We learned from this study that inhibiting all the PI3K isoenzymes with drugs like buparlisib is associated with undue toxicity. However, this study gives us further impetus to develop PI3K-alpha inhibitors.

— Carlos L. Arteaga, MD

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Press conference moderator ­Carlos L. Arteaga, MD, of Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, said that buparlisib will probably not be clinically useful, partly because it crosses the blood-brain barrier , thus causing mood disorders, and is not an ideal phosphoinositide 3-kinase (PI3K) inhibitor because of its lack of selectivity against PI3K alpha, the real culprit in this type of breast cancers. “We learned from this study that inhibiting all the PI3K isoenzymes is associated with undue toxicity,” revealed Dr. Arteaga, who added that patients taking buparlisib in clinical trials are first given a rigorous psychiatric evaluation because of its effects on mood.

Dr. Arteaga continued: “This study gives us further impetus to develop PI3K-alpha inhibitors.” These more specific PI3K-alpha inhibitors are now in randomized registration trials; these drugs target and inhibit the PI3K alpha isoenzyme, which is the one that is mutated in estrogen receptor–positive breast cancer cells.

Ongoing Studies

“This is not a necessarily sad day for all PI3K inhibitors,” said Sara ­Hurvitz, MD, of Jonsson Comprehensive Cancer Center at the University of California, Los Angeles. She said that this study provides important information from the subgroup analyses. “As we get smarter about identifying predictive markers, we will be able to design studies that combine PI3K inhibitors with other promising targeted drugs.”

This is not a sad day for PI3K inhibitors. As we get smarter about identifying predictive markers, we need studies that combine PI3K inhibitors with other drugs.

— Sara Hurvitz, MD

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Ongoing studies such as SOLAR-1 will provide more data on PI3K-alpha inhibitors in the next year, she said. ­SOLAR-1 is evaluating alpelisib, a more specific PI3K-alpha inhibitor, plus fulvestrant (Faslodex) in advanced breast cancer that progressed on an aromatase inhibitor. A separate phase III study is evaluating taselisib plus fulvestrant vs fulvestrant plus placebo in recurrent advanced hormone receptor–positive HER2-negative breast cancer.

Moving This Strategy Forward

“This study is positive for the combination of buparlisib and fulvestrant. It is encouraging to see a PI3K-targeted therapy can improve outcomes beyond standard therapy in heavily pretreated patients who progressed on mTOR [mammalian target of rapamycin] treatment,” declared ­Tufia Haddad, MD, a medical oncologist at Mayo Clinic, Rochester, Minnesota. “The progression-free survival improvement is modest and might be worth it if buparlisib did not have more toxicity than standard therapy.”

Tufia Haddad, MD

Dr. Haddad continued: “Buparlisib is a pan-PI3K inhibitor. Newer agents more specific for the alpha isoform appear to have a more favorable side-effect profile. In the early phase trials with these agents, we are not seeing the same rate of severe mood disorders. We hope to move this strategy forward with PIK3-alpha specific ­inhibitors.”

“The other take-home messages from this trial are signals for improved activity in patients with PIK3CA mutations,” added Dr. Haddad. “We need to validate the benefit in this subgroup, and identify the best method to detect this mutation. The best strategy may be to screen patients for a PIK3CA mutation for future clinical trials with these agents,” she concluded. ■

Disclosure: Drs. Arteagav and Haddad reported no potential conflicts of interest. Dr. Hurvitz has received research funding from Amgen, Bayer, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Lilly, Novartis, Dignitana, Pfizer, Roche, BioMarin, Merrimack, OBI Pharma, Puma Biotechnology, and Medivation.