in HER2 resistance. In this study, we introduce a novel PI3K-p110α Proteolysis TAargeting Chimera (PROTAC) that effectively inhibits the proliferation of breast cancer cells by degrading PI3K-p110α. When tested in two lapatinib-resistant cell lines, JIMT1 and MDA-MB-453, both of which harbor PIK3CA mutations, the PI3K PROTAC notably reduced cell proliferation and induced G1 phase cell cycle arrest. Importantly, even at very low concentrations, PI3K PROTAC restored sensitivity to lapatinib. Furthermore, the efficacy of PI3K PROTAC surpassed that of Alpelisib, a selective PI3K-p110α kinase inhibitor in clinic. The superior performance of PI3K PROTAC was also confirmed in lapatinib-resistant breast cancer xenograft tumors and patient-derived breast cancer organoids (PDOs). In conclusion, this study reveals that the novel PI3K PROTAC we synthesized could serve as an effective agent to overcome lapatinib resistance.

Quantitative characterization of the effects of fulvestrant alone or in combination with taselisib (PI3Kinase inhibitor) on longitudinal tumor growth in patients with estrogen receptor-positive, HER2-negative, PIK3CA-mutant, advanced or metastatic breast cancer.

Among cases of breast cancer, estrogen receptor-positive (ER +), PIK3CA-mutant, HER2- advanced breast cancer stands as a particularly complex clinical indication where approximately 40% of ER + /HER2- breast carcinomas present mutations in the PIK3CA gene. A significant hurdle in treating ER + breast cancer lies in surmounting the challenges of endocrine resistance. In the clinical setting, a multifaceted approach is essential for this indication, one that not only explores the effectiveness of individual treatments but also delves into the potential gains in therapeutic outcome from combination therapies. In the current study, longitudinal tumor growth inhibition (TGI) models were developed to characterize tumor response over time in postmenopausal women with ER + /HER2- advanced or metastatic breast cancer undergoing treatment with fulvestrant alone or in combination with the PI3K inhibitor, taselisib. Impact of clinically relevant covariates on TGI metrics was assessed to identify patient subsets most likely to benefit from treatment with fulvestrant monotherapy or combination with taselisib. Tumor growth rate constant (Kg) was found to increase with increasing baseline tumor size and in the absence of baseline endocrine sensitivity. Further, Kg decreased in the absence of baseline liver metastases both in fulvestrant monotherapy and combination therapy with taselisib. Overall, additive/potentially synergistic anti-tumor effects were observed in patients treated with the taselisib-fulvestrant combination. These results have important implications for understanding the therapeutic impact of combination treatment approaches and individualized responses to these treatments. Finally, this work, emphasizes the importance of model informed drug development for targeted cancer therapy. NCT02340221 Registered January 16, 2015, NCT01296555 Registered February 14, 2011.

Abstract RF02-02: BBO-10203, a first-in-class, orally bioavailable, selective covalent small molecule that inhibits RAS-driven PI3Kalpha activity without affecting glucose metabolism

Abstract PI3Kα is the most mutated kinase and the second most mutated oncogene in human cancer. Activation of PI3Ka can be achieved by receptor tyrosine kinases such as insulin receptor and insulin-like growth factor receptor 1 and/or by directly interacting with RAS family members. Previous elegant preclinical studies have established that RAS-driven PI3Ka activation is important in tumor cells but may not be involved in cell types controlling glucose metabolism. Alpelisib, a small molecule inhibitor of the kinase activity of PI3Ka, has been approved for the treatment of ER+ PIK3CA mutant breast cancer in combination with fulvestrant after endocrine therapy in advanced or metastatic breast cancer based on an improvement in PFS versus fulvestrant alone. Inhibition of PI3Ka activity by alpelisib in normal tissues resulted in a severe (G3/4) hyperglycemia rate of 37% with frequent dose interruptions and discontinuations. Additionally, preclinical studies have demonstrated that the dysregulation of glucose homeostasis resulting from PI3Ka kinase inhibition leads to hyperinsulinemia that increases pathway flux, rendering kinase inhibitors less effective. Here, we report on a novel covalent small molecule designed to inhibit RAS-mediated activation of the AKT pathway via PI3Ka without the resultant hyperglycemia associated with direct inhibition of PI3Ka kinase activity. BBO-10203 disrupts the physical interaction between RAS and PI3Ka in tumor cells resulting in potent signaling pathway inhibition. This agent selectively binds to PI3Ka and disrupts its interaction with K-,H-, and N-RAS with low single digit nanomolar potency (~5 nM). Breaking the interaction between these two oncogenes inhibits basal pAKT cellular levels (BT-474/KYSE-410 IC50: ~5 nM) in HER2 amplified (HER2amp) and wild-type or mutant PI3Ka cell lines. Even though BBO-10203 does not inhibit the kinase activity of PI3Ka, its effects on cancer cell signaling inhibition and transcriptional regulation highly resemble those of alpelisib. BBO-10203 displays excellent drug-like properties and oral bioavailability. Single dose treatment of KYSE-410 (HER2amp/KRASG12C) tumor bearing mice with increasing doses (1-100 mg/kg, PO) of BBO-10203 results in dose and time dependent inhibition of pAKT in vivo. Maximal inhibition (~80%) is achieved at 30 mg/kg and lasts for 24 hours. Repeated dose treatment of tumor bearing mice with BBO-10203 is well tolerated and results in significant efficacy in PIK3CA mutant as well as HER2amp human xenograft models. In the KYSE-410 xenograft model, BBO-10203 daily oral dosing of 30 mg/kg results in significant tumor regressions. Importantly, treatment with BBO-10203 does not affect insulin signaling in differentiated adipocytes in vitro, nor does it impact glucose metabolism in vivo at 3-times the maximal efficacious dose level in xenograft studies. In conclusion, we have identified a novel approach to inhibit the PI3Ka signaling pathway by blocking its interaction with, and activation by RAS. This approach can achieve strong pAKT inhibition in tumor cells without changes in glucose metabolism. Clinical investigation of BBO-10203 for the treatment of both ER+/PIK3CA mutant and HER2amp breast cancer is warranted. Citation Format: Pedro Beltran, Simanshu Dhirendra, Rui Xu, Ming Chen, Daniel Czyzyk, Sofia Donovan, Siyu Feng, Cindy Feng, Lijuan Fu, Felice Lightstone, Ken Lin, Anna Maciag, Dwight Nissley, Erin Riegler, Kerstin Sinkevicius, Andrew Stephen, James Stice, David Turner, Bin Wang, Keshi Wang, Yue Yang, Cathy Zhang, Frank McCormick, Eli Wallace. BBO-10203, a first-in-class, orally bioavailable, selective covalent small molecule that inhibits RAS-driven PI3Kalpha activity without affecting glucose metabolism [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF02-02.

