New ASCO Guidelines Offer a Practice-Changing Approach for PIK3CA/AKT1/PTEN Metastatic Breast Cancer

The American Society of Clinical Oncology (ASCO) has released a Rapid Recommendation Update on the guideline for endocrine and targeted therapy in hormone receptor-positive, HER2-negative- ( HR+/HER2) metastatic breast cancer patients, incorporating findings from the recent CAPItello-291 trial.

This trial showed that combining the AKT inhibitor capivasertib with fulvestrant boosts progression-free survival (PFS) in HR+/HER2- metastatic breast cancer patients, notably those with PIK3CA/AKT1/PTEN mutations for whom other treatments have failed.

Dr. Anupama Nehra, the clinical director of hematology/oncology at the Rutgers Cancer Institute at University Hospital in New Jersey, considers this development practice-changing because the effectiveness of the drug combination for the subset of patients with this specific mutation will help refine treatment plans.

“The world of cancer is changing. We rely a lot more on molecular diagnostics because we want to target things that a particular cancer is exhibiting so that we can get at the outcomes instead of the carpet bombing strategy that carries a lot of side effects which is what we do with chemotherapy,” she tells SurvivorNet.

As Dr. Nehra points out, next-generation sequencing and other molecular identification methods are enabling oncologists to pin down the unique characteristics of each patient’s cancer so treatments can be more personalized with better outcomes and fewer adverse effects.

This approach exemplifies the shift towards precision medicine and a move away from chemotherapy’s broad application.

Study results

CAPItello-291 was a phase III, double-blind, randomized trial involving 818 participants with locally advanced  (inoperable) or metastatic HR+/HER2- breast cancer who experienced recurrence or progression after being treated with an aromatase inhibitor treatment.

The trial, with a parallel assignment intervention model and quadruple masking (participant, care provider, investigator, outcomes assessor), compared the efficacy and safety of capivasertib plus fulvestrant (experimental group) against placebo plus fulvestrant (control group).

Treatment efficacy and safety were the primary endpoints.

• The overall median PFS was 7.2 months with capivasertib plus fulvestrant compared to 3.6 months for placebo plus fulvestrant.
• In the subgroup with PIK3CA/AKT1/PTEN-altered tumors (n=289), the median PFS was 7.3 months with capivasertib plus fulvestrant versus 3.1 months with placebo plus fulvestrant.
• Among patients whose tumors were AKT pathway non-altered, the median PFS was 5.3 months for capivasertib-treated patients and 3.7 months for placebo-treated patients, suggesting the greatest benefit when tumors harbored AKT pathway mutations.
• Measures of quality of life showed consistent overall global health status (GHS) for both groups from baseline, with no clinically meaningful changes in functional or symptom scores, apart from worsened diarrhea in the capivasertib plus fulvestrant arm.
• Time to deterioration of GHS was longer with capivasertib, and numerically longer for functional and symptoms, except for diarrhea.

Dr. Nehra considers the trial’s PFS notable and a reliable indication of the treatment’s success.

“Progression free survival is a good tangible end point for metastatic disease,” she says.

She also notes that earlier studies such as FAKTION suggest potential overall survival (OS) advantages with capivasertib, raising hopes for its tolerability and integration into treatment regimens.

Noted side effects

While the drug combo regimen does seem to carry fewer side effects than chemotherapy and some of the older drugs in use, Dr. Nehra acknowledges that oncologists will have to pay close attention to changes in blood sugar.

“One of the major effects with some of the older drugs we used to avoid chemotherapy was elevated blood sugar so we had to take patients off those drugs,” she explains. “This new drug does come with some degree of hyperglycemia, but it doesn’t seem to be as bad as the previous drugs.”

The study also reported a higher incidence of other grade ≥3 adverse events (AEs) like rash, diarrhea, in the capivasertib plus fulvestrant group. This necessitates proactive mitigation strategies to maintain patient quality of life.

But overall, the study’s findings and new guidelines have the potential to significantly impact clinical practice by providing a new therapeutic option that can be tailored to individual patient profiles, thereby improving outcomes for patients with advanced breast cancer.

“Until a few months ago, for patients who were showing an AKT reactivation, we didn’t really have a lot of drugs to offer. Now I have another option to go to after the patients who have failed the current standard of care.”