Endocrine Therapy Options for Women with Breast Cancer

Endocrine therapy is a valuable treatment option for women whose breast tumors express the estrogen receptor (ER).¹ In these women, endocrine therapy can block the tumor’s ability to produce estrogen–a hormone that promotes the growth of ER+ tumors–or interfere with its actions.² Endocrine therapies include:

• Selective estrogen receptor modulators (SERMs), such as tamoxifen, that prevent estrogen from binding to ERs²
• Aromatase inhibitors (AIs), such as letrozole, that block the activity of aromatase, an enzyme used in the production of estrogen²
• Selective estrogen receptor downregulators (SERDs), such as fulvestrant, that bind to and degrade ERs³
• Cell cycle inhibitors, such as palbociclib, that reduce cellular proliferation of ER+ breast cancer cell lines^4,5

Tamoxifen, an Established Endocrine Therapy for Over 30 Years²

Tamoxifen–one of the most widely used agents in the field of oncology–is a nonsteroidal agent that binds to ERs, blocking the proliferative effects of estrogen.^6,7 Unfortunately, in addition to its strong antiestrogenic effect on mammary epithelium, tamoxifen is also proestrogenic on uterine epithelium.^6,8 This proestrogenic effect–and its associated risk of endometrial cancer–has created significant controversy surrounding the use of tamoxifen.^6,8

Letrozole, a Potent and Selective AI⁹

Letrozole is a third-generation AI that was discovered using a structure-activity approach to drug design aimed at creating a highly potent and totally selective AI.⁹ AIs block the activity of aromatase, an enzyme that converts androgens produced in the adrenal glands to estrogen.^2,7 They do not affect the production of estrogen by the ovaries and, therefore, cannot be used in premenopausal women unless ovarian estrogen production is stopped with medications or oophorectomy.⁷

Unlike first- and second-generation AIs, however, letrozole is highly selective for aromatase and does not significantly impact the synthesis of cortisol, aldosterone, or thyroxine.⁹ Letrozole is more potent than other AIs, achieving greater suppression of estrogen and nearly complete inhibition of aromatase in peripheral tissues.

Fulvestrant, a Pure Antiestrogen²

At this time, fulvestrant is the only SERD marketed in the United States.^3,10 It inhibits binding of estrogen to ERs, thereby downregulating cellular ER levels and abolishing all estrogen signaling through the ER.¹ Fulvestrant lacks cross-resistance with tamoxifen, and unlike tamoxifen, it has no known estrogen agonist effects.^11,12

Palbociclib, the First Cell Cycle Inhibitor¹³

Palbociclib is a highly selective inhibitor of 2 cell cycle enzymes, cyclin-dependent kinase 4 and 6 (CDK4/6).^4,14 CDKs play an integral role in facilitating cell cycle progression.^5,14 Thus, abnormal activation of CDKs that occurs in certain cancers, including breast cancer, can lead to uncontrolled cell growth. By inhibiting CDK4/6, palbociclib reduces cellular proliferation and restores normal cell cycle function.^5,14 Cell cycle inhibition does not address the problem of metastases, however, and CDK4/6 inhibitors must be combined with other agents.⁵

Studies of Palbociclib Combination Therapy

Three randomized studies demonstrated the benefit of palbociclib in the management of women with ER+, HER2 advanced breast cancer:

• PALOMA-1: Palbociclib added to letrozole, phase 2
• PALOMA-2: Palbociclib added to letrozole, phase 3
• PALOMA-3: Palbociclib added to fulvestrant, phase 3

PALOMA-1

PALOMA-1 was a phase 2, open-label, randomized (1:1) trial that evaluated the combination of letrozole plus palbociclib (n = 84) versus letrozole alone (n = 81) as first-line therapy in postmenopausal women with ER+, HER2–advanced breast cancer.^14,15 Patients randomly assigned to letrozole plus palbociclib received continuous oral letrozole 2.5 mg once daily plus oral palbociclib 125 mg once daily for 3 weeks followed by 1 week off in 28-day cycles. Those assigned to letrozole alone received continuous oral letrozole 2.5 mg once daily.¹⁵

Letrozole plus palbociclib resulted in significantly longer progression-free survival (PFS) than letrozole alone (20.2 vs 10.2 months; hazard ratio [HR], 0.488; P = .0004), providing proof of concept for the activity of CDK4/6 inhibition in ER+, HER2– advanced breast cancer.¹⁵

PALOMA-2

The PALOMA-2 trial was designed to confirm the PALOMA-1 results.¹⁶ Although the final study report has yet to be published, data were presented at the 2016 ASCO Annual Meeting.

