Oral Selective Estrogen Receptor Degrader Research Articles

Abstract PS17-08: Population pharmacokinetic and exposure-response modeling of the oral selective estrogen receptor degrader, rintodestrant (G1T48), in patients with ER+/HER2- advanced breast cancer

Abstract Background: Rintodestrant is an orally bioavailable, potent and selective estrogen receptor degrader (SERD) that competitively binds to the estrogen receptor (ER) and blocks ER signaling in tumors resistant to other endocrine therapies. Clinical trials have been conducted to evaluate the safety and efficacy of rintodestrant in healthy volunteers and patients with ER+/HER2- locally advanced or metastatic breast cancer (ABC). Population pharmacokinetic (PK) and exposure-response (Ex/Re) analyses were performed to further characterize the PK profile of rintodestrant and identify potential Ex/Re relationships. Methods: The present analyses include data from two studies: (1) G1T48-01, a Phase 1 first-in-human study of rintodestrant monotherapy (200-1000 mg once daily [QD]) in women with ER+/HER2- ABC after progression on endocrine therapy (NCT03455270), and (2) G1T48-10, a study in healthy volunteers investigating potential drug-drug interactions between rintodestrant (200 mg QD) and palbociclib (125 mg QD). A PK model was developed using nonlinear mixed effects methodology to estimate PK parameters for individual patients. A tumor dynamic model was built to characterize the relationship between rintodestrant concentrations and the longitudinal tumor sizes according to RECIST v1.1. Ex/Re for key pharmacodynamic markers, including ER target engagement (18F-fluoroestradiol positron emission tomography [FES-PET]), dynamics of cell-free DNA mutational burden, ER degradation and proliferation (Ki67) in tumors, and enumeration of circulating tumor cells are being evaluated. Relationships between model-predicted exposures and study endpoints (objective response rate, clinical benefit rate) are also being evaluated. Results: Rintodestrant PK was best described using a linear two-compartment model with a mixed absorption model. The predicted population mean trough concentration of rintodestrant at the recommended Phase 2 dose (800 mg QD) exceeded the IC90 value for ER degradation established in vitro. A positive Ex/Re relationship was identified between total exposure and target ER engagement as measured by FES-PET. A clear Ex/Re relationship was not identified between any PK parameters and ER degradation or proliferation, potentially due to confounding effects from covariates in the model (eg, prior SERD treatment, ESR1 mutations, etc). Additional exploration of these covariates is ongoing. The final PK, Ex/Re and PK/tumor dynamics model results will be presented. Conclusions: A population PK model was developed and Ex/Re relationship analyses were performed to support the development of rintodestrant for the treatment of patients with ER+ breast cancer. Initial results identified an Ex/Re relationship with target ER engagement via FES-PET analysis. Citation Format: Andrew P Beelen, Chao Li, Praneeth Jarugula, Mathangi Gopalakrishnan, Jessica A Sorrentino, Curt D Wolfgang, Sarika Jain, Wenli Tao. Population pharmacokinetic and exposure-response modeling of the oral selective estrogen receptor degrader, rintodestrant (G1T48), in patients with ER+/HER2- advanced breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-08.

Abstract OT-09-03: EMBER: A phase 1a/b trial of LY3484356, a novel, oral selective estrogen-receptor degrader (SERD), in advanced ER+ breast cancer and endometroid endometrial cancer

