• Fabrice André, Eva Ciruelos, Gabor Rubovszky, Mario Campone, Sibylle Loibl, Hope S Rugo, Hiroji Iwata, Pierfranco Conte, Ingrid A Mayer, Bella Kaufman, Toshinari Yamashita, Yen-Shen Lu, Kenichi Inoue, Masato Takahashi, Zsuzsanna Pápai, Anne-Sophie Longin, David Mills, Celine Wilke, Samit Hirawat, Dejan Juric, and SOLAR-1 Study Group.
• From Institut Gustave Roussy, INSERM Unité 981, Université Paris-Sud, Villejuif (F.A.), Institut de Cancérologie de l'Ouest, St. Herblain (M.C.), and Novartis Pharma, Paris (A.-S.L.) - all in France; Hospital Universitario 12 de Octubre, Madrid (E.C.); National Institute of Oncology (G.R.) and Duna Medical Center (Z.P.), Budapest, Hungary; German Breast Group, Neu-Isenburg, and Center for Hematology and Oncology Bethanien, Frankfurt - both in Germany (S.L.); UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco (H.S.R.); Aichi Cancer Center, Nagoya (H.I.), Kanagawa Cancer Center, Yokohama (T.Y.), Saitama Cancer Center, Saitama (K.I.), and National Hospital Organization Hokkaido Cancer Center, Sapporo (M.T.) - all in Japan; Istituto Oncologico Veneto and the Departments of Surgery, Oncology, and Gastroenterology, University of Padua, Padua, Italy (P.C.); Vanderbilt University, Nashville (I.A.M.); Chaim Sheba Medical Center, Tel Hashomer, Israel (B.K.); National Taiwan University Hospital, Taipei (Y.-S.L.); Novartis Pharma, Basel, Switzerland (D.M., C.W.); Novartis Pharmaceuticals, East Hanover, NJ (S.H.); and Massachusetts General Hospital Cancer Center, Boston (D.J.).
• N. Engl. J. Med. 2019 May 16; 380 (20): 1929-1940.

BackgroundPIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The PI3Kα-specific inhibitor alpelisib has shown antitumor activity in early studies.MethodsIn a randomized, phase 3 trial, we compared alpelisib (at a dose of 300 mg per day) plus fulvestrant (at a dose of 500 mg every 28 days and once on day 15) with placebo plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status. The primary end point was progression-free survival, as assessed by the investigator, in the cohort with PIK3CA-mutated cancer; progression-free survival was also analyzed in the cohort without PIK3CA-mutated cancer. Secondary end points included overall response and safety.ResultsA total of 572 patients underwent randomization, including 341 patients with confirmed tumor-tissue PIK3CA mutations. In the cohort of patients with PIK3CA-mutated cancer, progression-free survival at a median follow-up of 20 months was 11.0 months (95% confidence interval [CI], 7.5 to 14.5) in the alpelisib-fulvestrant group, as compared with 5.7 months (95% CI, 3.7 to 7.4) in the placebo-fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001); in the cohort without PIK3CA-mutated cancer, the hazard ratio was 0.85 (95% CI, 0.58 to 1.25; posterior probability of hazard ratio <1.00, 79.4%). Overall response among all the patients in the cohort without PIK3CA-mutated cancer was greater with alpelisib-fulvestrant than with placebo-fulvestrant (26.6% vs. 12.8%); among patients with measurable disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisib-fulvestrant group vs. 0.7% in the placebo-fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the alpelisib-fulvestrant group, as compared with 0.3% of those in the placebo-fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued alpelisib and placebo owing to adverse events were 25.0% and 4.2%, respectively.ConclusionsTreatment with alpelisib-fulvestrant prolonged progression-free survival among patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. (Funded by Novartis Pharmaceuticals; SOLAR-1 ClinicalTrials.gov number, NCT02437318.).Copyright © 2019 Massachusetts Medical Society.

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