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The emergence of CDK4/6 inhibitors has reshaped the therapeutic landscape for advanced hormone receptor (HR)-positive breast cancer, extending progression-free survival (PFS) and in some cases overall survival (OS) when combined with first-line endocrine therapy.

Unfortunately, most patients eventually progress, and the next step after CDK4/6 inhibition is perhaps "the hottest topic that all of us are facing in our clinics," said Stephanie Graff, MD, of the Legorreta Cancer Center of Brown University in Providence, Rhode Island, during the introduction to an education session at the recent .

Upon progression, clinical guidelines generally recommend continuation of endocrine therapy. However, such a broad recommendation fails to take into account biological differences in HR-positive breast cancer, said Carlos H. Barrios, MD, of the Latin American Cooperative Oncology Group in Porto Alegre, Brazil. In reality, multiple individual and combination therapies have been used to treat HR-positive breast cancer in the post-CDK4/6 setting.

"Future developments and improvements in this area, as has clearly been shown in other areas of oncology, will come with the recognition, at every step of the journey, that not all patients are the same, particularly hormone receptor-positive patients, who represent most of the patient population," he said. "Our ability to identify these different clinical and biological profiles within this population of patients is, in my opinion, the single most important factor to improve treatment in this situation."

"We have not done a very good job of understanding why patients are treated with a certain drug in this situation and what the sequence of these drugs or treatments actually means in clinical practice," Barrios added.

In clinical practice, oncologists intuitively recognize that HR-positive breast cancers have different biologies and behave differently, but patients are treated as if they all have the same disease, he continued. A potential adaptive approach to the spectrum of HR-positive disease involves taking into account the tumor's endocrine sensitivity, using arbitrary definitions ranging from "highly sensitive" to "likely resistant":

• Highly sensitive: De novo metastatic disease or very long (15 years) disease-free interval (DFI) after adjuvant endocrine therapy, bone metastases only, asymptomatic
• Likely sensitive: Long (2 years) DFI, predominant bone and soft-tissue metastases, minimal symptoms
• Moderately sensitive: Short (6 months) DFI, bone and visceral disease, "few" symptoms
• Moderately resistant: Progression on adjuvant endocrine therapy (3.5 years after diagnosis), more extensive visceral metastases, symptomatic
• Likely resistant: Early (<1 year after diagnosis) and rapidly progressing, life-threatening disease; extensive visceral metastases; very symptomatic

That approach to risk stratification received support from the , which showed significant differences in PFS according to arbitrarily defined endocrine sensitivity subgroups.

Even though clinical guidelines are based on recent information, new studies continually challenge recommendations, said Barrios. The field of HR-positive breast cancer continues to change rapidly, and clinicians must be attentive to the change. Recent developments have challenged the recommendation of upfront chemotherapy, shown that continuation of CDK4/6 inhibition beyond progression benefits some patients, and introduced ESR1 mutations as a consideration in therapeutic choices.

Optimizing Endocrine Options

Differentiation of the various subgroups of patients with advanced HR-positive breast cancer is essential to treatment decisions in the post-CDK4/6 inhibition setting, said Ruth O'Regan, MD, of the University of Rochester in New York, continuing the theme introduced by Barrios. Specifically, decisions after progression of endocrine therapy and CDK4/6 inhibition should be based on genomic analysis of tumor or circulating tumor (ct) DNA.

"When we think about treating patients in the second-line, or even third-line, with metastatic hormone receptor-positive breast cancer, it's really all about genomics," she said. "When we see these patients in the clinic, checking the genomics and working out what's driving their cancers is super important."

Common mutations present at diagnosis are p53 and PIK3CA. Key acquired mutations include ESR1, ERBB2, and AKT. Results of genomic testing can inform decisions about which combination partner to pair with endocrine therapy, she said.