Abstract Background: Estrogen receptor (ER) is the key therapeutic target for the most common breast cancer (BC) subtype affecting patients worldwide. Novel degraders and antagonists of ER are under evaluation, to overcome both ER mediated resistance and the bioavailability and dosing limitations of fulvestrant (fulv), the only approved SERD. ER is also overexpressed in approximately 80% of endometroid endometrial cancers and endocrine therapy (ET) is a standard of care (SOC) option for this disease, though no ER-directed therapies are specifically approved in this setting. LY3484356 is a novel, orally bioavailable SERD with pure antagonistic properties which results in sustained inhibition of ER-dependent gene transcription and -cell growth. Preclinically, LY3484356 monotherapy shows favorable efficacy and pharmacokinetic (PK) properties, including antitumor activity in ESR1 mutants, along with enhanced antitumor efficacy when combined with abemaciclib, everolimus, or alpelisib. This trial investigates LY3484356 alone and in combination with other SOC anticancer therapies, in women with ER+ advanced BC and ER+ endometroid endometrial cancer. Trial Design: This global first-in-human phase 1a/b, study of LY3484356, includes dose escalation of LY3484356 monotherapy (n=100), followed by dose expansion (n=360) at the recommended phase 2 dose (RP2D) of LY3484356 alone and in combination with other anticancer therapies (Table). Monotherapy dose escalation will be evaluated using an interval 3+3 design. In dose expansion (Parts A-D), each combination cohort will include a safety lead-in of 3-6 patients. Premenopausal women must receive concomitant treatment with a GnRH agonist. Eligibility criteria: Eligible patients must have pre- or post-menopausal ER+, HER2- or HER2+, advanced BC or ER+ endometroid endometrial cancer. ER+, HER2- BC patients must have either untreated de novo disease or prior ET sensitivity. In dose escalation, BC patients may have received up to 3 prior therapies for metastatic disease. In dose expansion, prior therapy requirements are outlined in the Table below. ER+ endometroid endometrial cancer patients must have progressed on platinum-based therapy. Key Study endpoints: Recommended phase 2 dose determination; safety and tolerability assessment, PK evaluation, objective response rate and clinical benefit rate assessment per RECIST v1.1. Recruitment for the EMBER study is ongoing (NCT04188548). Table. Dose Expansion (Phase 1b)Patient SubgroupKey EligibilityStudy DrugsER+, HER2- BC Randomized (Part A)-≤1 prior metastatic therapy-LY3484356 + Abemaciclib-No prior CDK4 & 6 inhibitor-LY3484356 + Abemaciclib + Physician’s Choice AI*ER+, HER2- BC (Part B)-≤2 prior metastatic therapies (≤1 prior ET)-LY3484356 monotherapy-Prior CDK4 & 6 inhibitor required-LY3484356 + Everolimus-No prior Everolimus/Alpelisib-LY3484356 + Alpelisib-PIK3CA mutation required for AlpelisibER+, HER2+ BC Randomized (Part C)-≥2 prior HER2 therapies-LY3484356 + Trastuzumab-No prior fulv or CDK4 & 6 inhibitor-LY3484356 + Trastuzumab + AbemaciclibER+ endometroid endometrial cancer Randomized (Part D)-Progressed on platinum-based therapy-LY3484356 monotherapy-No prior AI or fulv-LY3484356 + Abemaciclib* anastrozole, letrozole, or exemestane Citation Format: Elgene Lim, Murali Beeram, Amy Prawira, Amita Patnaik, Xuejing A Wang, Suzanne RL Young, Lillian M Smyth, Erika P. Hamilton. EMBER: A phase 1a/b trial of LY3484356, a novel, oral selective estrogen-receptor degrader (SERD), in advanced ER+ breast cancer and endometroid endometrial cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-09-03.

