Oncology Update: Advances in Breast Cancer Management

New approvals and a broad pipeline promise advances in the treatment of breast cancer. The treatment landscape continues to shift with targeted therapies for breast cancers with different biomarkers.

Recent Approvals

Olaparib (LYNPARZA®)

The U.S. Food & Drug Administration (FDA) approved olaparib (LYNPARZA®, AstraZeneca) in March 2022 for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) human epidermal growth factor receptor 2 (HER2)-negative high-risk early breast cancer, who have been treated with neoadjuvant or adjuvant chemotherapy.1 An FDA-approved companion diagnostic for olaparib must be used to select patients for therapy.¹

Approval of olaparib was based on OlympiA, a randomized, double-blind, placebo-controlled, international study of patients with gBRCAm HER2-negative high-risk early breast cancer who completed definitive local treatment and neoadjuvant or adjuvant chemotherapy.² The 1,836 patients were randomized 1:1 to receive either 12 months of olaparib tablets, 300 mg orally twice daily, or placebo. They were required to have completed at least six cycles of neoadjuvant or adjuvant chemotherapy containing anthracyclines, taxanes, or both.² Per local guidelines, patients with hormone receptor positive (HR+) breast cancer were allowed to continue concurrent treatment with endocrine therapy.² Therapy continued for up to one year, or until disease recurrence or unacceptable toxicity.²

Invasive disease-free survival (IDFS) — the time from randomization to date of first recurrence, defined as invasive loco-regional, distant recurrence, contralateral invasive breast cancer, new cancer, or death from any cause — was the primary efficacy endpoint.² For patients receiving olaparib, IDFS was 86%, compared to 77% for those receiving placebo.² There was statistically significant improvement in IDFS and overall survival observed in the olaparib arm compared to the placebo arm.²

Adverse reactions associated with olaparib in the trial included nausea, fatigue, anemia, vomiting, headache, diarrhea, leukopenia, neutropenia, decreased appetite, dysgeusia, dizziness, and stomatitis.¹

Fam-trastuzumab deruxtecan-nxki (ENHERTU®)

In May 2022, the FDA approved fam-trastuzumab deruxtecan-nxki (ENHERTU®) for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and who have developed disease recurrence during or within six months of completing therapy.³

Famtrastuzumab deruxtecan-nxki was previously approved by the FDA under accelerated approval in December 2019 for adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.⁴ Approval was based on DESTINY-Breast03, the confirmatory trial for DESTINY-01, a multicenter, open-label, randomized trial that enrolled 524 patients with HER2-positive, unresectable, and/or metastatic breast cancer who received prior trastuzumab and taxane therapy for metastatic disease or developed disease recurrence during or within six months of completing neoadjuvant or adjuvant therapy.⁴ Patients received either fam-trastuzumab deruxtecan-nxki or ado-trastuzumab emtansine by intravenous (IV) infusion every three weeks until unacceptable toxicity or disease progression.⁴ The primary efficacy outcome was progression-free survival (PFS), with overall survival and confirmed objective response rate as secondary outcome measures.⁴ While PFS was not reached in the fam-trastuzumab deruxtecan-nxki arm, it was reached 6.8 months in the adotrastuzumab emtansine arm. In the fam-trastuzumab deruxtecannxki arm, objective response rate was 82.7%, compared to 36% in patients receiving ado-trastuzumab emtansine.⁴

Then, in August 2022, fam-trastuzumab deruxtecan-nxki received further FDA approval for adult patients with unresectable or metastatic HER2-low breast cancer who had received prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy.⁵ The DESTINYBreast04 randomized, multicenter, open-label clinical trial included 55-year-old patients with unresectable or metastatic HER2-low breast cancer, with 494 having HR+ disease.⁶ Patients were randomized 2:1 to receive either fam-trastuzumab deruxtecan-nxki or physician’s chemotherapy choice (PCC).6 PFS in patients with HR+ breast cancer was the primary efficacy measure, with secondary measures of PFS and overall survival in the HR+ and HR- groups combined and overall survival in HR+ patients.⁶ In the HR+ cohort, PFS was 10.1 months for patients on fam-trastuzumab deruxtecan-nxki, compared to 5.4 months for patients receiving PCC; PFS in the overall population was 9.9 months and 5.1 months for the fam-trastuzumab deruxtecan-nxki arm and PCC arm, respectively.⁶ Overall survival for patients receiving fam-trastuzumab deruxtecan-nxki was 23.9 months and 23.4 months in the HR+ cohort and the overall population, respectively.⁶ For patients receiving PCC, overall survival was 17.5 months for the HR+ group and 16.8 months for the overall population.⁶

Elacestrant

In January 2023, elacestrant (ORSERDU™, Stemline Therapeutics, Inc.) was approved by the FDA for postmenopausal women or adult men with estrogen receptor (ER)-positive, HER2-negative, estrogen receptor 1 gene (ESR1)-mutated advanced or metastatic breast cancer (MBC) with disease progression following at least one line of endocrine therapy.⁷ In the EMERALD randomized, open-label, phase 3 trial, the efficacy of elacestrant in men and women with ER-positive/HER2-negative advanced breast cancer was evaluated.⁷ Participating patients previously had one or two lines of endocrine therapy, one line of a cyclin dependent kinase 4/6 inhibitor and may have received one line of chemotherapy in the advanced or metastatic setting.⁷ A total of 477 patients were enrolled, with 228 having ESR1 mutations. Patients were randomized to receive either elacestrant 345mg orally once daily or standard of care (SOC) endocrine monotherapy.⁷

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Elacestrant (Radius Health, Eisai) is an oral selective estrogen receptor degrader currently under FDA review for the treatment of breast cancer.