Abstract PO2-19-09: INAVO122: a Phase III study of maintenance inavolisib or placebo + pertuzumab + trastuzumab following induction with pertuzumab + trastuzumab + a taxane in patients with PIK3CA-mutated, HER2-positive advanced breast cancer

Abstract Background The PI3K pathway plays a crucial role in HER2 signaling. Somatic mutations of PIK3CA, the gene that encodes the PI3K p110α subunit, may induce resistance to HER2-targeted therapies and are associated with poorer clinical outcomes (Swain SM, et al. SABCS 2022; P2-11-07). Inavolisib, a potent p110α-selective inhibitor that induces degradation of mutant p110α, has shown antitumor activity in PIK3CA-mutated HER2-positive breast cancer (HER2+ BC) and long-term tolerability with early intervention for common on-class toxicities, including hyperglycemia, diarrhea, and stomatitis (Bedard P, et al. ASCO 2022; 1052). The current study will assess the efficacy and safety of maintenance inavolisib + fixed-dose combination of pertuzumab + trastuzumab for subcutaneous injection (PH FDC SC) after first-line induction treatment in patients with PIK3CA-mutated, HER2+, advanced BC (aBC). Trial design INAVO122 is a multicenter, randomized, international, double-blind, placebo-controlled study. Patients will be enrolled for: first-line induction treatment if they are receiving/will receive PH + a taxane; or maintenance treatment completing induction treatment. In the maintenance phase, patients will be randomized 1:1 to receive inavolisib (9 mg orally once daily; Days 1–21 of 21-day cycles) + PH FDC SC (every 3 weeks), or placebo + PH FDC SC. Study treatment will continue until disease progression, unacceptable toxicity, death, consent withdrawal, or at the investigator’s discretion. ELIGIBILITY Enrolled patients must have centrally determined HER2+, PIK3CA-mutated tumors, with documented hormone receptor status per local assessment, and be disease-free for ≥ 6 months from completion of neoadjuvant/adjuvant systemic non-hormonal treatment. They must not have received any treatment for aBC prior to induction, and, at screening, fasting glucose must be < 126 mg/dL and HbA1c < 6.4%. To be randomized, patients must have completed induction therapy per standard of care without progression of disease and show left ventricular ejection fraction ≥ 50%. AIMS The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints are overall survival; investigator-assessed objective response rate, duration of response, clinical benefit rate, and time to second disease progression; health-related quality of life; safety; and pharmacokinetics. STATISTICAL METHODS The primary endpoint analysis will utilize a two-sided stratified log-rank test at a two-sided significance level of 5%. A stratified Cox proportional hazards model will be used to estimate the hazard ratio between the two treatment arms and its 95% confidence intervals. ACCRUAL Target randomization is ~230 patients; recruitment began in July 2023. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number NCT05894239. Citation Format: Sandra Swain, Carlos Barrios, Reva Basho, Giuseppe Curigliano, Nadia Harbeck, Chiun-Shen Huang, Sherene Loi, Nicholas Turner, Jessica Chen, Volkmar Henschel, Simon Warburton, Fabiola Amair-Pinedo, Javier Cortés. INAVO122: a Phase III study of maintenance inavolisib or placebo + pertuzumab + trastuzumab following induction with pertuzumab + trastuzumab + a taxane in patients with PIK3CA-mutated, HER2-positive advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-09.

Abstract PO5-21-10: Efficacy and Safety of Alpelisib in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor: An Open-label, Multi-centre, Prospective, Single Arm Clinical Trial