Abstract PD8-08: A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1

Abstract Background SERDs belong to a class of ER-targeted therapies that antagonize and degrade ERs, including in ER-dependent tumors resistant to other endocrine therapies (ET). This study (AMEERA-1; NCT03284957) investigates SAR439859, an oral SERD, as monotherapy and (in ongoing cohorts) in combination with targeted therapies in patients (pts) with ER+/HER2- mBC. Here we report updated safety and antitumor activity with SAR439859 monotherapy, including exploratory analyses by prior therapy and ESR1 status. Methods This open-label, phase 1/2, first-in-human study assessed SAR439859 as monotherapy in Parts A (dose escalation 20-600 mg once daily [QD]) and B (dose expansion with recommended dose at 400 mg QD). Eligible pts were heavily pre-treated, postmenopausal women with ER+/HER2- mBC and measurable disease who received ≥6 months of prior ET in the advanced setting. Prior chemotherapy, mammalian target of rapamycin inhibitors (mTORi) and cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) for advanced disease were allowed. This analysis pooled data from pts receiving SAR439859 ≥150 mg (Part A) and 400 mg (Part B), administered in 28-day cycles. Antitumor activity was assessed by the objective response rate and clinical benefit rate (CBR: complete response [CR], partial response [PR] and stable disease [SD] ≥24 weeks) per RECIST v1.1, determined by investigators. Analyses by prior therapy and baseline ESR1 mutation status were performed. Safety was also evaluated. Results Pts (n = 62; Part A: 13; Part B: 49) had a median age of 63 (range 37-88) years and ECOG PS 0 (59.7%) or 1 (40.3%); 93.5% had visceral metastases. Pts had a median of 2 (range 1-8) prior lines of therapy in the advanced setting (48.4% had ≥3 prior lines): all had prior ET and 72.6% had prior targeted therapy. SAR439859 monotherapy showed antitumor activity in the response-evaluable population (n = 59) and in subset populations with ≤3 prior lines (n = 33) or without prior mTORi, CDK4/6i, or SERD (n = 14) (Table 1). For pts with ESR1 status (n = 58), CBR with SAR439859 was comparable in ESR1 wild-type (36.7%) and mutant mBC (32.1%), with similar results in subpopulations. Treatment-related adverse events (TRAEs) occurred in 62.9% of pts (all grade 1-2); none resulted in SAR439859 discontinuation. Most frequent TRAEs were hot flush (16.1%); constipation and arthralgia (each 9.7%); decreased appetite, vomiting, diarrhea and nausea (each 8.1%); and fatigue (6.5%). Conclusions Among heavily pre-treated pts, SAR439859 demonstrated antitumor activity, similar to historical single-agent fulvestrant activity in less heavily pre-treated pts with advanced/mBC (2L+ setting; no prior targeted agents) (indirect comparison). In both subsets of pts with fewer prior advanced lines of therapy, SAR439859 showed trends of greater clinical activity versus historical fulvestrant activity. SAR439859 had a favorable safety profile with limited TRAEs. No safety signals of cardiac or ocular toxicities were observed. Ongoing parts of the study are investigating SAR439859 in combination with targeted therapies. Based on the monotherapy results, a randomized phase 2 study is investigating SAR439859 compared with physician’s choice in a 2L+ setting (AMEERA-3; NCT04059484). Funding: Sanofi. Antitumor activity overall and in subpopulations by prior lines of therapy (Parts A+B)Overall population (A+B)≤3 Prior advanced linesWithout prior targeted therapy(n = 59)a(n = 33)b(n = 14)cBOR, n (%)–CR000–PR5 (8.5)5 (15.2)3 (21.4)–SD24 (40.7)15 (45.5)8 (57.1)–PD30 (50.8)13 (39.4)3 (21.4)ORR, n (%)5 (8.5)5 (15.2)3 (21.4)CBR, n (%)20 (33.9)14 (42.4)9 (64.3)aPooled cohort (A ≥150 mg QD + B);bSubset of pooled cohort with ≤3 prior lines in the metastatic setting, including ≤1 of either prior chemotherapy or CDK4/6i and no prior mTORi; cSubset of pooled cohort with no prior mTORi, CDK4/6i, or fulvestrant.BOR, best overall response; CBR, clinical benefit rate; CR, complete response; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease. Citation Format: Hannah M Linden, Mario Campone, Aditya Bardia, Gary A Ulaner, Alice Gosselin, Séverine Doroumian, Vasiliki Pelekanou, Marina Celanovic, Sarat Chandarlapaty. A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD8-08.

Abstract PS17-16: Sar439859, a novel selective estrogen receptor degrader (serd), demonstrates effective and broad antitumor activity in wild-type and mutant er-positive breast cancer models

Abstract Primary treatment for estrogen receptor-positive (ER+) breast cancer is endocrine therapy. However, substantial evidence indicates a continued role for ER signaling in tumor progression. Selective estrogen receptor degraders (SERDs), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties. Furthermore, activating mutations in the ER have emerged as a resistance mechanism to current endocrine therapies. New oral SERDs with improved drug properties are under clinical investigation, but the biological profile that could translate to improved therapeutic benefit remains unclear. Here we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradation activities against both wild-type and mutant Y537S ER. Driven by its fluoropropyl pyrrolidinyl side chain, SAR439859 has demonstrated broader and superior ER antagonist and degrader activities across a large panel of ER+ cells, compared with other SERDs characterized by a cinnamic acid side chain, including improved inhibition of ER signaling and tumor cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models including MCF7-ESR1 wild type and mutant-Y537S mouse tumors, and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. These findings indicate that SAR439859 may provide therapeutic benefit to patients with ER+ breast cancer, including those have resistance to endocrine therapy with both wild-type and mutant ER. This presentation will highlight the global profile and key features of new SERD and its translation to patient. Citation Format: Maysoun Shomali, Fangxian Sun, Mikhail Levit, Jack Pollard, Joon Sang Lee, Laurent Schio, Youssef El-Ahmad, Chris Soria, Patrick Cohen, Laurent Debussche, Monsif Bouaboula. Sar439859, a novel selective estrogen receptor degrader (serd), demonstrates effective and broad antitumor activity in wild-type and mutant er-positive breast cancer models [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-16.

