Bartlett, Cynthia Huang

Abstract Background: More than two thirds of patients with advanced breast cancer (ABC) have estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−) tumors. In most countries, current standard-of-care first-line treatments include an aromatase inhibitor or fulvestrant, a selective ER degrader, combined with cyclin-dependent kinase 4/6 inhibitors. Concurrent use of luteinizing hormone-releasing hormone agonists is recommended for men and premenopausal women with ABC. Nevertheless, almost all ABCs eventually become resistant to endocrine therapy and the disease is incurable in these cases. New therapies are needed to combat endocrine therapy resistance, maintain patient health-related quality-of-life, and delay the need for chemotherapy. AZD9833 (camizestrant) is a highly potent, next-generation selective ER degrader and pure ER antagonist that has demonstrated anticancer properties across a range of preclinical models, including those with ER-activating mutations (Scott et al, AACR 2020). A Phase I dose-escalation and expansion study (SERENA-1) has demonstrated that AZD9833 is well tolerated and has a promising antitumor activity when administered alone or in combination with the cyclin-dependent kinase 4/6 inhibitor palbociclib (Baird et al, SABCS 2020). SERENA-4 (NCT04711252) is a randomized, multicenter, double-blind, Phase III trial to evaluate the safety and efficacy of AZD9833 in combination with palbociclib for patients with ER+/HER2− ABC who have not received systemic treatment in the advanced disease setting. Methods: SERENA-4 will enroll 1342 patients with de novo or recurrent ER+/HER2− ABC who have not previously received systemic treatment for their locoregionally recurrent or metastatic disease. Patients with recurrent disease must have received adjuvant aromatase inhibitor or tamoxifen therapy for at least 24 months without relapse. Patients will be randomized 1:1 to receive oral treatment with either (a) AZD9833 75 mg once daily, palbociclib 125 mg once daily for 21 days followed by 7 days off treatment and a placebo for anastrozole 1 mg once daily or (b) anastrozole 1 mg once daily, palbociclib (same as active arm) and a placebo for AZD9833 75 mg once daily. Men and premenopausal women will also receive a luteinizing hormone-releasing hormone agonist. The primary endpoint is progression-free survival (PFS; up to 5 years). Secondary endpoints include overall survival (up to 8 years), second PFS, time to chemotherapy, objective response rate, and changes in health-related quality-of-life measures. Enrollment began in January 2021. As of 02 July 2021, the number of open sites is 57 across 15 countries. Acknowledgments: We thank Julia Mawer, PhD, of Oxford PharmaGenesis, Oxford, UK, for providing medical writing support funded by AstraZeneca Funding: The SERENA-4 trial is funded and overseen by AstraZeneca. © 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 ASCO Annual Meeting. All rights reserved. Citation Format: Fabrice André, Seock-Ah Im, Patrick Neven, Richard D Baird, Johannes Ettl, Matthew P Goetz, Erika Hamilton, Hiroji Iwata, Zefei Jiang, Anil Abraham Joy, Vincent Haddad, Andrew Walding, Manuel Selvi Miralles, Cynthia Huang Bartlett, Antonio Llombart-Cussac. SERENA-4: A Phase III comparison of AZD9833 (camizestrant) plus palbociclib, versus anastrozole plus palbociclib, for patients with ER-positive/HER2-negative advanced breast cancer who have not previously received systemic treatment for advanced disease [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-11-06.

TPS1101 Background: More than two thirds of patients with advanced breast cancer (ABC) have estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−) tumors. Current standard-of-care first-line treatments include an aromatase inhibitor (AI) or fulvestrant, a selective ER degrader (SERD), combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Concurrent use of luteinizing hormone-releasing hormone (LHRH) agonists is recommended for men and premenopausal women with ABC. Nevertheless, almost all ABCs eventually become resistant to endocrine therapy (ET) and the disease is incurable. New therapies are needed to combat ET resistance, maintain patient quality of life (QoL), and delay the need for chemotherapy. AZD9833 (camizestrant) is an orally bioavailable, highly potent, next-generation SERD that demonstrated anti-cancer properties across a range of preclinical models, including those with ER-activating mutations (Scott et al, 2020). A phase I study (SERENA-1) has demonstrated that AZD9833 is well tolerated and has a promising antitumor profile when administered alone or in combination with palbociclib, a CDK4/6 inhibitor (Baird et al, SABCS 2020). SERENA-4 (NCT04711252) is a randomized, multicenter, double-blind, phase III trial to evaluate the safety and efficacy of AZD9833 in combination with palbociclib for patients with ER+ HER2− ABC who have not received any systemic treatment in the advanced disease setting. Methods: SERENA-4 will enroll 1,342 patients with de novo or recurrent ER+ HER2– ABC who have not previously received systemic treatment for their locoregionally recurrent or metastatic disease. Patients with recurrent disease must have received adjuvant AI or tamoxifen therapy for at least 24 months without relapse. Patients will be randomized 1:1 to receive orally either (a) AZD9833 (75 mg, once daily), palbociclib (125 mg, once daily for 21 days followed by 7 days off treatment) and anastrozole-matching placebo (once daily) or (b) anastrozole (1 mg, once daily), palbociclib (same as active arm), and AZD9833-matching placebo (once daily). Premenopausal women and men will also receive LHRH agonists. The primary endpoint will be progression-free survival (PFS; up to 5 years). Secondary endpoints will include overall survival (up to 8 years), length of second PFS period, objective response, time to chemotherapy, and changes in QoL measures. Enrollment began in January 2021. Acknowledgments: We thank Rose Goodchild, PhD, of Oxford PharmaGenesis, UK, for providing medical writing assistance. Funding: The SERENA-4 trial is funded and overseen by AstraZeneca. Clinical trial information: NCT04711252 .

Abstract Purpose: Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor–positive (ER+) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. Experimental Design: Eligible patients with clinical stage II/III ER+/HER2− breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1–21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 > 10%, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7%). Results: Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs. C1D1 26%, P < 0.001). Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and PIK3CA status with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression. Conclusions: Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect. Clin Cancer Res; 23(15); 4055–65. ©2017 AACR.