Can PI3K Inhibitors Reduce Endocrine Therapy Resistance in Early Breast Cancer?

The addition of the PI3K inhibitor taselisib to endocrine therapy in the neoadjuvant setting resulted in a higher response rate than with endocrine therapy alone in patients with estrogen receptor-positive, HER2-negative breast cancer, according to a new study published in Lancet Oncology. This is similar to what was previously shown in the metastatic setting.

“Not all ER-positive breast cancer responds optimally to endocrine therapy,” wrote study authors led by Cristina Saura, MD, of Vall d'Hebrón University Hospital in Barcelona, Spain. “Upregulation of the PI3K–AKT–mTOR pathway is one of the mechanisms that can lead to primary or secondary endocrine resistance, or both.”

The new phase II LORELEI trial tested whether the PI3K inhibitor taselisib could improve response rates when added to letrozole in the neoadjuvant setting. It included a total of 334 patients with ER-positive, HER2-negative stage I–III operable breast cancer, treated at 85 hospitals in 22 countries. They were randomized to receive either letrozole plus placebo (168 patients) or letrozole plus taselisib (166 patients) prior to surgery and they were followed for a median of 4.9 months.

The addition of taselisib did in fact increase response rates, with 50% of the patients in that group achieving an objective response to the therapy compared with 39% of those receiving letrozole and placebo. This yielded an odds ratio for response of 1.55 (95% CI, 1.00–2.38; P = 0.049). In a subset of patients with PIK3CA mutations, 56% of the 73 patients in the taselisib group achieved a response, compared with 38% of the 79 patients in the placebo group, for an OR of 2.03 (95% CI, 1.06–3.88; P = 0.033).

Rates of pathologic complete response were generally low, and no differences were seen between the two groups. With taselisib, there were three pathological complete responses (pCR) (2%) in the taselisib group, compared with one (1%) in the placebo group, for an overall response of 3.07 (95% CI, 0.32–29.85; P = 0.37). The same was true when restricted to just the patients with PIK3CA mutations.

Serious adverse events (AEs) occurred more often in the taselisib group, including 5% with infections and 4% with gastrointestinal effects. In the placebo group, serious AEs included 1% each with postoperative wound and hematoma infection, hypertensive encephalopathy, cardiac failure, and breast pain. The authors noted that the AEs were generally manageable in the study, and that taselisib is more tolerable than other pan-PI3K inhibitors.

“Taken together, our results support future investigation of specific PI3K inhibitors plus endocrine treatment in ER-positive, HER2-negative breast cancer, especially in patients with PIK3CA-mutant tumors,” the authors concluded.

In an accompanying editorial, Christian Jackisch, MD, PhD, of Sana Hospital Offenbach in Offenbach, Germany, agreed that these results suggest taselisib might offer a better therapeutic index and a more favorable toxicity profile than other similar agents.

“In future studies, it might be important to increase the relative total dose intensity of the combination therapy to be tested in order to evaluate the effect on toxicity,” he wrote.

Jackisch noted, though, that the low pCR rate and the lack of a clear decrease in presurgical Ki67 levels “suggest that this combination is not a breakthrough neoadjuvant endocrine treatment.”