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The major efficacy outcome was PFS with overall survival as an additional measure. Comparison of the PFS for the intention to treat and the ESR1 groups showed a statistically significant difference, demonstrating the magnitude of the benefit seen in the ESR1-mutated population.⁸ Specifically, in patients with the ESR1 mutation taking elacestrant, the median PFS was 3.8 months compared to 1.9 among SOC patients, representing a 45% risk reduction of progression.⁷ Overall, 22.3% of the elacestrant group achieved 12-month PFS compared to 9.5% of the SOC group.⁷

Common adverse events associated with elacestrant were musculoskeletal pain; increased cholesterol, AST, creatinine and triglycerides; decreased sodium, hemoglobin, and appetite; and fatigue, nausea, vomiting, diarrhea, headache, constipation, abdominal pain, hot flash, and dyspepsia.⁷

Pipeline Outlook

There are many exciting advancements and expanded approvals in the breast cancer category. See Table 1 for an expanded pipeline. Imminent approval decisions by the FDA of oral selectiveestrogen receptor degraders (SERD) offer particularly interesting opportunities for shifts in the treatment of breast cancer.

Vic-trastuzumab duocarmazine

An intravenous anti-HER2 antibody-drug conjugate, victrastuzumab duocarmazine, is currently under review by the FDA with an expected approval decision in May 2023.⁸ A Biologics License Application (BLA) was accepted for vic-trastuzumab duocarmazine for the treatment of patients with HER2+ unresectable locally advanced or MBC.⁸ Data from the Phase 3 TULIP trial supported the BLA. TULIP was a multi-center, open-label, randomized clinical trial comparing vic-trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER2+ unresectable locally advanced or metastatic breast cancer (MBC) with at least two previous MBC regimens or previous MBC treatment with ado-trastuzumab emtansine.⁹ Patients were randomized to receive either 1.2mg/kg of vic-trastuzumab duocarmazine every three weeks or physician’s choice chemotherapy (lapatinib/ capecitabine, trastuzumab/capecitabine, trastuzumab/vinorelbine, or trastuzumab/eribulin mesylate).⁹

For patients in the vic-trastuzumab duocarmazine group, median PFS was seven months compared to 4.9 months in the physician’s choice group.⁹ Median overall survival was 20.4 months and 16.3 months for vic-trastuzumab duocarmazine and physician’s choice chemotherapy, respectively.⁹ This endpoint did not meet statistical significance. Adverse events associated with treatment with victrastuzumab duocarmazine were conjunctivitis, keratitis, and fatigue; interstitial lung disease, or pneumonitis, was reported for 7.5% of patients in the vic-trastuzumab duocarmazine group.⁹

This therapy is potentially a third-line treatment for MBC. Currently, the National Comprehensive Cancer Network lists tucatinib + trastuzumab + capecitabine as the Category 1 preferred third line treatment for stage IV HR+/ or HR-/HER2+ MBC. Final overall survival results are needed for vic-trastuzumab duocarmazine to determine whether it will provide improved outcomes over current preferred regimens.

Management Impact

The recent approval of oral SERDs for breast cancer will cause shift in the management of breast cancer. Elacestrant is the first oral SERD for the treatment of breast cancer. Currently, fulvestrant (Faslodex®) injection is the only available SERD to treat breast cancer. Endocrine therapy is so crucial in the treatment for ER+ breast cancer; SERDs remain effective in treating some ESR-bearing breast cancers that can be resistant to some anti-estrogen therapy.¹⁰ Increasing treatment options in this space will provide alternative opportunities for all stakeholders.

Elacestrant could potentially become a preferred endocrine monotherapy regimen in second- or third-line ER-positive/HER2- negative advanced metastatic breast cancer. An oral alternative could shift the treatment landscape for breast cancer. Patients could avoid the administrative burden of the three initial fulvestrant injections and follow-up monthly injection doses. Elacestrant could present a more effective and convenient option to intramuscular fulvestrant, specifically in patients with ESR1- mutation. With the potential approval of a second oral SERD later in 2023, competition in this space could lead to better cost management.

