Targeted Agents Expand the HR+/HER2– Metastatic Breast Cancer Treatment Arena

Developments across second-line targeted therapies for patients with endocrine-sensitive hormone receptor (HR)–positive, HER2-negative metastatic breast cancer supplement the first-line standard of care (SOC) of CDK4/6 inhibitors, underscoring the continued importance of biomarker testing in this patient population, according to Erica Stringer-Reasor, MD.

“HR blockade continues to be the mainstay in the treatment of these HR-positive breast cancers, but we know that endocrine resistance continues to be a persistent problem, and over [the [past] 5 to 10 years, we know that there have been many advances in targeted pathways, particularly in blocking those HRs,” Stringer-Reasor said in a presentation during the 41st Annual Miami Breast Cancer Conference.¹

In the presentation, Stringer-Reasor highlighted novel and emerging therapies for patients with HR-positive, HER2-negative metastatic breast cancer, explaining current treatment CDK4/6 inhibition approaches for patients who have progressed on frontline CDK4/6 inhibitors, ongoing progress with selective estrogen receptor degraders (SERDs), and the array of agents that target the PI3K/AKT/PTEN pathway.

Stringer-Reasor is an assistant professor of medicine in the Division of Hematology & Oncology at the University of Alabama at Birmingham.

Blocking the CDK4/6 Pathway

HR-positive, HER2-negative breast cancer comprises approximately 70% to 80% of breast cancer cases, and approximately 30% of early-stage breast cancers will progress to metastatic disease, Stringer Reasor explained. Furthermore, the 5-year relative survival rate is an estimated 34% in patients with HR-positive metastatic disease.

Targeted agents such as aromatase inhibitors, CDK4/6 inhibitors, PI3K inhibitors, mTOR inhibitors, estrogen receptor (ER) downregulators, SERDs, and selective estrogen receptor modulators have made their way into the HR-positive advanced breast cancer treatment paradigm.

Findings from several clinical trials support the use of CDK4/6 inhibitors in the frontline setting vs SOC endocrine therapy alone in HR-positive, HER2-negative metastatic breast cancer. Stringer-Reasor notes that the efficacy and safety profiles of these agents make them attractive therapies for use in this patient population. Some of the most common any-grade AEs associated with CDK4/6 inhibitors are neutropenia (palbociclib [Ibrance]/ribociclib [Kisqali], 75%; abemaciclib [Verzenio], 41%), nausea (35%-45%; 40%), fatigue (30%-35%; 40%), alopecia (30%; 26%), diarrhea (25%-30%; 81%), and anemia (25%; 25%). Furthermore, ribociclib is associated with a 1.38% risk of QTc prolongation, which should be monitored for during the first few months of therapy, and abemaciclib is associated with a 5% incidence of venous thromboembolism, Stringer-Reasor noted in her presentation.

“All in all, there were few grade 3 and 4 toxicities, and patients often tolerate these therapies well,” Stringer-Reasor emphasized. “Efficacy rates are quite nice compared with endocrine therapy monotherapy or even single-convention chemotherapy, so that’s why [CDK4/6 inhibitors] would be the mainstay of first-line therapy in advanced HR-positive breast cancers.”

Continuing Treatment After CDK4/6 Inhibitors

However, questions remain regarding optimal treatment sequencing post-progression on frontline CDK4/6 inhibitors plus endocrine therapy, Stringer-Reasor explained. The phase 2 MAINTAIN trial (NCT02632045) aimed to answer this challenge and randomly assigned patients who had progressed on any CDK4/6 inhibitor plus endocrine therapy to receive switched endocrine therapy with or without the CDK4/6 inhibitor ribociclib.² The median progression-free survival (PFS) was 5.29 (95% CI, 3.02-8.12) in the ribociclib arm (n = 60) vs 2.76 months (95% CI, 2.66-3.25) in the endocrine therapy–alone arm (n = 59; HR, 0.57; 95% CI, 0.39-0.85; P = .006). Stringer-Reasor explained that an exploratory analysis found that this PFS benefit was limited to patients with ESR1 wild-type disease (HR, 0.30; 95% CI, 0.15-0.62).¹

“This was the first prospective study that showed a benefit with ribociclib plus switching endocrine therapy after CDK4/6 inhibition,” Stringer-Reasor emphasized. “[Approximately] 34% of all patients who have seen aromatase inhibitors may have an ESR1 mutation, so it’s important to always check for that.”