The design of PALOMA-2 was similar to that of the PALOMA-1 study, but it was not identical.¹⁶ Although it studied the same treatments (letrozole plus palbociclib or letrozole alone) in the same patient group (women with advanced ER+, HER2– breast cancer who had not received systemic therapy), PALOMA-2 was a phase 3, double-blind study, randomized 2:1 in favor of the combination therapy.¹⁶ Patients assigned to combination therapy received continuous oral letrozole 2.5 mg once daily plus oral palbociclib 125 mg once daily for 3 weeks followed by 1 week off in 28-day cycles. Those in the letrozole alone group received continuous oral letrozole 2.5 mg once daily plus placebo. The primary end point was investigator-assessed PFS; select secondary end points were objective response rate (ORR), clinical benefit rate (CBR = complete response + partial response + stable disease ≥24 weeks), overall survival (OS), and safety.¹⁶

Six hundred sixty-six postmenopausal patients were randomized to receive letrozole plus palbociclib or letrozole plus placebo.¹⁶ There were no clinically significant differences in baseline characteristics between the 2 treatment groups. As in PALOMA-1, the letrozole plus palbociclib combination therapy resulted in significantly longer median PFS compared with letrozole monotherapy (24.8 vs 14.5 months, respectively; HR, 0.58; P <.000001).¹⁶

Secondary end points were significantly better as well.¹⁶ ORR was significantly higher in the letrozole plus palbociclib treatment group compared with letrozole alone (42.1% vs 34.7%, respectively; P = .031), as was CBR (84.9% vs 70.3%, respectively; P <.0001). The final OS analysis is still pending.

Common adverse events (all grades) with letrozole plus palbociclib combination therapy versus letrozole monotherapy were neutropenia (79.5% vs 6.3%), fatigue (37.4% vs 27.5%), nausea (35.1% vs 26.1%), arthralgia (33.3% vs 33.8%), and alopecia (32.9% vs 15.8%).¹⁶ The most common severity for neutropenia was grade 3 (56.1%); for other adverse events, grade 1 was most common. Febrile neutropenia was seen only in the letrozole plus palbociclib treatment group (2.5%). Less than 10% (9.7%) of patients in the letrozole plus palbociclib treatment group discontinued therapy permanently, whereas 5.9% of patients in the letrozole monotherapy group did so.¹⁶

Based on these preliminary findings, PALOMA-2 confirmed the safety and significant clinical benefit of letrozole plus palbociclib combination therapy in women who had not received systemic therapy for their ER+, HER2– advanced breast cancer.¹⁶

PALOMA-3

Unlike PALOMA-2, which assessed the efficacy and safety of letrozole with or without palbociclib,¹⁶ PALOMA-3 evaluated that of fulvestrant with or without palbociclib.¹⁷

PALOMA-3 was a phase 3, double-blind, randomized (2:1) trial of fulvestrant plus palbociclib versus placebo plus palbociclib in women of any menopausal status with HR+, HER2– metastatic breast cancer whose disease had progressed after previous endocrine therapy.¹⁷ Patients assigned to combination therapy received fulvestrant 500 mg IM (days 1 and 15 of cycle 1, then on day 1 of each subsequent 28-day cycle) plus palbociclib 125 mg PO (once daily for 3 weeks followed by 1 week off in 28-day cycles). Those in the fulvestrant alone group received fulvestrant 500 mg IM (days 1 and 15 of cycle 1, then on day 1 of each subsequent 28-day cycle) plus placebo. The primary end point was investigator-assessed PFS; select secondary end points were confirmed objective response (COR = complete response + partial response + stable disease ≥24 weeks), OS, and safety.¹⁷

Five hundred twenty-one patients were enrolled and randomly assigned to either fulvestrant and palbociclib (n = 347) or fulvestrant and placebo (n = 174).¹⁷ Baseline characteristics did not differ substantially between groups.