Abstract Introduction: Currently, patients with luminal metastatic breast cancer receive a CDK4/6 inhibitor in combination with endocrine therapy as a first or second line of treatment. When tumors become resistant to the CDK4/6 inhibitors, treatment with alpelisib (PI3K inhibitor) in combination with an endocrine agent can be a next treatment option if an activating PIK3CA mutation is confirmed (cfr. SOLAR-1 trial). However, limited data is available after treatment with CDK4/6 inhibitors (cfr. BYLieve trial) and even less about alpelisib in later lines of therapy. Therefore, we aim to investigate the therapeutic efficacy and safety of alpelisib in combination with an endocrine agent in PIK3CA-mutated advanced breast cancer patients in later lines after prior CDK4/6i treatment. Methods: This is an open-label, prospective, multi-centre, single arm clinical trial enrolling patients from both the University Hospital of Leuven (UHL) and Ghent University Hospital (GUH). For each patient, metastatic tumor was tested for PIK3CA mutations using the UHL 96 gene panel. Our endpoints are clinical benefit rate, progression-free survival, time to treatment discontinuation (defined as the date of starting alpelisib to the date of treatment discontinuation or death) and safety. Descriptive statistics were used. Results: Between June 18th 2019 and August 23rd 2021, 38 patients have been included with confirmed PIK3CA hotspot mutations. All patients had CDK4/6 inhibitor in an earlier treatment line. Median age at alpelisib initiation was 64 years (range: 39-82 years). Included patients had a median of four lines of systemic therapy for advanced disease prior to starting alpelisib (range: 1- 11). Clinical benefit rate (patients receiving ³ 6 months of treatment) was 26.3% (10/38). The median progression-free-survival as well as time to treatment discontinuation were 3 months (range: 1 – 18). Dose reduction due to toxicity occurred in 11 patients (29%), of which 7 due to hyperglycemia grade 3, 2 due to diarrhea grade 3, 1 due to rash grade 2 and 1 due to anorexia. Finally, 84% of patients (32/38) stopped alpelisib treatment because of progressive disease, 8% (3/38) because of intolerance, one patient died because of cerebral hemorrhage during treatment, one patient withdrew their informed consent and one patient is still ongoing with the treatment. Conclusion: Our trial demonstrates activity of alpelisib in patients with PIK3CA mutated advanced breast cancer in later lines of treatment after treatment with CDK4/6 inhibitors with a clinical benefit rate of 26.3%. Discontinuation of therapy due to toxicity was seen in only 8% of patients, although toxicity induced dose reduction was needed in 29% of patients. These findings support the results of the BYLieve trial and additionally show efficacy of alpelisib in later lines of treatment for hormone receptor-positive advanced breast cancer. Citation Format: Rik Van Severen, Anne-Sofie De Crem, Hava Izci, Laurence Slembrouck, Isabelle Vanden Bempt, Hans Wildiers, Kevin Punie, Eline Naert, Ingeborg Hilderson, Ann Smeets, Ines Nevelsteen, Anne Deblander, Nynke Willers, Patrick Berteloot, Ignace Vergote, Sileny Han, Adriaan Vanderstichele, Giuseppe Floris, Christine Desmedt, Hannelore Denys, Patrick Neven. Efficacy and Safety of Alpelisib in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor: An Open-label, Multi-centre, Prospective, Single Arm Clinical Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-21-10.

Abstract PO4-12-12: An Updated analysis of risk factor identification and Hyperglycemia prevention with alpelisib + fulvestrant in PIKC3A-mutated, hormone-receptor positive, human epidermal growth factor-2 negative advanced breast cancer

Abstract Background: SOLAR-1 investigated use of alpelisib (ALP) + fulvestrant (FLV) in patients (pts) with hormone-receptor positive (HR+)/human epidermal growth factor-2 negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC) after progression on endocrine-based therapy and demonstrated a clinically significant increase in all-grade (G) and G3-4 hyperglycemia (HG) compared to placebo + FLV. Current guidance recommends an insulin sensitizer (metformin, thiazolidinedione, SGLT2i) at HG onset. Given high rates of HG, a preventative protocol and identification (ID) of associated risk factors (RFs) was implemented to minimize HG, dose reductions and discontinuation. Although METALLICA investigated the implementation of metformin for hyperglycemia prophylaxis, there is limited data for alpelisib use and hyperglycemia prevention in high risk or controlled type 2 diabetic patients. Duke Breast Oncology Clinic (DBOC) implemented a preventive strategy to minimize HG and treatment disruptions in patients receiving alpelisib, including pre-diabetic and controlled-diabetic patients. Methods: This single-center, retrospective study included pts receiving at least one 28-day cycle of ALP+FLV between June 2019 and April 2023. One week prior to ALP initiation, pts initiated an insulin-sensitizer. Pts had fasting plasma glucose (FPG) levels drawn on day 8, 15, 28, and monthly while on ALP. The primary outcome was incidence of G2-4 HG. Descriptive statistics were used to summarize results. Number of RFs for HG (age ≥ 65 years, BMI ≥ 25 kg/m2, baseline FPG ≥ 100 mg/dL, and A1c ≥ 5.7%) were compared between pts with and without HG using Wilcoxon rank-sum test. Results A total of 30 pts (29 females; 1 male) were included with a median age of 60 years. The cohort was 70% White, 23% Black, while 67% were overweight/obese, and 50% had a history of type 2 diabetes mellitus (T2DM), gestational diabetes, or pre-diabetes. 29 pts received a CDK4/6 inhibitor prior to starting ALP. By day 28, 13 pts (43%) had G2-4 HG, with only 4 (13%) having G3 HG and zero having grade 4. Pts with G2-4 HG had a median of 2 RFs compared to only 1 RF if no HG. 8 pts (27%) required a temporary hold of ALP and 5 pts (17%) required a dose reduction in ALP due to HG. 25 pts permanently discontinued ALP; 14 due to disease progression and 8 due to an adverse event with only 3 due to HG. Median duration of ALP was 86 days (range 24-442), with 5 pts continuing to receive ALP at time of analysis. Patients with grade 2-4 HG by day 28 after ALP initiation had an older median age (66 years), higher BMI (median 28.1 kg/m2), higher baseline FPG (median 100 mg/dL), and higher baseline HbA1c (median 5.6%) compared to those without grade 2-4 HG (Table). Conclusions: Implementation of a HG prevention protocol with ALP in the real-world setting demonstrated fewer G3-4 HG events compared to that seen in SOLAR-1 (13% vs 36.6%) but slightly higher than METALLICA (6%) although we included a higher risk patient population. An increase in HG-associated RFs correlated with a higher incidence of G2-4 HG. Early risk identification and optimization of prophylactic antihyperglycemics can reduce ALP dose reductions and discontinuations secondary to HG. ALP use in higher-risk patients can be considered with a HG prevention protocol. Table 1. Hyperglycemia outcomes Citation Format: Heather Moore, Sarah Burnette, Emily Poehlein, Hui-Jie Lee, Kelly Westbrook, Thomas Bagwell, Kervin Novido, Susan Dent. An Updated analysis of risk factor identification and Hyperglycemia prevention with alpelisib + fulvestrant in PIKC3A-mutated, hormone-receptor positive, human epidermal growth factor-2 negative advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-12-12.