The phase 2 PACE trial (NCT03147287) of palbociclib plus avelumab and fulvestrant (Faslodex) vs palbociclib plus fulvestrant vs fulvestrant alone in patients with HR-positive, HER2-negative metastatic breast cancer also addressed the question of optimal treatment decisions after initial progression on a CDK4/6 inhibitor.3 The triplet elicited a median PFS of 8.1 months (95% CI, 3.2-10.7) vs 4.8 months (95% CI, 2.1-8.2) with fulvestrant alone and 4.6 months (95% CI, 3.6-5.9) with the doublet. Notably, over 90% of the patients in this trial had received prior palbociclib. An exploratory analysis demonstrated that patients with ESR1 alterations experienced improved PFS outcomes vs those with ESR1 wild-type disease. In the triplet arm, the median PFS was 8.3 months (95% CI, 3.2-17.2) in patients with ESR1-altered disease vs 5.7 months (95% CI, 2.1-13.6) in those with ESR1 wild-type disease.³

“It’s still unclear if CDK4/6 inhibition after CDK4/6 [inhibitor] progression is the best step for all patients,” Stringer-Reasor said.¹ “It’s certainly still a question if [patients with] ESR1 mutations or [ESR1] wild-type [disease] can see the benefit or not. There will be more studies on the way to help us tease that out and see which patients should go on to a second CDK4/6 inhibitor after progression.”

Leveraging SERDs in the ER Pathway

The oral SERD elacestrant (Orserdu) was approved by the FDA in 2023 for patients with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer.⁴ The phase 3 EMERALD trial (NCT03778931), which evaluated the agent in men and postmenopausal women with advanced or metastatic breast cancer, demonstrated that patients with ESR1 mutations who received a prior line of endocrine therapy plus a CDK4/6 inhibitor for at least 12 months prior to receiving elacestrant experienced a median PFS of 8.61 months (95% CI, 4.14-10.84) with elacestrant vs 1.91 months (95% CI, 1.87-3.68) with SOC (HR, 0.410; 95% CI, 0.262-0.634).⁵ There was a nearly 40% improvement in OS with elacestrant, as well (HR, 0.592; 95% Cim 0.361-0.958; P = .0325). Elacestrant is associated with adverse effects (AEs) including nausea, vomiting, elevated cholesterol levels, and elevated triglyceride levels.

“Often, patients are approximately 60 years or older when we diagnose them with breast cancer, so high cholesterol…may be a natural phenomenon in that aging population,” Stringer-Reasor noted.¹

Furthermore, the phase 2 SERENA-2 trial (NCT04214288) found that patients with ER-positive, HER2-negative advanced breast cancer who received the SERD camizestrant at 150 mg (n = 73) achieved an investigator-assessed median PFS of 7.7 months (95% CI, 5.5-12.9) vs 7.2 months (95% CI, 3.7-10.9) with camizestrant at 75 mg (n = 74) and 3.7 months (95% CI, 2.0-6.0) with fulvestrant.⁶ Notably, approximately 50% of this trial population had received a prior CDK4/6 inhibitor, and approximately 30% to 48% of patients had ESR1-mutated disease, although this rate was higher in the fulvestrant arm. Patients with detectable ESR1 mutations at baseline who received camizestrant at either dose experienced PFS benefits vs fulvestrant.

Treatment-related AEs associated with the 75-mg dose of camizestrant included photopsia, sinus bradycardia, and anemia. Based on the SERENA-2 safety data, 75 mg was selected as the maximum-tolerated dose of camizestrant.

Targeting the PI3K/AKT/PTEN Pathway

Stringer-Reasor explained that approximately 50% of patients with HR-positive, HER2-negative metastatic breast cancer have alterations in the PI3K/AKT/PTENpathway.¹ The phase 3 SOLAR-1 trial (NCT02437318) was the first phase 3 trial to investigate a PI3K inhibitor in patients with PIK3CA-mutated HR-positive, HER2-negative metastatic breast cancer. In this trial, alpelisib (Piqray) plus fulvestrant (n = 169) generated a median PFS of 11.0 months (95% CI, 7.5-14.5) vs 5.7 months (95% CI, 3.7-7.4) with placebo plus fulvestrant (n = 172; HR, 0.65; 95% CI, 0.50-0.85; P < .001).⁷ Stringer-Reasor explained that one critique of SOLAR-1 is that only approximately 5% to 6% of patients in the trial had received a prior CDK4/6 inhibitor, which have since become the first-line SOC. Therefore, the phase 2 BYLieve trial (NCT03056755) confirmed the PFS benefit of alpelisib plus fulvestrant in patients who had received a prior CDK4/6 inhibitor.¹

