To our knowledge, this study represents the largest analysis of ALP with a focus on minimizing hyperglycemic events and is the first to examine clinical treatment patterns and safety outcomes outside of the SOLAR-1 trial. The key findings of our study are: 1) the lower rate of grade 3–4 hyperglycemic events seen from ALP with the use of a pre-emptive anti-hyperglycemic protocol compared to rates cited in previous studies [7, 16] and 2) the significantly higher number of risk factors in patients prescribed ALP who ultimately experienced grade 2–4 hyperglycemia compared to those who did not.
Identification of risk factors for hyperglycemia is critical due to the risk of toxicity from high glucose levels, which can present most critically as acute hyperglycemia with resulting ketoacidosis and may warrant an emergency room visit or even admission into the hospital for glucose control. Additional concerns include both microvascular and macrovascular diseases if not managed quickly – ranging from cardiovascular and cerebrovascular pathologies to neuropathy, nephropathy, and retinopathy [17, 18]. A detailed safety analysis of the SOLAR-1 trial elaborated on the baseline characteristics and outcomes of patients experiencing hyperglycemia [10]. Increases in FPG were more pronounced and the incidence of all-grade and grade 3–4 HG was higher in the pre-diabetic and diabetic subgroup compared to those who were euglycemic at baseline [10]. By evaluating ALP use in a community-based population, we included a large proportion of patients with pre-disposing risk factors for hyperglycemia (i.e. controlled T2DM, pre-diabetes, obesity, elevated baseline FPG or HbA1c, hypertension, hyperlipidemia, and cardiovascular disease), which are all prevalent in the Southeast region of the United States. In our patients, implementation of a pre-emptive hyperglycemia prevention protocol in patients being prescribed ALP demonstrated fewer grade 3–4 hyperglycemic events (19%) compared to rates reported in SOLAR-1 (36.6%) and BYLieve (28%), indicating that even high-risk patients may be eligible for ALP therapy if prevention is optimized [7, 16]. However, a larger study is warranted to confirm this finding.
Based on this retrospective study, it is our recommendation that patients being considered for ALP be started on anti-hyperglycemic prophylaxis with an insulin-sensitizing agent one week prior to initiating ALP, with metformin extended-release (XR) being an ideal first-line option due to ease of access, low cost, and increased tolerability of the XR formulation and low risk of hypoglycemia [19]. In patients unable to tolerate metformin, a thiazolidinedione or SGLT2 inhibitor are both optimal second-line options as their mechanism still serves to increase insulin sensitivity, with choice being dependent of patient-specific factors and preference [19]. Patients already receiving anti-hyperglycemic therapy for pre-diabetes or type 2 diabetes mellitus should continue on anti-hyperglycemics, and consideration should be given to dose titration and/or addition of an adjunctive agent prior to starting ALP consistent with management of ALP-induced hyperglycemia and its understood mechanism.
Metformin is generally considered to be a good first-line option. However, it demonstrated only a minor benefit on HG reduction in mouse models receiving ALP, while SGLT-2 inhibition was associated with a more profound decrease in HG and hyperinsulinemia [11]. For higher risk patients, SGLT-2 inhibition could be considered in the first line setting or in combination with metformin in higher risk patients. Alternatively, patients without the presence of risk factors and deemed to be at the lowest risk could be initiated on ALP without anti-hyperglycemia prophylaxis. However, more research is needed to provide definitive recommendations in these populations.
Optimized blood glucose control may also serve to improve efficacy outcomes with ALP if dose intensity is maintained. The BYLieve study demonstrated relatively longer progression-free survival in patients who received a higher median dose intensity of ALP, although patients receiving high-dose (≥ 248 mg/day) and low-dose (< 248 mg/day) ALP both demonstrated improved PFS over placebo [10]. By optimizing HG prevention strategies initially and minimizing the occurrence of high-grade HG, we anticipate fewer dose reductions, therapy interruptions, and discontinuations. This may correlate with improved efficacy outcomes though future research in this area is necessary.
Endocrine therapy is the therapeutic backbone for managing HR+/HER2- advanced or metastatic breast cancer and is recommended first-line in combination with a CDK4/6 inhibitor [3]. Notably, only a small subset of the SOLAR-1 population received previous treatment with a CDK4/6 inhibitor, and when stratified based on prior lines of therapy, a lack of prior CDK4/6 inhibitor treatment was associated with a significant improvement in progression-free survival in patients with a PIK3CA-mutation receiving ALP + FLV [7]. In our population, all but one patient prescribed ALP received a prior CDK4/6 inhibitor and all patients continued FLV from prior therapy or initiated FLV prior to starting ALP, which is representative of real-world clinical practice. The phase II trial, BYLieve, is investigating the therapeutic efficacy of ALP + FLV in patients after disease progression on a CKD4/6 inhibitor to further answer this question of sequencing. While our retrospective study did not specifically evaluate these outcomes, our data does reflect feasibility and benefit of ALP + FLV post-CDK4/6 inhibitor therapy.
Although our sample size is relatively small, it is representative of one of the only patient populations receiving ALP in combination with prophylactic antihyperglycemic therapy. Our study is limited by its observational and retrospective nature and lack of a control group. We were not able to control for concomitant dietary changes, although all patients did receive a referral to nutritional counseling for dietary modifications, or for patient adherence to the preventative anti-hyperglycemic regimen or prophylactic antihistamine for rash prevention. Some patients also elected to have labs obtained externally, which may have led to inconsistencies between lab sites. Lastly, we did not include patient-reported glucose levels obtained via home monitoring, so it is possible that patients may have experienced hyperglycemia earlier than is reported here.
Additional prospective data is needed to further assess the benefit of prophylactic antihyperglycemics in the prevention of ALP-induced hyperglycemia. There is currently an on-going study in which the safety and efficacy of dapagliflozin in combination with metformin XR will be reviewed in patients with HR+, HER2-, advanced breast cancer while receiving treatment with ALP and fulvestrant (EPIK-B4) [20]. Results will further elucidate prevention tactics for ALP-induced hyperglycemia and will further shape guideline recommendations.