Abstract GS03-10: Allosteric PI3K-alpha inhibition overcomes on-target resistance to orthosteric inhibitors mediated by secondary PIK3CA mutations

Abstract Background: PIK3CA mutations occur in ~40% of HR-positive breast cancers, where alpelisib, an orthosteric PI3Kα inhibitor, is FDA-approved in combination with fulvestrant. Although prior studies have identified potential resistance mechanisms, such as PTEN loss, clinical acquired resistance to orthosteric PI3Kα inhibitors and the role of next-generation allosteric PI3Kα inhibitors remain poorly understood. Methods: To identify on-target and off-target alterations potentially mediating resistance to PI3Kα inhibitors, we used a targeted next-generation sequencing assay (Guardant360; Guardant Health) to analyze ctDNA in serially collected plasma samples from 32 patients with PIK3CA-mutated advanced HR-positive, HER2-negative breast cancer treated with alpelisib and inavolisib. In addition, we performed whole exome sequencing (WES) of 100 tissue samples collected from 8 autopsy series from patients with metastatic, PIK3CA-mutant HR-positive, HER2-negative breast cancer previously treated with PI3Kα inhibitors. Acquired alterations were prioritized through a combination of structural modeling and free-energy perturbation simulation and validated in genomically engineered PIK3CA mutant breast cancer cell lines T47D (PIK3CA H1047R-mutant) or MCF7 (PIK3CA E545K-mutant). Results: We observed that 50% of patients acquire genomic alterations within the PI3K-pathway, including PTEN loss and activating AKT1 mutations. Notably, while secondary PIK3CA mutations were previously reported to increase sensitivity to PI3Ka-inhibitors, we identified emergent secondary resistance mutations in PIK3CA that alter the inhibitor binding pocket including PIK3CA Q859K and PIK3CA W780R. Some mutations had differential effects on PI3Ka-selective vs. pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Ka-inhibitor RLY-2608. Conclusion: In one of the largest patient cohorts analyzed to date, this study defines the clinical landscape of acquired resistance to PI3Ka inhibitors. Genomic alterations within the PI3K pathway represent a major mode of resistance and identify a novel class of secondary PIK3CA resistance mutations that can be overcome by an allosteric PI3Ka inhibitor. Together, these findings provide insights to guide strategies to overcome resistance in PIK3CA-mutated cancers. Citation Format: Andreas Varkaris, Ferran Fece de la Cruz, Elizabeth Martin, Bryanna Nordern, Nicholas Chevalier, Ignaty Leshchiner, Anastasia Stavridi, Janice Kim, Alkistis Papatheodoridi, Hakan Gunaydin, Brian Danysh, Laxmi Parida, Ioannis Sanidas, Yongli Ji, Kayao Lau, Gerburg Wulf, Aditya Bardia, Laura Spring, Steven Isakoff, Jochen Lennerz, Levi Pierce, Ermira Pazolli, Gad Getz, Ryan Corcoran, Dejan Juric. Allosteric PI3K-alpha inhibition overcomes on-target resistance to orthosteric inhibitors mediated by secondary PIK3CA mutations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS03-10.

Methylation of the chromatin modifier KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer

Activating mutations in PIK3CA are frequently found in estrogen-receptor-positive (ER+) breast cancer, and the combination of the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib with anti-ER inhibitors is approved for therapy. We have previously demonstrated that the PI3K pathway regulates ER activity through phosphorylation of the chromatin modifier KMT2D. Here, we discovered a methylation site on KMT2D, at K1330 directly adjacent to S1331, catalyzed by the lysine methyltransferase SMYD2. SMYD2 loss attenuates alpelisib-induced KMT2D chromatin binding and alpelisib-mediated changes in gene expression, including ER-dependent transcription. Knockdown or pharmacological inhibition of SMYD2 sensitizes breast cancer cells, patient-derived organoids, and tumors to PI3K/AKT inhibition and endocrine therapy in part through KMT2D K1330 methylation. Together, our findings uncover a regulatory crosstalk between post-translational modifications that fine-tunes KMT2D function at the chromatin. This provides a rationale for the use of SMYD2 inhibitors in combination with PI3Kα/AKT inhibitors in the treatment of ER+/PIK3CA mutant breast cancer.

Preventing alpelisib-related hyperglycaemia in HR+/HER2−/PIK3CA-mutated advanced breast cancer using metformin (METALLICA): a multicentre, open-label, single-arm, phase 2 trial

Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with HR+/HER2-/PIK3CA-mutated advanced breast cancer (ABC). Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2-/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose <100mg/dL [<5.6mmol/L] and HbA1c <5.7%), and cohort B, prediabetes (fasting plasma glucose 100-140mg/dL [5.6-7.8mmol/L] and/or haemoglobin A1C [HbA1c] 5.7-6.4%). Participants were at least 18 years old, with Eastern Cooperative Oncology Group performance status of 0-1, and up to two prior lines of endocrine therapy (ET) for ABC. Alpelisib plus ET were administered in 28-day cycles after initiation of prophylactic metformin plus ET. Primary endpoint was the incidence of grade 3-4 hyperglycaemia over the first 8 weeks. Secondary endpoints included safety, progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). The primary objective for cohort A and B is met with ≤7 (14.6%) and ≤4 (20%) patients with grade 3-4 hyperglycaemia over the first 8 weeks, respectively. 233 patients were screened, and 68 (20.2%) patients were enrolled in cohorts A (n=48) and B (n=20). Median follow-up was 7.8 months (IQR 1.4-19.6). Over the first 8 weeks, one (2.1%) of 48 patients in cohort A (95% CI: 0.5-11.1; P<0.0001), and three (15.0%) of 20 patients in cohort B (95% CI: 5.6-37.8; P=0.016) had grade 3-4 hyperglycaemia. Serious treatment-related adverse events occurred in seven patients (10.3%). The most common were rash (two [2.9%]), vomiting (two [2.9%]), and diarrhoea (two [2.9%]). Discontinuation of alpelisib caused by AEs was reported in nine patients (13.2%), none caused by hyperglycaemia. At data cutoff (15 June, 2022), no treatment-related deaths were observed. In the full analysis set, median PFS was 7.3 months (95% CI: 5.9-not reached), ORR was 20.6% (95% CI: 11.7-32.1%), and CBR was 52.9% (95% CI: 40.4-65.2). In HR+/HER2-/PIK3CA-mutated ABC, prophylactic metformin before alpelisib plus endocrine treatment has low incidence and severity of alpelicib-induced hyperglycaemia. Novartis Pharmaceuticals.

Abstract 7196: Evaluation of nab-sirolimus in combination with fulvestrant or PI3K pathway inhibitors to overcome resistance in breast cancer cell lines

Abstract Background: Endocrine therapy (ET) is the standard of care for hormone receptor positive (HR+) breast cancer (BC), but ET resistance develops in most patients (pts). One resistance mechanism involves cross talk between the PI3K-AKT-mTOR and estrogen receptor (ER) signaling pathways, resulting in increased ER signaling and tumor proliferation. This is mitigated by mTOR inhibition as demonstrated by improved outcomes with exemestane plus the mTOR inhibitor (mTORi) everolimus in pts with HR+ advanced BC. While PI3K inhibitors (PI3Ki [e.g. alpelisib]) are efficacious in pts with HR+, PIK3CA-mutated BC, resistance can occur due to acquired genomic alterations in the PI3K-AKT-mTOR pathway. Combination therapy that targets a critical downstream node, mTOR, could delay or overcome acquired resistance due to activation of upstream components of the PI3K-AKT-mTOR pathway. nab-Sirolimus is an intravenously administered, albumin-bound nanoparticle form of the mTORi sirolimus, with significantly greater tumor accumulation, mTOR target suppression, and improved antitumor effects than oral mTORis in nonclinical tumor models. We evaluated the antiproliferative and cytotoxic effects of nab-sirolimus in combination with ET or PI3Kis in BC cell lines. Methods: HR+, PI3K-mutated BC cell lines (MCF7 or MDA-MB-361) were incubated for 5 days with increasing concentrations of nab-sirolimus and the selective ER degrader fulvestrant. MDA-MB-361 cells or HR-negative (HR−), PI3K-mutated BC cells, MDA-MD-453, were incubated for 5 days with increasing concentrations of nab-sirolimus and PI3K-AKT-mTOR pathway inhibitors gedatolisib or alpelisib. Antiproliferative/cytotoxic effects of single-agent and combination treatment were assessed via an automated trypan blue exclusion assay. Results: Addition of 20 or 80 nM nab-sirolimus to fulvestrant (12.5-500 nM) markedly decreased cell viability and nearly doubled cell death in MCF7 and MDA-MB-361 cells. Antiproliferative effects of low-dose gedatolisib (2.5-10 nM) were enhanced by 61-71% when nab-sirolimus (20 or 80 nM) was added to MDA-MB-453 cells. While low doses (2.5, 5, and 10 nM) of gedatolisib alone led to limited cytotoxicity (4.2-9.6%), up to 48.9% of cell death occurred when 20 or 80 nM nab-sirolimus was added. Results were similar with alpelisib (1 uM) plus nab-sirolimus (20 or 80 nM). Western blot showed increased p4EBP1 in response to fulvestrant or PI3Ki treatment, which was reversed with the addition of nab-sirolimus. Conclusions: nab-Sirolimus enhanced the cytotoxic effects of fulvestrant in HR+ BC cells and of PI3Kis in HR+ and HR− BC cells. Addition of nab-sirolimus to ET or other PI3K-AKT-mTOR pathway inhibitors may overcome mechanisms of resistance; further exploration is warranted to elucidate clinical relevance. Citation Format: Khine Nyein Myint, Sean Wallace, Shihe Hou, Maria Zalath, Brian McMorran, Andrew Kwon, Igor Vivanco. Evaluation of nab-sirolimus in combination with fulvestrant or PI3K pathway inhibitors to overcome resistance in breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7196.

