Sequencing of Therapies in Premenopausal Metastatic Breast Cancer Patients

Azka Ali, MD

In addition to the consideration of patient age, treatment selection for advanced breast cancer should include consideration of disease characteristics as outlined in evidence-based guidelines. For instance, the American Society of Clinical Oncology (ASCO) guideline recommends the use of ovarian function suppression (OFS) in all premenopausal patients.¹ Furthermore, the addition of cyclin-dependent kinase (CDK)4/6 inhibitors to endocrine therapy (ET) plus goserelin in the first-line setting has shown significant gains in progression-free survival (PFS) compared with ET plus goserelin alone in premenopausal hormone receptor–positive breast cancer.²

In the first-line setting, a meta-analysis of 4 studies published in 2001 showed that the combination of OFS plus ET is more effective than OFS alone.³ In a separate study, the benefit of OFS with goserelin was as effective as oophorectomy.⁴ In the MONALEESA-7 study, the addition of the CDK4/6 inhibitor, ribociclib, to ET (tamoxifen or an aromatase inhibitor) plus goserelin was superior to ET plus goserelin as evidenced by improved PFS from 13 months to 23.8 months.² In the second-line setting, the use of CDK4/6 inhibitors has been shown to provide significant clinical benefit in premenopausal women with breast cancer.^5,6 In the PALOMA-3 study, patients received a CDK4/6 inhibitor plus fulvestrant with or without goserelin as a second or subsequent line of therapy.⁵ In the MONARCH-2 study, women of any menopausal status (only pre- or perimenopausal women received a gonadotropin-releasing hormone [GnRH] agonist) received second-line treatment with a CDK4/6 inhibitor plus fulvestrant or placebo6 Overall results from these studies indicated that the addition of a CDK4/6 inhibitor resulted in improvement in treatment outcomes.^5,6

Treatment with ET plus OFS in the second line also demonstrated potential clinical benefit. A phase 2 trial showed that treatment with an aromatase inhibitor plus goserelin in the second line resulted in a median PFS of 13 months.⁷ Observational data showed that fulvestrant (250 mg) plus goserelin resulted in a clinical benefit rate of 57.7%, with 3.9% complete response, 11.5% partial response, and 42.3% stable disease.⁸ The use of a CDK4/6 inhibitor after progression on a CDK4/6 inhibitor–based regimen also showed statistically significant improvement in PFS in the phase 2 MAINTAIN study, which included patients with metastatic breast cancer who progressed after treatment with ET plus CDK4/6 and were switched to ET (exemestane or fulvestrant) with ribociclib versus placebo.⁹ However, the phase 2 PACE trial, which evaluated the activity of continuing a CDK4/6 inhibitor (palbociclib) beyond progression on an aromatase inhibitor with fulvestrant versus fulvestrant alone, showed no difference in PFS.¹⁰

The US Food and Drug Administration recently approved the addition of the AKT inhibitor, capivasertib, to fulvestrant therapy in patients with estrogen receptor–positive, human epidermal growth factor receptor 2–negative locally advanced or metastatic breast cancer with ≥1 PIK3CA/AKT1/PTEN alterations.¹¹ The approval was based on the CAPItello-291 study, in which premenopausal patients received a GnRH agonist.¹² This study demonstrated PFS improvement from 3.6 months in the placebo-fulvestrant group to 7.2 months in the capivasertib-fulvestrant group (hazard ratio [HR], 0.6; P<.001). In patients with AKT alterations, PFS was 3.1 months and 7.3 months in the placebo-fulvestrant and capivasertib-fulvestrant groups, respectively (HR, 0.5; P<.001).¹² In an exploratory analysis of 313 patients without the PIK3CA/AKT1/PTEN alterations—excluding those with unknown results on next-generation sequencing—there was a numerical but not statistically significant improvement in PFS with capivasertib-fulvestrant compared with placebo-fulvestrant (HR, 0.79; 95% confidence interval, 0.61-1.02).¹²

Azka Ali, MD, discussed that optimal sequencing in young patients is very similar to postmenopausal patients with the inclusion of some special considerations for younger patients, such as OFS. Other therapies include targeting PIK3CA mutations, ESR1 mutations, gBRCA1/2, SBRCA, gPALB2, and MSI-H. Second-line therapies include the use of elacestrant, poly (ADP) ribose polymerase inhibitor, pembrolizumab with or without ET, and fulvestrant plus capivasertib. Following those therapies are single-agent chemotherapies, and finally antibody–drug conjugates.¹³

In summary, the treatment landscape for patients with premenopausal estrogen receptor–positive metastatic breast cancer continues to evolve with the introduction of novel targeted therapies and advances in immune therapies.

References

1. Rugo HS, Rumble RB, Macrae E, et al. Endocrine therapy for hormone receptor–positive metastatic breast cancer: American Society of Clinical Oncology guideline. J Clin Oncol. 2016;34:3069-3103.
2. Tripathy D, Im SA, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19:904-915.
3. Klijn JGM, Blamey RW, Boccardo F, et al. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol. 2001;19:343-353.
4. Taylor CW, Green S, Dalton WS, et al. Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study. J Clin Oncol. 1998;16:994-999.
5. Loibl S, Turner NC, Ro J, et al. Palbociclib combined with fulvestrant in premenopausal women with advanced breast cancer and prior progression on endocrine therapy: PALOMA-3 results. Oncologist. 2017;22:1028-1038.
6. Sledge GW, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35:2875-2884.
7. Wang J, Xu B, Yuan P, et al. Phase II trial of goserelin and exemestane combination therapy in premenopausal women with locally advanced or metastatic breast cancer. Medicine (Baltimore). 2015;94:e1006.
8. Bartsch R, Bago-Horvath Z, Berghoff A, et al. Ovarian function suppression and fulvestrant as endocrine therapy in premenopausal women with metastatic breast cancer. Eur J Cancer. 2012;48:1932-1938.
9. 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;41:4004-4013.
10. Mayer EL, Ren Y, Wagle N, et al. Abstract GS3-06: GS3-06 palbociclib after CDK4/6i and endocrine therapy (PACE): a randomized phase II study of fulvestrant, palbociclib, and avelumab for endocrine pre-treated ER+/HER2- metastatic breast cancer. Cancer Res. 2023;83 (5_Supplement):GS3–06.
11. US Food and Drug Administration. FDA approves capivasertib with fulvestrant for breast cancer. FDA. Published online November 16, 2023. Accessed December 17, 2023. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-fulvestrant-breast-cancer
12. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor–positive advanced breast cancer. N Engl J Med. 2023;388:2058-2070.
13. Azka A. Sequencing of therapies in premenopausal metastatic patients. Presented at Ovarian Function Suppression Summit. San Antonio, Texas. December 4, 2023.