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Patients with advanced estrogen receptor (ER)-positive breast cancer that progressed on CDK4/6 inhibitors had better survival if they continued CDK4/6 inhibition plus endocrine therapy rather than switch to endocrine therapy alone, a large meta-analysis showed.

The hazard for progression-free (PFS) and overall survival (OS) decreased by about 40% when patients continued CDK4/6 inhibition and also received an endocrine agent. The benefit was similar whether patients continued with the same CDK4/6 inhibitor or switched to a different agent in the class.

Switching to everolimus (Afinitor) plus endocrine therapy led to PFS similar to that of endocrine therapy alone but to a significantly shorter OS, reported Maryam Lustberg, MD, MPH, of the Yale Cancer Center in New Haven, Connecticut, and co-authors in the .

"Our study reveals that continuing CDK4/6 inhibitors with ET [endocrine therapy] post-progression improves survival compared with ET alone, supporting guidelines against [second-line] chemotherapy, without endocrine resistance or visceral crisis," the authors concluded. "It underscores the need for tailored strategies on the basis of clinical and biologic profiles."

"This analysis, to our knowledge, the largest of its kind, addresses a key clinical challenge, offering a comprehensive foundation for guiding future oncologic strategies in [advanced breast cancer] care."

Unresolved Controversy

The call for tailored strategies resonated with Adam Brufsky, MD, PhD, of the University of Pittsburgh Hillman Cancer Center, who called treatment post-CDK4/6 inhibition an "incredibly intensive area of controversy right now."

"We're not quite sure what to do," Brufsky told MedPage Today. "It really depends on how fast you've progressed ... how bulky and how much disease burden you have, whether you have a lot of liver lesions. Things like that."

Recently, however, consensus has begun to coalesce around two strategies based on the rate of disease progression.

"If you have really rapid progression on a CD4/6 inhibitor -- something like 6 to 10 months, and certainly less than 6 months -- I think most of us will use an antibody-drug conjugate, like in HER2 breast cancer," said Brufsky. "Probably 80-90% of ER-positive breast cancers are HER2-low or ultra-low."

"If you had a very long progression-free survival, which is very common with CDK4/6 inhibitors -- 4, 5, or 6 years without progression -- I think we would do next-generation sequencing to look for ESR1 mutations, PI3K mutations, HER2 mutations. Then, on the basis of those results, I think some of us would give fulvestrant and abemaciclib [Verzenio], based on the data, but eventually give imlunestrant and abemaciclib, based on the EMBER-3 results, if that gets approved by the FDA."

For patients with progression-free intervals that are neither rapid nor exceptionally prolonged -- such as 12 months to 3 years -- a common strategy is a targeted agent plus hormonal therapy, he said.

"It's still a matter with some controversy," Brufsky added. "We're not really sure about the right sequence. We don't have biomarkers to guide us. We really have a lot of options, and it's just unclear how to sequence them."

In the current state of uncertainty, chemotherapy still has a seat at the therapeutic table.

"If you don't want to put someone on an antibody-drug conjugate [ADC] and their disease is progressing, I think we still use a lot of oral capecitabine," said Brufsky. "Some of us even go back to intravenous paclitaxel or nanoparticle paclitaxel [Abraxane]. When someone progresses on an ADC, we really don't have a lot to offer, so [chemotherapy] is just being pushed back to later lines."

The situation will likely remain unresolved until reliable biomarkers can be identified to guide treatment, he added.

Study Background, Results

Noting the absence of "established post-progression sequencing guidelines," Lustberg and colleagues performed a systematic review and meta-analysis of clinical trials that evaluated therapeutic strategies in the post-CDK4/6 inhibitor setting. The search included trials published from 2016 through 2023, comparing alternative post-CDK4/6 progression treatment strategies versus standard-of-care, single-agent endocrine therapy.

The authors identified 18 studies comprising a total of 4,899 patients. The studies consisted of eight randomized controlled trials and 10 retrospective cohort studies. The vast majority of patients (4,838) received a CDK4/6 inhibitor in second line, and the rest received the therapy in third line or later.

The most common first-line therapy was palbociclib (Ibrance) and an aromatase inhibitor. Following progression on first-line CDK4/6 inhibition, the most common second-line strategies were a CDK4/6 inhibitor plus endocrine therapy (34.6%), single-agent endocrine therapy (30.9%), and chemotherapy (29.4%).

As compared with single-agent endocrine therapy, continuation with a CDK4/6 inhibitor was associated with a PFS hazard ratio of 0.61 (95% CI 0.53-0.70, P<0.01). In a subgroup analysis, continuation of a CDK4/6 inhibitor was superior to fulvestrant monotherapy (HR 0.61, 95% CI 0.53-0.70, P<0.01). The advantage held up whether the CDK4/6 inhibitor was the same (HR 0.67, 95% CI 0.56-0.79, P<0.01) or different (HR 0.68, 95% CI 0.54-0.85, P<0.01).

By contrast, subsequent treatment with everolimus, chemotherapy, or a selective estrogen receptor degrader was associated with PFS similar to endocrine monotherapy (HR 0.94 to HR 1.10).

Seven studies comprising 3,822 patients reported OS data. Continuing with a CDK4/6 inhibitor plus endocrine therapy was associated with an HR of 0.68 (95% CI 0.60-0.77, P<0.01) versus single-agent endocrine therapy. Patients who switched to everolimus or chemotherapy had significantly shorter OS (HR 1.52, P<0.01 and HR 1.64, P<0.01). Continuing the same CDK4/6 inhibitor but switching the endocrine therapy combination improved OS (HR 0.63, P<0.01), while switching to a different CDK4/6 inhibitor showed no significant difference (HR 0.90, P=0.33).

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