Abstract 4125: Exploring the efficacy of alpelisib and combined PI3Kα-S6K inhibition in LIN28B-mediated colorectal cancer metastasis

Abstract Introduction: Colorectal cancer (CRC) is the third most diagnosed cancer worldwide. LIN28B, an RNA-binding protein that regulates mRNA translation, has garnered significant interest in recent cancer research. Our lab has established that LIN28B is an oncogene and promotes CRC metastasis. However, the exact mechanisms through which LIN28B exerts these effects remain elusive. The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is altered in 50-70% of CRCs and is characterized by PIK3CA gene mutations in 20-30% of CRC cases. PIK3CA encodes the catalytic subunit p110α of the PI3Kα enzyme, which is critical for PI3K/AKT signaling. Activation of this pathway is associated with worse CRC prognosis. Among the components of this signaling cascade, the ribosomal protein S6 kinase (S6K) is a crucial downstream effector, playing a pivotal role in protein synthesis and cell growth. Despite the frequent occurrence of PIK3CA mutations in CRC, targeted therapies for PIK3CA-mutant CRC are lacking. Alpelisib, a PI3Kα-specific inhibitor approved by the FDA for a subset of PIK3CA-mutant breast cancers, remains largely unassessed in CRC. We hypothesize that LIN28B-mediated CRC metastasis is facilitated by the activation of the PI3K/AKT pathway, representing a potential target for Alpelisib or other related inhibitors. Results: Our data indicate that LIN28B expression in CRC cells promotes liver metastasis in mouse models of metastatic CRC (mCRC). Furthermore, LIN28B expression activates the PI3K/AKT pathway, as measured by an AKT phosphorylation array. Treatment of CRC cells with SC79, a pan-AKT activator, enhanced cell migration and invasiveness. Similarly, VillinCre;R26Pik3ca transgenic mice, expressing a constantly active mutant form of PI3Kα in the intestinal epithelium, demonstrated crypt hyperplasia and an amplified propensity for tumorigenesis, mirroring the effects of LIN28B expression in CRC. Importantly, Alpelisib effectively hinders LIN28B-driven CRC progression in cell lines, transgenic mice-derived organoids, and mCRC mouse models, as well as the growth rate of CRC patient-derived organoids (PDOs). The effects observed with Alpelisib treatment were replicated with inhibition of S6K using either LY25284702 or PF4708671. Moreover, a combination of low-dose Alpelisib with low-dose LY25284702 or PF4708671 synergistically restricted the growth of PDOs. Conclusion: Our data provide compelling evidence that the PI3K/AKT pathway regulates LIN28B-mediated CRC metastasis, and its inhibition by Alpelisib is feasible. This underscores the potential for precision medicine in CRC, offering targeted therapies to PIK3CA-mutant CRC patients who lack specific treatment options. Furthermore, our study highlights the clinical advantages of combined inhibition strategies for improved anti-metastatic outcomes, a field in dire need of interventions in mCRC. Citation Format: Alice E. Shin, Kensuke Sugiura, Secunda W. Kariuki, David A. Cohen, Christopher J. Lengner, Peter A. Sims, Joel T. Gabre, Anil K. Rustgi. Exploring the efficacy of alpelisib and combined PI3Kα-S6K inhibition in LIN28B-mediated colorectal cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4125.

Alpelisib for PIK3CA-mutated advanced gynecological cancers: First clues of clinical activity

ObjectiveRecurrent gynecological tumors (e.g., endometrial, and ovarian cancers) are incurable diseases; therefore, new treatment options are urgently needed. The PTEN-AKT-PI3K pathway is frequently altered in these tumors, representing a potential treatment target. Alpelisib is an α-specific PI3K inhibitor approved in PIK3CA-mutated advanced breast cancer. We report outcomes from a large series of patients with PIK3CA-mutated gynecological cancers prospectively treated with alpelisib within a controlled program. MethodsFrom April 2021 to December 2022, 36 patients with PIK3CA-mutated advanced gynecological cancers received alpelisib 300 mg orally once daily. Objective response (ORR) and disease control (DCR) rates provided measure of the antitumor activity of alpelisib, the primary objective of the study. ResultsIncluded patients had endometrial (17/36 [47%]), ovarian (10/36 [28%]), or other gynecological cancers (9/36 [25%]). Most patients had received 2–3 prior systemic treatments (endometrial, 47·2%; ovarian, 60%; other, 56%), and presented with visceral metastases at baseline (82%, 70%, and 56%, respectively). Overall, 17 different PIK3CA mutations were found, including 53% in the kinase domain (most commonly H1047R) and 36% in the helical domain (most commonly E545K). Overall, the ORR was 28% and DCR was 61%, with the greatest benefit observed in patients with endometrial cancer (35% and 71%, respectively). ConclusionAlpelisib represents an active treatment option in patients with recurrent gynecological cancers harboring a PIK3CA mutation. These findings support the need of biomarker-driven randomized trials of PI3K inhibitors in gynecological cancers.

A real-world disproportionality analysis of FDA adverse event reporting system (FAERS) events for alpelisib

In this study, we delved into the safety profile of alpelisib, an FDA-approved treatment for hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer, and PIK3CA-Related Overgrowth Spectrum (PROS). Despite its approval, real-world, long-term safety data is lacking. Our research scrutinizes the FDA database to assess alpelisib 's safety. We retrospectively analyzed data from April 2019 to June 2023 using four algorithms. Among 7,609,450 reports, 6692 implicated alpelisib as the primary suspected drug, uncovering adverse events (AEs) across 26 organ systems. Notably, we identified 21 previously unlisted AEs. Furthermore, differences in AEs emerged between patients with PIK3CA-mutated breast cancer and those with PROS. This study provides vital insights for healthcare professionals to navigate AEs in clinical practice and informs future research for enhancing alpelisib 's safety profile.

