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MUNICH -- Patients with advanced hormone receptor-positive (HR+) breast cancer associated with PIK3CA mutations lived almost twice as long without disease progression if they received the PI3K inhibitor alpelisib with endocrine therapy, a randomized trial showed.

Median progression-free survival (PFS) was 11.0 months with the combination of alpelisib (BLY719) and fulvestrant (Faslodex) as initial therapy versus 5.7 months with fulvestrant alone. The trial delivered a strong win for precision medicine, as only those patients with PIK3CA-mutated tumors benefited from the addition of the PI3K inhibitor, reported Fabrice Andre, MD, of Institute Gustave Roussy in Villejuif, France, at the European Society for Medical Oncology congress.

"Alpelisib is the first drug to show a benefit in a genomic subgroup of breast cancer patients," Andre said. "We have had HER2-targeted drugs ... but until now, the use of tumor genomics has not really entered the practical care of breast cancer, unlike melanoma or breast cancer."

"This study opens the door for clinical genomics for breast cancer as the first study to show that treatment based on a patient's tumor genomic profile -- specifically, PI3KCA mutation -- can improve the outcome," he added. "These results will have a major impact for practice, because we have to implement genomic testing for breast cancer."

The strongly positive results represent the beginning of the precision medicine era in breast cancer, said Nadia Harbeck, MD, PhD, of the University of Munich.

"We've had numerous trials with PI3 kinase inhibitors, including phase III trials, where we saw marginal benefit, and the drugs weren't usable in clinical practice because their tolerability was so bad," she said. "This is the first phase III data proving that if you have a targeted drug and a tumor with that target, you can almost double the progression-free survival. I think this will change the way we practice, with respect to hormone receptor-positive breast cancer."

The results offered a stark contrast to a trial reported earlier this year involving the PI3K inhibitor talelisib, which led to a modest 2-month improvement in PFS when added to fulvestrant. Beyond the relatively small clinical benefit, tolerability proved to be an issue with the combination, as seven times as many patients randomized to the talelisib arm discontinued treatment, as compared with fulvestrant alone.

Nonetheless, the talelisib trial provided support for a "lock and key" therapeutic relationship between the PI3K pathway and drugs that target mutations in the pathway. Investigators suggested that more specific inhibitors would lead to better results.

Andre said the alpelisib trial, known as SOLAR-1, provided compelling proof that high specificity for a treatment target would improve results with PI3K inhibitors. PI3K activates cell cycle progression and metabolism in a variety of tumors. However, the enzyme has multiple isoforms, some of which are involved in normal cellular activities. As a result, specificity of an inhibitor is crucial to clinical activity and toxicity, he noted.

About 70% of all breast cancers are HR+ and HER2-, and early-stage disease usually has a good prognosis. However, metastatic HR+/HER2- breast cancer has a median survival of about 42 months and has not improved in more than a decade, said Andre.

Approximately 40% of HR+/HER2- breast cancers have an activating mutation of PIK3CA, which encodes the alpha isoform of PI3K. Alpelisib has high specificity for PI3K-α.

SOLAR-1 tested the hypothesis that specific targeting of PI3K-α with alpelisib, in addition to fulvestrant, would improve PFS in men or postmenopausal women with untreated metastatic HR+/HER2- breast cancer, as compared with fulvestrant alone.

Investigators in the international multicenter trial randomized a total of 572 patients with receive fulvestrant plus alpelisib or placebo. The study p0pulation consisted of 341 patients with PIK3CA-mutant breast cancer and 231 without PIK3CA mutations and results were stratified by mutation status.

The trial had a primary endpoint of PFS in the PIK3CA-mutant cohort. The primary analysis demonstrated a 35% reduction in the hazard for death or disease progression for patients treated with alpelisib and fulvestrant (95% CI 0.50-0.85, P=0.00065). Consistent with the trial hypothesis, "no clinically relevant effect was observed in patients with PIK3CA non-mutant tumors," said Andre.

More than twice as many patients with PIK3CA-mutant tumors had objective responses with alpelisib (35.7% versus 16.2%, P=0.0002). Response rates for the entire study population were 26.6% with alpelisib and 12.8% with placebo (P=0.0006).

The most common adverse events (all grades) in the alpelisib arm were hyperglycemia (63.7%), diarrhea (57.7%), nausea (44.7%), decreased appetite (36.6%), and rash (35.6%). The most common grade 3/4 adverse events were hyperglycemia (36.6%), rash (9.9%), and diarrhea (6.7%). Andre characterized the toxicity as manageable, supported indirectly by low rate of treatment discontinuation associated with adverse events in the alpelisib arm (5.0% versus 1.0% with fulvestrant alone).

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