Adverse Event Management Strategies and Interventions for Treatment of Patients with HR+, HER2– Advanced Breast Cancer with Alpelisib plus Fulvestrant

November 2019 Vol 10, No 11
Gretchen Santos, NP, MSN, FNP-BC
University of California San Francisco Helen Diller Family Comprehensive Cancer Center
Sarah Donahue, MPH, NP
University of California San Francisco Helen Diller Family Comprehensive Cancer Center

Background: Activating mutations in PIK3CA (the gene encoding the p110α catalytic subunit of class I phosphatidylinositol 3-kinase [PI3K] [PI3Kα]) lead to increased activity of the PI3K pathway and play a role in endocrine treatment resistance in breast cancer. Pan-PI3K inhibitors, which inhibit all four isoforms of class I PI3K (α, β, δ, γ), and β-sparing PI3K inhibitors demonstrated modest clinical activity but considerable toxicity,1-3 which precluded further clinical development. Alpelisib (ALP) is a PI3Kα-specific inhibitor. Because it selectively targets a single PI3K isoform, ALP may be associated with less toxicity than broader PI3K inhibitors.

Objectives: The efficacy and safety of ALP+fulvestrant (FUL) versus placebo (PBO)+FUL were evaluated in SOLAR 1 (NCT02437318), a randomized, double blind phase 3 trial in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC) who relapsed/progressed on/after prior endocrine therapy.4

Methods: Outcomes from SOLAR-1 are reviewed. Based on clinical experience with ALP in SOLAR-1, management strategies for select adverse events (AEs) are recommended.

Results: ALP+FUL was associated with a statistically significant and clinically meaningful benefit in progression-free survival (PFS) in patients with PIK3CA-mutant disease (median PFS, 11.0 vs 5.7 months with PBO+FUL; hazard ratio, 0.65; 95% confidence interval, 0.50-0.85; P <0.001). In the overall population, hyperglycemia, gastrointestinal toxicities (including diarrhea, nausea, and vomiting), and rash were the most frequent AEs in ALP-treated patients. Rates of grade 3/4 AEs in ALP+FUL versus PBO+FUL arms were as follows: 36.6% versus 0.7% for hyperglycemia, 9.9% versus 0.3% for rash, and 6.7% versus 0.3% for diarrhea. Management of hyperglycemia included dietary/lifestyle modification, early intervention with metformin and other insulin sensitizers,5 and reduction in ALP for grade ≥3 hyperglycemia. Rash may be reduced by prophylactic second-generation antihistamines and treated with topical steroids6 and a hold/reduction in ALP for resistant cases. Management of diarrhea included hydration and use of loperamide7 and a reduction in ALP for grade ≥2 diarrhea. Additional considerations for monitoring/managing AEs in ALP treated patients, as per expert guidance and clinical experience, will be discussed.

Conclusions: ALP+FUL demonstrated efficacy and a generally manageable tolerability profile in SOLAR 1. Awareness and early prevention and management of AEs associated with ALP are important to ensure continued therapy and optimal clinical benefit.


  1. Baselga J, Im SA, Iwata H, et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:904-916.
  2. Di Leo A, Johnston S, Lee KS, et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018;19:87-100.
  3. Baselga J, Dent S, Cortés J, et al. Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): primary analysis from SANDPIPER. Presented at: 2018 American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, IL.
  4. André F, Ciruelos EM, Rubovsky G, et al. Alpelisib + fulvestrant for HR+, HER2- advanced breast cancer: results of the phase III SOLAR-1 trial. Presented at: ESMO 2018 Congress; October 19-23, 2018; Munich, Germany.
  5. Goldman JW, Mendenhall MA, Rettinger SR. Hyperglycemia associated with targeted oncologic treatment: mechanisms and management. Oncologist. 2016;21:1326-1336.
  6. Lacouture ME. Management of dermatologic toxicities associated with targeted therapy. J Adv Pract Oncol. 2016;7:331-334.
  7. Benson AB, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol. 2004;22:2918-2926.
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Last modified: August 10, 2023

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