Integrative modeling uncovers p21-driven drug resistance and prioritizes therapies for PIK3CA-mutant breast cancer

Utility of PI3Kα inhibitors like BYL719 is limited by the acquisition of genetic and non-genetic mechanisms of resistance which cause disease recurrence. Several combination therapies based on PI3K inhibition have been proposed, but a way to systematically prioritize them for breast cancer treatment is still missing. By integrating published and in-house studies, we have developed in silico models that quantitatively capture dynamics of PI3K signaling at the network-level under a BYL719-sensitive versus BYL719 resistant-cell state. Computational predictions show that signal rewiring to alternative components of the PI3K pathway promote resistance to BYL719 and identify PDK1 as the most effective co-target with PI3Kα rescuing sensitivity of resistant cells to BYL719. To explore whether PI3K pathway-independent mechanisms further contribute to BYL719 resistance, we performed phosphoproteomics and found that selection of high levels of the cell cycle regulator p21 unexpectedly promoted drug resistance in T47D cells. Functionally, high p21 levels favored repair of BYL719-induced DNA damage and bypass of the associated cellular senescence. Importantly, targeted inhibition of the check-point inhibitor CHK1 with MK-8776 effectively caused death of p21-high T47D cells, thus establishing a new vulnerability of BYL719-resistant breast cancer cells. Together, our integrated studies uncover hidden molecular mediators causing resistance to PI3Kα inhibition and provide a framework to prioritize combination therapies for PI3K-mutant breast cancer.

Phase Ib and pharmacokinetics study of alpelisib, a PIK3CA inhibitor, and capecitabine in patients with advanced solid tumors.

This phase Ib study was performed to determine the safety of combination capecitabine with alpleisib (phosphatidylinositol 3-kinase catalytic subunit p110α blockade) and determine the maximal tolerated dose (MTD) and recommended phase ll dose (RP2D) of this combination regimen in patients with advanced solid tumors refractory to standard therapy. The synergistic anti-tumor activity and pharmacokinetics (PK) were investigated. Dose escalation phases were conducted in patients with advanced solid cancers who were refractory to standard therapy regardless of PIK3CA mutation. Patients were administered orally once daily alpelisib (200mg and 300mg) and twice daily capecitabine (850mg, 1000mg, 1250mg orally, days 1-14) every 3 weeks. Standard "3+3" dose escalation was used to define the MTD. The effect of alpelisib on the PK of capecitabine was assessed. Patients with 6 colorectal cancer (three PIK3CA mutation) and 6 breast cancer (all PIK3CA mutation) were enrolled. The first three patients in dose level 0 (alpelisib 200mg daily, capecitabine 1,000 mg/m2 twice daily) had no dose-limiting toxicities (DLTs). In dose level 1 (alpelisib increased to 300 mg daily, capecitabine 1,000mg twice daily), one of six patients had DLT (grade (Gr) 3 hyperglycemia). When dose level 2 (alpelisib 300mg daily, capecitabine 1,250 mg/m2 twice daily) was expanded to 3 patients, no patients had DLTs. The combination of alpelisib 300mg daily and capecitabine 1,250 mg/m2 twice daily was declared as the MTD/RP2D in patients with advanced solid tumors. The most common AEs were Gr 1-3 hyperglycemia (75.0%). Frequent all-grade, treatment-related AEs included Gr 2-3 nausea (75.0%), Gr 1-2 diarrhea (50.0%), Gr 1-2 hand-foot syndrome (41.7%), Gr 1-2 anorexia (41.7%), Gr 2 mucositis (33.3%). Antitumor activity was observed in patients with PIK3CA mutant breast cancer (3 partial response and 3 stable disease of total 6 patients). Alpelisib exposure (Cmax and AUC0-12) was unaffected by concomitant capecitabine. There were no clinically relevant drug-drug interactions observed between alpelisib and capecitabine. The combination of alpelisib and capecitabine is generally tolerated, without pharmacokinetic interactions, and shows antitumor activity in patients with PIK3CA mutant advanced cancers.

Alpelisib-Induced Diabetic Ketoacidosis: A Pharmacovigilance Analysis of the FDA Adverse Event Reporting System and Review of the Literature

BackgroundAlpelisib is a PI3K inhibitor indicated with fulvestrant for treatment of advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated breast cancer. In the phase III SOLAR-1 trial, grade 3/4 hyperglycemic events were reported in 36.6% of patients receiving alpelisib-fulvestrant compared to 0.7% receiving placebo-fulvestrant. As case reports of diabetic ketoacidosis (DKA) have been associated with alpelisib use, the goal of this study was to characterize the FAERS reported cases of this severe adverse effect. MethodsA retrospective disproportionality analysis was performed using the FAERS database by calculating the reporting odds ratio (ROR) of DKA events with alpelisib from 2019 to 2022. A PubMed literature review of case reports characterizing alpelisib-induced DKA was performed. ResultsPharmacovigilance database analysis revealed significance in reporting among 87 DKA cases with alpelisib (ROR 9.84, 95% confidence interval 7.3-13.2), including hospitalization and death as reported outcomes. Review of 11 published case reports reveals median onset of DKA at 14 days with successful rechallenge possible. ConclusionSignificant association with reporting exists between DKA and alpelisib exposure. We observed similar median time to onset of hyperglycemia between our analysis compared to that reported in SOLAR-1. Considering early onset of this toxicity, it is imperative that patients be closely monitored when initiating alpelisib. Addition of a preemptive antihyperglycemic or escalation in those previously on antihyperglycemic medications is beneficial in decreasing the severity of hyperglycemia with alpelisib. Further study investigating risk factors is warranted to better elucidate which patients require preemptive therapy.

Development, cross-validation and greenness assessment of capillary electrophoresis method for determination of ALP in pharmaceutical dosage forms - an alternative to liquid chromatography.

