Patient-Reported Outcome Data Support Alpelisib Vs Placebo in HR+/HER2– PIK3CA-Mutant Advanced Breast Cancer

April 30, 2021
Jessica Hergert
Jessica Hergert

Assistant Editor, OncLive®
Jessica joined the company in August 2019 and is one of the point contacts for the OncLive On Air™ podcast. She is a Rider University alumna and holds a degree in journalism and biology. Prior to joining MJH Life Sciences, she interned with the Ireland-based social media monitoring agency Olytico and served as a copy editor and writer for The Rider News. Email:

No statistically significant difference in Global Health Status or quality of life was observed with alpelisib vs placebo plus fulvestrant in patients with hormone receptor–positive, HER2-negative advanced breast cancer; however, symptom subscales for known adverse effects associated with PI3K inhibitors favored placebo vs alpelisib.

No statistically significant difference in Global Health Status or quality of life (QOL) was observed with alpelisib (Piqray) vs placebo plus fulvestrant (Faslodex) in patients with hormone receptor–positive, HER2-negative advanced breast cancer; however, symptom subscales for known adverse effects (AEs) associated with PI3K inhibitors favored placebo vs alpelisib, according to a patient-reported outcome (PRO) analysis of the phase 3 SOLAR-1 trial published in the Journal of Clinical Oncology.1

Global Health Status/QOL was maintained from baseline, with mean changes of less than 10 points, in the alpelisib and placebo arms. The overall change from baseline was -3.50 (95% CI, -8.02 to 1.02) with alpelisib vs 0.27 (95% CI, -4.48 to 5.02) with placebo.

Moreover, the overall treatment effect in Global Health Status/QOL (-3.77; 95% CI, -8.35 to 0.80; P = .101) and time to 10% deterioration in Global Health Status/QOL (HR, 1.03; 95% CI, 0.72 to 1.48) was similar between arms.

Baseline European Organisation for Research and Treatment of Cancer (EORTC) Core Quality of Life questionnaire (QLQ)-C30 symptom subscale scores were also similar between the alpelisib and placebo cohorts. The overall mean change from baseline over time in appetite loss was 10.96 with alpelisib vs 1.83 with placebo (P < .001). Similarly, other key symptom subscales demonstrated worsening scores over time with alpelisib vs placebo, including diarrhea (13.39 vs 1.63, respectively; P < .001), nausea/vomiting (6.97 vs 4.14, respectively; P = .019), and fatigue (9.85 vs 3.34, respectively; P = .014). However, constipation scores, at -8.54 vs -3.61, respectively, improved in the alpelisib treatment arm.

“Building on previous SOLAR-1 data demonstrating the efficacy and tolerability of alpelisib plus fulvestrant in patients with hormone receptor–positive, [HER2]-negative PIK3CA-mutated advanced breast cancer, this analysis supports further consideration of alpelisib as a well-tolerated treatment option for this population,” Eva Maria Ciruelos, MD, PhD, a medical oncologist in the Breast Cancer Unit of the Hospital Universitario 12 de Octubre, and co-authors, wrote in the study publication.

Hormone receptor–positive, HER2-negative breast cancer comprises over 70% of all breast cancer cases in the United States. Standard therapy options include endocrine therapy plus mTOR inhibitors, CDK4/6 inhibitors, and PI3K inhibitors, with the goal of delaying the need for chemotherapy while providing prolonged progression-free survival (PFS) and good QOL.

PIK3CA mutations are present in about 40% of patients with hormone receptor–positive, HER2-negative disease and confer a poor prognosis.

In the PIK3CA-mutant cohort of the SOLAR-1 trial, 341 patients were randomized to alpelisib plus fulvestrant (n = 169) or placebo plus fulvestrant (n = 172).2

Data from the trial demonstrated that with a median follow-up of 20 months, the median PFS was 11 months with alpelisib plus fulvestrant vs 5.7 months with placebo plus fulvestrant in patients with HR-positive, HER2-negative, PIK3CA-mutant advanced breast cancer (HR, 0.65; 95% CI, 0.50-0.85; P < .001).

Findings from the final overall survival (OS) analysis of study, which were presented during the 2020 ESMO Virtual Congress, demonstrated a 7.9-month improvement in median OS with alpelisib plus fulvestrant vs placebo plus fulvestrant in this patient population (HR, 0.86; 95% CI, 0.64-1.15; P = .15). However, the difference did not cross the prespecified O’Brien-Fleming efficacy boundary for significance (P ≤ .0161).3

Additional findings from subgroup analyses suggested that the addition of alpelisib to fulvestrant improved OS in patients with liver and/or lung metastases, as well as those whose circulating tumor DNA indicated the presence of a PIK3CA mutation. Moreover, patients who received alpelisib plus fulvestrant were able to delay chemotherapy initiation.