Beginning with non-mutated HR-positive breast cancer, after progression on an endocrine-CDK4/6 inhibitor combination, potential strategies include CDK4/6 inhibition through progression with endocrine "switch" and introduction of the mTOR inhibitor everolimus (Afinitor). Three recent studies evaluated the switch-progression strategy. All three involved patients who had progressed on an endocrine-CDK4/6 combination. All three were phase II studies, meaning they were relatively small, O'Regan cautioned.

The MAINTAIN trial compared continuation of a CDK4/6 inhibitor (ribociclib, Kisqali) or placebo, paired with a different endocrine agent. Median PFS almost doubled with the CDK4/6 inhibitor-endocrine combination versus placebo and endocrine therapy.

On the other hand, the randomized PACE trial showed no difference in 6- or 12-month PFS for patiens who received endocrine therapy alone or paired with palbociclib (Ibrance). However, the addition of the PD-L1 inhibitor avelumab (Bavencio) to palbociclib and endocrine therapy produced a consistent and intriguing trend toward improved 6-month, 12-month, and median PFS versus the other two arms.

The randomized PALMIRA trial also questioned the strategy of continuing a CDK4/6 inhibitor through progression. Patients received fulvestrant (Faslodex) or letrozole alone or in combination with palbociclib after progression on a CDK4/6 inhibitor-based combination. A 1.3-month improvement in median PFS with palbociclib failed to meet statistical significance. PFS at 6 months favored the combination but was virtually identical at 12 months.

"Taking all of these trials together, I think continuing the same CDK4/6 inhibitor just doesn't appear to be effective," said O'Regan. "There may be selected patients who may benefit from switching to a different CDK4/6 inhibitor. That's very important because now that we're using adjuvant CDK4/6 inhibitors, it's important that we know how to treat those patients when they have disease relapse."

Changing the focus to endocrine resistance, she noted that progression to endocrine resistance involves increased upstream signaling through growth factor receptors. In general, trials targeting individual receptors showed little benefit. In contrast, targeting downstream signaling through the PI3K/AKT/mTOR pathway appears to be effective.

"Basically what's happening here is the growth factors are setting off phosphorylation cascades that make the estrogen receptor no longer a viable target," said O'Regan. "If you block this pathway, you can restore endocrine sensitivity in these cancers."

One of the first studies to target downstream signaling with everolimus was the , which showed that adding everolimus to tamoxifen almost doubled time to progression as compared with tamoxifen alone. Those preliminary findings were corroborated in the BOLERO 2 registration trial, which showed a median PFS of 10.6 months with everolimus and a nonsteroidal aromatase inhibitor (AI) versus the AI alone.

Finally, the showed that adding everolimus to fulvestrant doubled median PFS versus fulvestrant and placebo in patients with AI-resistant metastatic HR-positive breast cancer.

"I would urge you to keep everolimus in mind," said O'Regan. "There's no biomarker for everolimus, but these results are quite impressive. One of the nice things about everolimus is that you can give it with any endocrine therapy. I think this is a very viable option for certain patients."

Turning her attention to breast cancers with actionable mutations, O'Regan said PI3K inhibitors in particular have shown beneficial effects in multiple trials. Early trials of buparlisib and taselisib showed modest, but statistically significant, improvements in median PFS of about 2 months. More recently, combining the PI3K inhibitor alpelisib (Piqray) or the AKT inhibitor capivasertib (Truqap) with endocrine therapy has yielded more substantial benefits.

The SOLAR 1 trial evaluated fulvestrant with or without alpelisib in patients whose breast cancer had progressed on prior AI treatment. The primary analysis showed that the addition of the PI3K inhibitor doubled median PFS in patients with PIK3CA-mutated cancers. Adding alpelisib did not significantly improve PFS in PIK3CA-wild type tumors.

More recently, the nonrandomized evaluated alpelisib plus fulvestrant or letrozole in three separate cohorts: progression on prior CDK4/6 inhibitor plus AI, progression on prior CDK4/6 inhibitor plus fulvestrant, and prior progression on AI with subsequent chemotherapy or a different endocrine agent.

