Final Analysis of SOLAR-1: 8-Month Survival Benefit Misses Statistical Significance for Alpelisib

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The statistically significant benefit of alpelisib in reducing disease progression, as reported at the European Society for Medical Oncology (ESMO) Congress 2 years ago, did not translate into a significant improvement in overall survival, although a numerical 8-month gain was observed in the final analysis of the phase III SOLAR-1 trial reported at the ESMO Virtual Congress 2020.1 The study evaluated alpelisib plus fulvestrant vs fulvestrant alone in patients with hormone receptor–positive, HER2-negative breast cancer with and without PIK3CA mutations, which alpelisib targets.

“The data suggest that PIK3CA mutations detected by ctDNA may be indicative of greater disease burden and more aggressive disease, and these patients may respond better to alpelisib.”
— Fabrice André, MD, PhD

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As previously reported, SOLAR-1 met its primary endpoint, demonstrating a median progression-free survival of 11.0 months with alpelisib plus fulvestrant compared with 5.7 months with fulvestrant alone (hazard ratio [HR] = 0.65; one-sided P = .00065) in patients with PIK3CA mutations.2 In the final analysis, this benefit did not result in a statistically significant overall survival advantage, although the investigators maintained that the 8-month gain is clinically meaningful.

“The statistically significant prolongation of progression-free survival [previously reported] was observed in a numerical increase in overall survival,” said Fabrice André, MD, PhD, Research Director and Head of INSERM Unit U981, Professor in the Department of Medical Oncology at Institut Gustave Roussy in Villejuif, France, and SOLAR-1 principal investigator.

Alpelisib targets the PIK3CA mutation, which is present in approximately 40% of patients with hormone receptor–positive, HER2-negative disease. The mutation results in PI3K pathway hyperactivation and endocrine resistance, thus worsening the prognosis for these patients.

SOLAR-1 Details

The phase III SOLAR-1 trial evaluated alpelisib (300 mg oral) or placebo plus fulvestrant (500 mg intramuscular) in 572 chemotherapy-naive patients with advanced breast cancer with disease progression on or following treatment with an aromatase inhibitor. The population included 341 patients with PIK3CA mutations and 231 patients with PIK3CA wild-type tumors.

A key secondary endpoint was overall survival in the cohort of patients with PIK3CA mutations. Median overall survival was 39.3 months with alpelisib plus fulvestrant compared with 31.4 months with fulvestrant alone (HR = 0.86; 95% confidence interval [CI], 0.64–1.15; P = .15). The difference did not cross the study’s prespecified efficacy boundary (one-sided P ≤ .0161), Dr. André said.


  • In the final analysis of SOLAR-1, the PI3K inhibitor alpelisib given with fulvestrant yielded an 8-month gain in overall survival in patients with hormone receptor–positive, HER2-negative advanced breast cancer with PIK3CA mutations, compared with fulvestrant alone. However, this difference did not meet the study’s threshold for statistical significance.
  • Patients with PIK3CA mutations detected in plasma ctDNA and patients with lung and/or liver metastases appeared to derive particular benefit from the combination therapy.

Of note, a larger numerical overall survival gain was shown for the combination in patients with visceral disease (35.1 months vs 23.0 months; HR = 0.75, 95% CI = 0.52–1.08), in particular lung and/or liver metastases (37.2 months vs 22.8 months; HR = 0.68, 95% CI = 0.46–1.00). The combination also delayed the time to chemotherapy; the median time for this was 23.3 months vs 14.8 months (HR = 0.72; 95% CI = 0.54–0.95), he reported.

“Keeping in mind some subgroups have a small sample size, the hazard ratio was 0.68 in patients with lung and/or liver metastases, compared with 1.18 in those without…. This translated into a 14-month improvement for these patients,” Dr. André pointed out.

Additionally, the use of plasma circulating tumor DNA (ctDNA), collected at baseline, seemed to select for another group especially benefiting from alpelisib. In an exploratory analysis, patients with detectable ctDNA (regardless of their tumor mutation status) had a median overall survival of 34.4 months with the combination vs 25.2 months with fulvestrant alone (HR = 0.74).

“The data suggest that PIK3CA mutations detected by ctDNA may be indicative of greater disease burden and more aggressive disease, and these patients may respond better to alpelisib,” he said.

A similar proportion of patients in the two arms received subsequent antineoplastic treatment; approximately 12% in both arms received a cyclin-dependent kinase 4 and 6 inhibitor.

No new safety signals were observed with alpelisib. Hyperglycemia was not further increased with longer time on treatment. Rash continued to be primarily grades 1 and 2. Quality of life was maintained for patients receiving alpelisib and fulvestrant. 

DISCLOSURE: Dr. André has received institutional research funding from AstraZeneca, Daiichi Sankyo, Lilly, Novartis, Pfizer, and Roche and has been reimbursed for travel, accommodations, and other expenses by AstraZeneca, GlaxoSmithKline, Novartis, and Roche.


1. André F, Ciruelos EM, Juric D, et al: Overall survival results from SOLAR-1, a phase III study of alpelisib + fulvestrant for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. ESMO Virtual Congress 2020. Abstract LBA18. Presented September 19, 2020.

2. André F, Ciruelos E, Rubovszky G, et al: Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med 380:1929-1940, 2019.

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