Breast cancer treatment has made tremendous progress in recent years and new therapies are emerging continuously. Alpelisib (ALP) is a novel phosphoinositide-3-kinase (PI3K) inhibitor recently approved for human receptor-positive, human epidermal growth factor receptor 2-negative, PIK3CA-mutated metastatic breast cancer in combination with fulvestrant. ALP has been the subject of only a limited number of preclinical in vitro and in vivo studies using different chromatographic techniques. However, no research has been published on analyzing ALP using capillary electrophoresis (CE). The absence of pharmacopoeial monographs for ALP in both the European and United States Pharmacopoeias highlights the urgent need to develop a reliable analytical method for its quality control in both industry and regulatory authorities. In this work, we have developed a first-ever CE method for the determination of ALP in pharmaceutical dosage forms in just 1.4 minutes. This was achieved with a 25 mM borate buffer at pH 9.3, 30 kV separation voltage and 30 °C capillary temperature. The proposed method was validated according to the ICH guidelines regarding selectivity, linearity (r = 0.9988), precision (RSD < 5.9%), accuracy (bias < 3.0%) and robustness (RSD < 3.2%). It was applied to the pharmaceutical dosage form of ALP and was shown to be suitable for the reliable determination of ALP. Furthermore, to demonstrate the applicability of the CE as an alternative technique to more commonly used HPLC in the analysis of drugs, cross-validation of CE and HPLC methods was performed. Bland-Altman analysis showed that the average difference in determined concentrations between CE and HPLC over a range of 10-100 μg mL-1 was 0.87 μg mL-1 (p = 0.6390, N = 19) meaning that there is no difference in the performance of CE and HPLC in the determination of ALP in pharmaceutical dosage forms. The environmental impact of both methods was assessed using AGREE software and scores for CE and HPLC were calculated to be 0.74 and 0.51, respectively. Because of equally reliable analytical performance and greener analysis, CE should be considered as an alternative technique to HPLC in the analysis of ALP pharmaceutical dosage forms.

Is Alpelisib Plus Fulvestrant Cost-Effective for Treating PIK3CA-Mutation, HR+/HER2- Advanced Breast Cancer in the USA?

There is a considerable survival benefit of alpelisib in patients with PIK3CA-mutated, hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC), yet the financial burden may limit its use. Therefore, this study evaluated the cost-effectiveness of alpelisib plus fulvestrant in patients with PIK3CA-mutated, HR+/HER2- ABC in the USA. A Markov model was constructed to simulate the progression of PIK3CA-mutated, HR+/HER2- ABC. Efficacy and safety data were derived from the SOLAR-1 trial. A parametric survival model was used to explore the long-term effect. From a US payer perspective, only direct medical costs were considered. The cost data were estimated based on local pricing and relevant literature. The health outcomes were expressed in quality-adjusted life years (QALYs). Model stability was assessed using one-way sensitivity analysis and probability sensitivity analysis. Subgroup analyses were performed to explore cost-effectiveness outcomes for patients with different clinical characteristics. The QALY increased by 0.28 withalpelisib plus fulvestrant with an additional cost of $94,345.87 compared with placebo plus fulvestrant, leading to an incremental cost-effectiveness ratio (ICER) of $340,153.30/QALY gained. Sensitivity analyses suggested that the model is most sensitive to the price of alpelisib. At a willingness-to-pay (WTP) threshold of $150,000/QALY, alpelisib plus fulvestrant was cost effective when the cost of alpelisib was less than $71 per 300 mg (36.5 % of the original price), whereas this cost would be less than $168 per 300 mg (86.5 % of the original price) at a WTP threshold of $300,000/QALY. In addition, alpelisib + fulvestrant was not cost effective in all subgroups compared with placebo + fulvestrant at the WTP threshold of $150,000/QALY. In contrast, at the WTP threshold of $300,000/QALY, alpelisib + fulvestrant was cost effective in nearly all subgroups except for endocrine-sensitive patients. At current drug prices, alpelisib plus fulvestrant is not cost effective for patients with PIK3CA-mutated, HR+/HER2- ABC from a US payer perspective. Given the considerable progression-free survival (PFS) and overall survival (OS) benefits observed with alpelisib in this setting, further discussion and negotiation of the price of alpelisib are warranted to provide more favorable economic outcomes and thereby increase the value of the alpelisib plus fulvestrant regimen in patients.

Incidence, risk factors, and management of alpelisib-associated hyperglycemia in metastatic breast cancer.

The combination of fulvestrant with alpelisib, a PI3K inhibitor, improves progression-free survival in metastatic hormone receptor-positive, PIK3CA-mutant breast cancer. This study describes the incidence, risk factors, and treatment of alpelisib-associated hyperglycemia. Patients with metastatic breast cancer who received alpelisib from 2013 to 2021 at Memorial Sloan Kettering Cancer Center were included in this retrospective study. Alpelisib prescription dates and patient/tumor characteristics were abstracted from medical records. Risk factors associated with hyperglycemia and alpelisib dose reduction/discontinuation were evaluated using Pearson's χ2 tests. Among 247 patients, baseline median body mass index was 25.4kg/m2 and median hemoglobin A1c (HbA1c) was 5.5%. A total of 152 patients (61.5%) developed any-grade hyperglycemia and 72 patients (29.2%) developed grade 3-4 hyperglycemia; median time to onset was 16days. A total of 100 patients (40.5%) received alpelisib on a clinical trial; rates of hyperglycemia were significantly higher in patients treated as standard care versus on a clinical trial (any-grade hyperglycemia 80.3% vs. 34.0%, grade 3-4 hyperglycemia 40.2% vs. 13.0%, p<.001). Baseline HbA1c was significantly associated with development of hyperglycemia (p<.001) and alpelisib dose reduction/discontinuation (p=.015). Among those who developed hyperglycemia, 101 (40.9%) received treatment, most commonly with metformin. A total of 49 patients (19.8%) were referred to an endocrinologist, which was associated with SGLT2 inhibitor prescription (p=.007). Rates of hyperglycemia among patients treated with alpelisib as standard care were significantly higher than patients treated on clinical trials. Elevated baseline HbA1c is associated with alpelisib-induced hyperglycemia and requiring dose modification. Optimization of glycemic status before alpelisib initiation should become routine practice.