Abstract OT-09-11: AMEERA-4, a phase 2 window study of SAR439859 vs letrozole in post-menopausal women with newly diagnosed estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer

Abstract Background Endocrine therapy targeting estrogen receptor (ER) signaling is the standard of care for women with ER+ breast cancer. Selective ER degraders (SERDs) block ER signaling through dual competitive antagonism and receptor degradation. SAR439859, a potent, oral SERD, is in clinical development for ER+/HER- breast cancer. AMEERA-4 (NCT04191382; ACT16106) is a 14-day preoperative, non-therapeutic ‘window of opportunity’ trial to assess the direct effects of SAR439859 on tumor cell proliferation by evaluating the pharmacodynamic activity of SAR439859 in ER+/HER2- breast cancer. Methods This international, open-label, Phase 2 randomized study evaluates SAR439859 at two dose levels vs the aromatase inhibitor letrozole by assigning 126 preoperative patients 1:1:1 to receive SAR439859 400 mg/day, SAR439859 200 mg/day or letrozole 2.5 mg/day. SAR439859 dosing is based on an ongoing AMEERA-1 Phase 1/2 study (NCT03284957; TED14856) in metastatic breast cancer. Postmenopausal women with ER+/HER2- breast cancer indicated for immediate surgery (Stage I, Stage II or operable Stage III), Eastern Cooperative Oncology Group performance status 0-1, and Ki67 levels of ≥ 15% are eligible. Exclusion criteria include disorders potentially affecting absorption of SAR439859 or letrozole, and any prior therapy for breast cancer. Patients receive study treatment for 14 days, with the last dose given on the day before surgery. Paired tumor biopsies for assessment of biomarkers are performed at baseline and during surgery. The primary study endpoint is change in Ki67, a predictor of treatment benefit and long-term survival outcomes, after 14 days of treatment compared with baseline. Secondary endpoints include proportion of patients with ≥ 50% decrease in Ki67, ER expression to assess degradation, and safety. Pharmacokinetics of SAR439859, additional tumor markers, genomic mutation profile, Preoperative Endocrine Prognostic Index and pathological complete response will also be assessed. The study is currently recruiting. Funding: Sanofi. © 2020 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2020 ASCO Annual Meeting. All rights reserved. Citation Format: Mario Campone, Christina Herold, Qiuyan Wang, Vasiliki Pelekanou, Sylvaine Cartot-Cotton, Bethany Ling. AMEERA-4, a phase 2 window study of SAR439859 vs letrozole in post-menopausal women with newly diagnosed estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-09-11.

Abstract OT-09-02: A randomized, open-label, parallel-group, multicenter phase 2 study comparing the efficacy and safety of oral AZD9833 versus fulvestrant in women with advanced ER-positive HER2-negative breast cancer (SERENA-2)

Abstract Background AZD9833 is a next-generation oral selective estrogen receptor (ER) antagonist and degrader (SERD) that has shown anti-tumor efficacy in a range of pre-clinical xenograft models of breast cancer. The first-in-human study, assessing AZD9833 as a monotherapy and in combination with palbociclib (SERENA-1; NCT03616587), established a dose-dependent safety profile with clinical benefit and target engagement in pre- and post-menopausal women at all dose levels. Here, we describe the design of SERENA-2, a Phase 2 randomized, open-label trial of three different doses of AZD9833 versus fulvestrant. Methods SERENA-2 is a global comparative study of three different doses of AZD9833 versus fulvestrant in post-menopausal women with advanced ER+, HER2− breast cancer with disease recurrence or progression after ≥1 endocrine therapy. The study will evaluate the efficacy and safety of AZD9833 monotherapy once daily at three dose levels, versus fulvestrant monotherapy administered according to its label. Eligible patients will have received no prior fulvestrant or other oral SERD, and no more than one endocrine therapy and one chemotherapy in the advanced setting. Prior treatment with CDK4/6 inhibitors is permitted. Patients will be randomized 1:1:1:1 to one of four treatment groups: AZD9833 75 mg, 150 mg, 300 mg, or fulvestrant. The primary objective of the study is to determine the clinical efficacy of AZD9833 as assessed by progression-free survival, compared with fulvestrant. Secondary objectives include objective response rate, duration of response, percentage change in tumor size at 16 weeks, clinical benefit rate at 24 weeks, and overall survival. Pharmacokinetics, pharmacodynamic biomarker changes from baseline, and effects of AZD9833 and fulvestrant on patients’ health-related quality of life will also be assessed. Exploratory endpoints include predictive markers of response and/or acquired resistance to AZD9833 and fulvestrant, including circulating tumor DNA mutation profiling and dynamics, circulating tumor cell enumeration, and analysis of tumor samples. Patient enrollment commenced in Q2 2020, with a target enrollment of 288 patients across approximately 100 sites in up to 17 countries. Efficacy analyses will compare each dose of AZD9833 with fulvestrant. Sample size was calculated to provide 80% power for the primary endpoint. The primary analysis will use a Cox proportional hazards model stratified by prior use of CDK4/6 inhibitors and presence of lung and/or liver metastases to compare progression-free survival in each dose of AZD9833 versus fulvestrant. Another randomized, open-label, parallel-group, pre-surgical study investigating the biological effects of AZD9833 in ER+, HER2− primary breast cancer (SERENA-3) is also ongoing. For more information please contact Dr Mafalda Oliveira at: moliveira@vhio.net. Citation Format: Mafalda Oliveira, Maxine Bennett, Ali Khalil, Richard Mather, Rhiannon Maudsley, Sam McGuinness, Christopher J Morrow, Andy Sykes, Li Zhang, Teresa Klinowska, Justin PO Lindemann, Danielle Carroll. A randomized, open-label, parallel-group, multicenter phase 2 study comparing the efficacy and safety of oral AZD9833 versus fulvestrant in women with advanced ER-positive HER2-negative breast cancer (SERENA-2) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-09-02.