Regarding AKT inhibitors, Stringer-Reasor mentioned that the phase 1/2 FAKTION trial (NCT01992952) demonstrated PFS and overall survival benefits with capivasertib (Truqap) plus fulvestrant vs fulvestrant alone in patients with PI3K/AKT/PTEN pathway alterations (PFS, P = .001; OS, P = .005). Based on these findings, the randomized phase 3 CAPItello-291 trial (NCT04305496) evaluated capivasertib plus fulvestrant in patients with HR-positive, HER2-negative advanced disease. The median PFS was 7.3 months (95% CI, 5.5-9.0) in the capivasertib arm vs 3.1 months (95% CI, 2.0-3.7) with placebo plus fulvestrant (HR, 0.50; 95% CI, 0.38-0.65; P < .0001) in patients with PI3K/AKT/PTEN-altered disease.8 Based on these data, in 2023, the FDA approved capivasertib plus fulvestrant for patients with HR-positive, HER2-negative, locally advanced or metastatic breast cancer harboring at least 1 PIK3CA, AKT1, or PTEN alteration who have progressed on 1 or more endocrine-based regimens in the metastatic setting or experienced disease recurrence within 12 months of completing adjuvant therapy.

Stringer-Reasor emphasized the unique dosing schedule for capivasertib, which is taken at 400 mg orally twice daily with or without food for 4 days followed by 3 days off.¹

“Specifically looking at those dose levels, we typically tell patients to start their tablets on Mondays and take the weekend off, so that’s an easy way to patients can think about how to dose this medication,” Stringer-Reasor said.

Acknowledging the limitations of cross-trial comparisons, Stringer-Reasor noted that alpelisib, capivasertib, and the mTOR inhibitor everolimus (Afinitor) appear to have similar safety profiles, and are each associated with AEs including diarrhea, rash, hyperglycemia, and stomatitis. She emphasized that each of these AEs are manageable.

Bringing Novel ER-Targeted Agents Into the Fold

Stringer-Reasor concluded with a glance at the future of ER-targeted breast cancer therapies. Several phase 3 trials are ongoing, including studies investigating proteolysis targeting chimeras and complete ER antagonists.

“There are even some nice studies looking at [ARV-471 in patients with ER]-positive, early-stage breast cancer, which could be a nice pathway for some of those patients in luminal subgroups [whose disease] might be able to downstage before surgery,” Stringer-Reasor said.

For patients without targetable mutations, Stringer-Reasor concluded by stating that fulvestrant monotherapy remains the SOC, although promising data support the use of everolimus-based therapy combined with exemestane or fulvestrant.

References

1. Stringer-Reasor E. New directions for novel and emerging endocrine therapies. Presented at: 41st Annual Miami Breast Cancer Conference. March 7-10, 2024; Miami, Florida.
2. Kalinsky K, Accordino MK, Chiuzan C, et al. Randomized phase II trial of endocrine therapy with or without ribociclib after progression on cyclin-dependent kinase 4/6 inhibition in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: MAINTAIN trial. J Clin Oncol. 2023;41(24):4004-4013. doi:10.1200/JCO.22.02392
3. Mayer EL, Ren Y, Wagle N, et al. GS3-06 palbociclib after CDK4/6i and endocrine therapy (PACE): a randomized phase II study of fulvestrant, palbociclib, and avelumab for endocrine pretreated ER+/HER2- metastatic breast cancer. Cancer Res. 2023;83(suppl 5):GS3-06. doi:10.1158/1538-7445.SABCS22-GS3-06
4. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. January 27, 2023. Accessed March 9, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/
5. Bardia A, Bidard FC, Neven P, et al. GS3-01 EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: updated results by duration of prior CDK4/6i in metastatic setting. Cancer Res. 2023;83(suppl 5):GS3-01. doi:10.1158/1538-7445.SABCS22-GS3-01
6. Camizestrant significantly delayed disease progression in advanced ER-positive breast cancer, adding at least 3.5 months benefit versus Faslodex. News release. AstraZeneca. December 8, 2022. Accessed March 9, 2024. https://www.astrazeneca.com/media-centre/press-releases/2022/camizestrant-significantly-delayed-disease-progression-in-advanced-er-positive-breast-cancer.html
7. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940. doi:10.1056/NEJMoa1813904
8. FDA approves capivasertib with fulvestrant for breast cancer. News release. FDA. November 16, 2023. Accessed November 16, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-fulvestrant-breast-cancer