Provider education will be crucial to help inform the process of selecting the appropriate population for treatment.¹¹ Additionally, biomarker testing will be key to identifying the patients who will most benefit from treatment with these particular agents.¹¹

References

1. “FDA approves laparib for adjuvant treatment of high-risk early breast cancer.” U.S. Food & Drug Administration, 11 Mar. 2022, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-adjuvant-treatment-high-risk-early-breastcancer.
2. Tutt, Andrew, et al. “Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer,” The New England Journal of Medicine, 24 June 2021, https://www.nejm.org/doi/full/10.1056/
3. “FDA D.I.S.C.O. Burst Edition: FDA approval of Enhertu (famtrastuzumab deruxtecan-nxki) for adult patients with unresectable or metastatic HER2-positive breast cancer.” U.S. Food & Drug Administration, 24 May 2022, https://www.fda.gov/drugs/resourcesinformation-approved-drugs/fda-disco-burst-edition-fda-approvalenhertu-fam-trastuzumab-deruxtecan-nxki-adult-patients.
4. Cortés, Javier, et al. “Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer.” The New England Journal of Medicine, 24 Mar. 2022, https://www.nejm.org/doi/10.1056/NEJMoa2115022.
5. “FDA D.I.S.C.O. Burst Edition: FDA approvals of Enhertu (famtrastuzumab deruxtecan-nxki) for unresectable or metastatic HER2-low breast cancer, and Nubeqa (darolutamide) in combination with docetaxel for metastatic hormone-sensitive prostate cancer.” U.S. Food & Drug Administration, 7 Sept. 2022, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burstedition-fda-approvals-enhertu-fam-trastuzumab-deruxtecan-nxkiunresectable-or.
6. Modi, Shanu, et al. “Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer.” The New England Journal of Medicine, 7 July 2022, https://www.nejm.org/doi/10.1056/
7. “FDA approves elacestrant for ER-positive, HER2-negative, ESR1- mutated advanced or metastatic breast cancer.” U.S. Food and Drug Administration, 27 Jan. 2023, https://www.fda.gov/drugs/resourcesinformation-approved-drugs/fda-approves-elacestrant-er-positiveher2-negative-esr1-mutated-advanced-or-metastatic-breast-cancer.
8. ADC Review Editorial Team, “Following Positive Results of Phase III TULIP Trial: FDA Accepts Byondis’ BLA for [Vic-] Trastuzumab Duocarmazine in HER+ mBC,” ADC Review, 12 July 2022, https:// www.adcreview.com/news/following-positive-results-of-phaseiii-tulip-trial-fda-accepts-byondis-bla-for-vic-trastuzumabduocarmazine-in-her2-mbc/.
9. Saura Manich, Cristina, et al. “LBA 15- Primary outcome of the phase III SYD985.002/TULIP trial comparing [vic-]trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER2-positive locally advanced or metastatic breast cancer,” Annals of Oncology, 19 Sept. 2021, https://oncologypro.esmo.org/meeting-resources/esmo-congress-2021/primaryoutcome-of-the-phase-iii-syd985.002-tulip-trial-comparing-victrastuzumab-duocarmazine-to-physician-s-choice-treatment-inpatients-with-p.
10. Wang, Yating, et al. “The race to develop oral SERDs and other novel estrogen receptor inhibitors: recent clinical trial results and impact on treatment options.” Cancer and Metastasis Review, 14 Oct. 2022, https://link.springer.com/article/10.1007/s10555-022-10066-y.
11. Fernando, Surani. “Pipeline Report 2022: Patient experience takes center stage,” MM+M, 7 Dec. 2022, https://www.mmm-online.com/ home/channel/features/pipeline-report-2022-patient-experiencetakes-center-stage/.

Table 1. Pipeline: Breast Cancer Management

Drug	Manufacturer	Route of Administration	Mechanism of Action	Indication	Status
vic-trastuzumab duocarmazine (SYD985)	Byondis	IV	anti-HER2 antibody cytotoxic agent	HER2+breast cancer	pending (5/12/2023)
buparlisib (BKM120)	Novartis	oral	PI3K inhibitor	breast cancer	phase 3
capivasertib (AZD5363)	AstraZeneca; Astex Pharmaceuticals	oral	Akt inhibitor	breast cancer	phase 3
imlunestrant (LY3484356)	Eli Lilly and Company/Loxo Oncology	oral	SERD	breast cancer	phase 3
pyrotinib (HTI-1001)	Jiangsu Hengrui Medicine	oral	EGFR inhibitor; HER inhibitor	HER2+ breast cancer	phase 3
datopotamab deruxtecan (DS-1062)	Daiichi Sankyo; AstraZeneca	IV	topoisomerase I inhibitor; anti-Trop2 antibody	HR+ breast cancer	phase 3
GLSI-100	Greenwich LifeSciences	intradermal	immunostimulant	HER2+ breast cancer	phase 3
toripalimab (TAB001)	Junshi Biosciences/Coherus BioSciences	injectable	PD-1 inhibitor	breast cancer	phase 3
camizestrant (AZD9833)	AstraZeneca	oral	SERD	HR+ breast cancer	phase 3
giredestrant (RGP6171)	Roche; Genentech	oral	SERD	HR+ breast cancer	phase 3

Abbreviations: EGFR = estimated glomerular filtration rate; HER = human epidermal growth factor receptor; HR = hormone receptor; IV = intravenous; PD-1 = programmed cell death protein 1; PI3K =phosphoinositide 3-kinase; SERD = selective estrogen receptor degrader