ASCO studies explore medicine combinations, order to treat metastatic hormone receptor-positive breast cancer

Two studies, presented as part of the 2020 ASCO Annual Meeting, provide guidance on how medicines approved in the past few years are best used in combination and after other treatments.

PARSIFAL looked at whether the CDK 4/6 inhibitor palbociclib (Ibrance) is better paired with an aromatase inhibitor or fulvestrant (Faslodex) in first-line treatment. BYLieve looked at use of the PI3K inhibitor alpelisib (Piqray) in people who have a PIK3CA mutation and already received treatment with a CDK 4/6 inhibitor.

Though studies like these do not bring the excitement of a new medicine, they help progress understanding about which medicines provide the best treatment to which people, and when.

Background

Standard therapy for metastatic hormone receptor-positive breast cancer has changed a lot in just a few years.

Palbociclib was the first CDK 4/6 inhibitor approved by the Food and Drug Administration for use in breast cancer. There are now three approved CDK 4/6 inhibitors, and they are part of standard care for metastatic hormone receptor-positive breast cancer.

Alpelisib was the first PI3K inhibitor approved for breast cancer treatment, just last year.

Both medicines are given with hormonal therapy, and it is important to understand what combinations are most effective and how well they work in different lines of treatment.

PARSIFAL

The phase II PARSIFAL study looked at whether combining fulvestrant with palbociclib would lead to people going longer without cancer growing than palbociclib with aromatase inhibitors, a standard first-line treatment in 2020. Fulvestrant is an estrogen receptor antagonist approved for metastatic hormone-receptor breast cancer.

Researchers noted that a past clinical trial, called FALCON, found that when fulvestrant was given alone it led to people going longer without cancer growing than when they received the aromatase inhibitor anastrozole (Arimidex and generic) alone. Based on these results, PARSIFAL was designed to see if fulvestrant would also be more effective than aromatase inhibitors when given in combination with CDK 4/6 inhibitors.

PARSIFAL had 486 participants with metastatic hormone receptor-positive, HER2-negative breast cancer. The study compared fulvestrant to the aromatase inhibitor letrozole (Femara and generic). Participants had never been treated for metastatic breast cancer, and had not received hormonal therapy for early-stage disease for at least a year. Premenopausal women took medicine to stop the function of their ovaries for these treatments. Everyone in the study was randomly assigned to get either

• fulvestrant and palbociclib
• letrozole and palbociclib

The main goal was to measure progression-free survival, or how long people went without cancer growing.

Results of PARSIFAL

The study found no meaningful difference between the groups in how long people went without cancer growing. The average time was

• 27.9 months on fulvestrant and palbociclib
• 32.8 months on letrozole and palbociclib

Although people given letrozole went longer on average than those getting fulvestrant, the results were not statistically significant, meaning the difference could be the result of chance.

Researchers also looked at results in subgroups within the study

• breast cancer that returned after an early-stage diagnosis
• breast cancer that was metastatic when it was first diagnosed (called de novo)
• breast cancer that had spread to internal organs, like the liver or lungs
• breast cancer that had not spread to internal organs

Even in these cases, fulvestrant did not lead to people going significantly longer without cancer growing than letrozole. There was also no statistical difference between how long people lived after starting treatment in this study. The likelihood a person was living 3 years after treatment was

• 79.4 percent on fulvestrant and palbociclib
• 77.1 months on letrozole and palbociclib

Side effects were similar in both arms of the study, the most common being low counts of certain types of blood cells. Fulvestrant resulted in severe side effects more often and to more people stopping treatment because of side effects.

What this means for you

PARSIFAL showed fulvestrant can be paired with a CDK 4/6 inhibitor in first line treatment of metastatic hormone receptor-positive breast cancer, but it did not lead to people going longer without cancer growing or to longer life than the current standard of palbociclib and an aromatase inhibitor. Further research will look into what this means in the larger picture of treatment combinations, and what role the choice of hormonal therapy has on treatment with CDK 4/6 inhibitors.

For treatment in 2020, a CDK 4/6 inhibitor with fulvestrant may be an option, but you will make the decision with your doctor. Fulvestrant is also used in some treatments after the first line, so planning for future treatments should be part of your discussion about the first treatment.

BYLieve

Alpelisib was FDA approved last year for metastatic hormone receptor-positive breast cancer that has a mutation on the PIK3CA gene. The SOLAR-1 trial found that adding alpelisib to fulvestrant led to people going 5 months longer without cancer growing, on average, than fulvestrant alone.

Everyone in the SOLAR-1 study had cancer that grew despite hormonal therapy, but most had not been treated with CDK 4/6 inhibitors. Standard treatment today includes CDK 4/6 inhibitors and hormonal therapy as the first medicine for people diagnosed with metastatic hormone receptor-positive, HER2-negative breast cancer.

BYLieve is a phase II, open label study designed to look at how alpelisib worked in people who already received treatment with a CDK 4/6 inhibitor. Participants all had tumors with a mutation in the PIK3CA gene and had been treated with a CDK 4/6 inhibitor for metastatic breast cancer before starting this study.

Participation was open to men and women, but the group, or cohort, presented at ASCO had only women participants, and it was the only cohort presented at the meeting. It was one of three cohorts grouped by what treatment combination had been used in the first line of treatment. This cohort included 127 women who received a CDK 4/6 inhibitor with an aromatase inhibitor before participating.

Results of BYLieve

BYLieve was a non-comparative study, meaning it didn’t include a control group of people getting standard care to compare results against. Instead, researchers defined their goal as having 30 percent of participants go without cancer growth for 6 months. That goal was met:

• 50.4 percent of cancers had not progressed after 6 months.
• The average time until cancer progressed was 7.3 months.

Researchers also used four models to match and compare these results with patient information from the U.S. Flatiron Health-Foundation Medicine database. Doing so allowed the researchers to compare how the study participants might have fared if they received standard treatment instead. In each comparison, alpelisib had longer progression-free survival than observed results from the database. The average time until cancer progressed was

• 6.5 to 8.0 months for BYLieve participants on alpelisib
• 3.4 to 3.7 months for standard treatment outcomes from the database

In BYLieve, 20.5 percent of participants stopped treatment because of side effects.

• 59.8 percent had diarrhea
• 58.3 percent had high blood sugar (hyperglycemia)
• 28 percent had a rash

Rash was the most common side effect listed as the reason for people stopping treatment: 3.9 percent of women stopped because of rash. Researchers say this may be controlled by using antihistamines to prevent rashes before they begin.

What this means for you

BYLieve is an important update on medicines that have come into use in recent years. Studies take years to design and complete, and the treatment standards in place when a study starts may not be the same as the standards when it is completed. CDK 4/6 inhibitors have been approved for less than 6 years and are now standard treatment.

The SOLAR-1 trial showed that adding alpelisib to treatment for cancers with a PIK3CA mutation leads to people going longer without cancer growing. BYLieve confirms that benefit continues in people who have already had treatment with a CDK 4/6 inhibitor. Komal L. Jhaveri, MD, FACP, who led a discussion of studies from the metastatic breast cancer session, brought attention to the high rate of people stopping treatment due to side effects. She pressed the need for strategies to better manage side effects to help people stay on treatment as long as it helps.

Both these studies provide information that is important for discussions about your treatment plan with your doctor. Your treatment history and conditions will not always align exactly with the conditions of a controlled, randomized clinical trial. Studies that show a new treatment works in a group are exciting, but follow-up studies help fill out the picture so you and your healthcare team can make the best decisions for your care, backed by evidence.