The fulvestrant plus palbociclib combination therapy resulted in significantly longer median PFS compared with fulvestrant plus placebo (9.5 vs 4.6 months, respectively; HR, 0.46; 95% CI, 0.36-0.59; P <.0001).¹⁷ Of patients with measurable disease at baseline, significantly more patients in the fulvestrant plus palbociclib group demonstrated an objective response (ie, confirmed partial response or complete response) compared with the fulvestrant plus placebo group (66 vs 15, respectively; OR = 2.69; 95% CI, 1.43-5.26; P = .0012). Follow-up of OS is in progress.¹⁷

Grade 3 or 4 adverse events occurred in 73% of patients in the fulvestrant plus palbociclib group and 22% of patients in the fulvestrant plus placebo group.¹⁷ In the fulvestrant plus palbociclib group versus the fulvestrant plus placebo group, respectively, the most common grade 3 or 4 adverse events were neutropenia (65% vs 1%), anemia (3% vs 2%), and leukopenia (28% vs 1%), and serious adverse events occurred in 13% versus 17% of patients, respectively.

Based on the results of PALOMA-3, the authors concluded that targeting CDK4 and CDK6–by adding palbociclib to fulvestrant–is a novel, efficacious, and safe approach for the treatment of patients with metastatic breast cancer.¹⁷

References

1. Nicholson RI, Johnston SR. Endocrine therapy—current benefits and limitations. Breast Cancer Res Treat. 2005;93(suppl 1):S3-S10.
2. National Cancer Institute website. Hormone Therapy for Breast Cancer. www.cancer.gov/types/breast/breast-hormone-therapy-fact-sheet.Accessed August 31, 2016.
3. Garner F, Shomali M, Paquin D, et al. RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models. Anticancer Drugs. 2015;26:948-956.
4. Ibrance [package insert]. New York, NY: Pfizer Labs; 2016.
5. Brower V. Cell cycle inhibitors make progress. J Natl Cancer Inst. 2014;106:dju221.
6. Goldstein SR, Siddhanti S, Ciaccia AV, et al. A pharmacological review of selective oestrogen receptor modulators. Hum Reprod Update. 2000;6:212-224.
7. American Cancer Society. Breast Cancer Facts & Figures 2015-2016. Atlanta, GA: American Cancer Society, Inc; 2015.
8. Sporn MB, Lippman SM. Agents for Chemoprevention and Their Mechanism of Action. In: Kufe DW, Pollock RE, Weichselbaum RR, et al, eds. Holland-Frei Cancer Medicine. 6th edition. Hamilton, ON: BC Decker; 2003.
9. Bhatnagar AS. The discovery and mechanism of action of letrozole. Breast Cancer Res Treat. 2007;105(suppl 1):7-17.
10. Lumachi F, Santeufemia DA, Basso SM. Current medical treatment of estrogen receptor-positive breast cancer. World J Biol Chem. 2015;6:231-239.
11. Ciruelos E, Pascual T, Arroyo Vozmediano ML, et al. The therapeutic role of fulvestrant in the management of patients with hormone receptor-positive breast cancer. Breast. 2014;23:201-208.
12. Addo S, Yates RA, Laight A. A phase I trial to assess the pharmacology of the new oestrogen receptor antagonist fulvestrant on the endometrium in healthy postmenopausal volunteers. Br J Cancer. 2002;87:1354-1359.
13. Lu J. Palbociclib: a first-in-class CDK4/CDK6 inhibitor for the treatment of hormone-receptor positive advanced breast cancer. J Hematol Oncol. 2015;8:98.
14. Murphy CG, Dickler MN. The role of CDK4/6 inhibition in breast cancer. Oncologist. 2015;20:483-490.
15. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16:25-35.
16. Finn RS, Martin M, Rugo HS, et al. PALOMA-2: primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2– advanced breast cancer (ABC). J Clin Oncol. 2016;34(suppl). Abstract 507.
17. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17:425-439.