PROs served as secondary or exploratory end points for each cohort of patients in the SOLAR-1 trial.1 However, the PROs analyses were only conducted in the PIK3CA-mutant cohort because the primary efficacy end point of the study was met in just this population.

Regarding the PROs questionnaires, the compliance rates for completion were at least 93% at baseline in both cohorts. For post-baseline visits, the compliance rates ranged from 79% to 95% in the alpelisib cohort and 84% to 95% in the placebo cohort.

Based on the EORTC QLQ-C30 questionnaire, the mean baseline Global Health Status/QOL scores were 69.7 (standard deviation [SD], 21.0) in the alpelisib group vs 68.0 (SD, 21.6) in the placebo group.

EORTC QLQ-C30 functioning scale and symptom scale scores were similar between arms at baseline. The mean changes in physical functioning from baseline over 96 weeks was -2.89 in the alpelisib cohort (95% CI, -6.86 to 1.08) vs -3.57 in the placebo cohort (95% CI, -7.66 to 0.51). Respectively, median changes were -1.84 (95% CI, -6.58 to 2.90) vs -1.97 (95% CI, -6.85 to 2.91) for emotional functioning, -5.29 (95% CI, -10.27 to -0.31) vs -0.31 (95% CI, -5.48 to 4.86) for social functioning, -6.59 (95% CI, -12.55 to -0.63) vs -7.07 (95% CI, -13.18 to -0.96) for role functioning, and -2.05 (95% CI, -6.00 to 1.90) vs -3.47 (95% CI, -7.54 to 0.59) for cognitive functioning.

A numeric worsening of pain was observed in the placebo arm at 0.95 (95% CI, -4.60 to 6.50) vs 4.34 (95% CI, -1.38 to 10.05) in the alpelisib arm.

By week 32, both treatment arms were reduced by less than 50% of patients because of disease progression or treatment discontinuation. As such, a pattern-mixture model as a sensitivity analysis for Global Health Status/QOL was conducted to account for the missing data. However, no significant differences were observed in the analysis groups for Global Health Status/QOL between the alpelisib and placebo cohorts.

Hyperglycemia was the most frequently reported grade 3/4 AE with alpelisib in the SOLAR-1 trial.2,3 However, significant changes from normal or elevated baseline glucose levels were not observed in either treatment arm, which suggests that hyperglycemia does not have a significant effect on a patient’s health-related QOL over time.

Finally, the baseline scores for the Brief Pain Inventory-Short Form (BPI-SP) Worst Pain, Pain Severity Index, and Pain Interference Index were similar between arms. The Worst Pain item and Pain Severity Index findings suggest that patients receiving alpelisib had a delay in worsening pain and pain severity vs those receiving placebo. Moreover, patients reported a 42% improvement and 24% worsening in Worst pain with alpelisib vs 32% and 35%, respectively, with placebo at week 24 (P = .090). Similar numeric changes were observed at weeks 8 and 16.

Similar reports were seen between patients who had pain at baseline vs those who did not; however, a responder analysis in the patients who had baseline pain demonstrated a consistently greater numeric response with alpelisib vs placebo at weeks 16 and 24.

“Clinical decision making should include consideration of these results along with the statistically significant and clinically meaningful PFS observed with the addition of alpelisib to fulvestrant in patients with [hormone receptor–positive], HER2[-negative], PIK3CA-mutated [advanced breast cancer],” concluded the authors.


  1. Ciruelos EM, Rugo HS, Mayer IA, et al. Patient-reported outcomes in patients with PIK3CA-mutated hormone receptor–positive human epidermal growth factor receptor 2–negative advanced breast cancer from SOLAR-1. J Clin Oncol. Published online March 29, 2021. doi:10.1200/JCO.20.01139
  2. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940. doi:10.1056/NEJMoa1813904
  3. André F, Ciruelos EM, Juric D, et al. LBA18 - Overall survival (os) results from SOLAR-1, a phase III study of alpelisib (ALP) + fulvestrant (FUL) for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC). Ann Oncol. 2020;31(suppl 4):S1150-S1151. doi:10.1016/j.annonc.2020.08.2246