Focusing on the post-CDK inhibitor/AI cohort, Regan noted that alpelisib-fulvestrant led to a median PFS of 7.3 months.

The CAPItello-291 trial evaluated fulvestrant with or without capivasertib in patients with recurrence during or within 12 months of adjuvant AI or progression while on prior AI for advanced breast cancer. The addition of the AKT inhibitor doubled median PFS in the overall population and more than doubled PFS in the subgroup with AKT pathway-altered cancers (PIK3CA, AKT1, or PTEN). OS improved significantly with capivasertib in the all-comer analysis and just missed statistical significance in the AKT-altered subgroup.

"These are very exciting results," said O'Regan. "I think one of the questions is, if you have somebody with a PIK3 mutation, do you start with [capivasertib] or with alpelisib. We'll need to address that."

Cytotoxics Maintain a Role

Beyond endocrine-therapy backbone strategies, cytotoxic agents remain a standard of care for endocrine-resistant HR-positive breast cancer, said Erica Stringer-Reasor, MD, of the University of Alabama at Birmingham. The National Comprehensive Cancer Network's latest guidelines for recurrent/unresectable/metastatic disease continue to recommend systemic chemotherapy for patients without germline BRCA1/2 mutations, patients who are not candidates for trastuzumab deruxtecan (T-DXd, Enhertu), and those who are receiving third-line therapy or beyond.

Antibody-drug conjugates (ADCs) continue to carve out an important therapeutic niche in advanced HR-positive breast cancer. Most recently, T-DXd demonstrated activity in patients with HER2-low metastatic breast cancer, which accounts for about 55% of all advanced HER2-negative tumors.

The DESTINY-Breast04 trial compared single-agent T-DXd against physician's choice of chemotherapy in patients with endocrine-refractory HR-positive breast cancer with HER2-low status (IHC 1+ or IHC 2+/in situ hybridization negative). Median PFS approximately doubled in both the HR-positive population and the overall population, which included a small number of HR-negative patients.

The FDA also has approved the ADC sacituzumab govitecan (Trodelvy) for advanced HR-positive breast cancer. Consisting of an antibody directed at Trop-2 linked to a topoisomerase I inhibitor payload, sacituzumab govitecan was compared with physician's choice of chemotherapy in patients with HR-positive/HER2-negative metastatic breast cancer in the TROPiCS-02 trial. Eligible patients had received one or more prior endocrine therapies, a taxane, and a CDK4/6 inhibitor and as many as four prior lines of chemotherapy for metastatic disease.

The ADC modestly improved median PFS (5.5 vs 4.0 months, P=0.0003) and proved superior to chemotherapy at 6, 9, and 12 months. Sacituzumab govitecan also improved PFS in HER2-low and HER2 IHC 0 groups. A planned interim analysis showed about a 2-month improvement in OS with the ADC, which achieved statistical significance (P=0.02).

As the number of proven options for advanced/metastatic HR-positive breast cancer continues to increase, sequencing considerations become a more prominent issue.

"We want to utilize and exhaust all of our endocrine therapy backbones and utilize targeted agents that address PIK3CA mutations and AKT and ESR1, which give patients potential oral medication options that can improve or maintain progression-free survival and quality of life," said Stringer-Reasor.

For patients with germline BRCA mutations, PARP inhibitors offer a proven option when sequential endocrine therapies have run the course. Consider testing patients for HER2 expression status, she continued. T-DXd is an effective option for patients with HER2-low tumors and sacituzumab govitecan has shown the ability to improve outcomes in HER2-zero tumors.

Clinicians should stay abreast of ongoing clinical trials of new ADCs and other new therapies. Once the agents have demonstrated efficacy, examine and compare toxicities to achieve the best outcomes with the least toxicity, she added.

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