Abstract PS11-05: Updated data from SERENA-1: A Phase 1 dose escalation and expansion study of the next generation oral SERD AZD9833 as a monotherapy and in combination with palbociclib, in women with ER-positive, HER2-negative advanced breast cancer

Abstract Background: AZD9833 is an oral selective estrogen receptor (ER) antagonist and degrader (SERD) in Phase 2 clinical development for the treatment of ER+ HER2− breast cancer. Here we report data from Parts C and D of the ongoing Phase 1 study (SERENA-1) examining AZD9833 in combination with palbociclib, together with updated data from Parts A and B examining AZD9833 monotherapy. Methods: SERENA-1 (NCT03616587) is an ongoing open-label Phase 1 study of AZD9833 in pre- and post-menopausal women with ER+, HER2− advanced breast cancer who have previously received ≥1 endocrine therapy and ≤2 prior chemotherapies. Prior treatment with fulvestrant and/or CDK4/6 inhibitors was permitted. The primary objective is to determine the safety and tolerability of once daily (QD) AZD9833, with dose-limiting toxicities (DLTs) in the first 28 days defining the maximum tolerated dose. Secondary objectives include anti-tumor response (including circulating tumor [ct] DNA response) and pharmacokinetics. Parts A (escalation) and B (expansion) assess AZD9833 as a monotherapy, and Parts C (escalation) and D (expansion) assess AZD9833 in combination with palbociclib. Results: At a data cut-off of March 24 2020, 17 patients had received either 150 mg or 300 mg AZD9833 in combination with palbociclib, given according to its product labeling. Eighty patients had received AZD9833 monotherapy at doses of 25, 75, 150, 300, and 450 mg QD. In patients treated with AZD9833 and palbociclib, treatment-related adverse events (AEs; experienced by ≥10% of patients) included visual disturbances*, bradycardia*, asthenia, anemia, QTcF prolongation, nausea, neutropenia, decreased white blood cell count, and vomiting (*combined terms). All instances of AZD9833-related bradycardia were Grade 1. One DLT was observed in the 150 mg cohort: CTCAE Grade 2 visual disturbances, which began on Cycle 1 Day 8 and resolved by Cycle 1 Day 9 following dose interruption. The patient restarted treatment on Cycle 1 Day 15 at 75 mg and continued this dose until data cut-off. No causally related AEs led to discontinuation of AZD9833. The tolerability of AZD9833 with palbociclib was consistent with the observed tolerability profile of AZD9833 monotherapy, and the known tolerability profile of palbociclib. Pharmacokinetic analysis showed similar AZD9833 exposure for monotherapy and palbociclib combination therapy. Similarly, palbociclib exposure was comparable with simulations using a published population pharmacokinetic model. In Part A, ESR1 hotspot mutations were detected in ctDNA at baseline in 26/56 (46%) patients; 13/26 (50%) of these patients achieved a partial response or stable disease at 24 weeks, including 5/10 (50%) with a Y537S ESR1 mutation. Further, in patients with ESR1 mutations and samples available for longitudinal ctDNA analysis, 17/20 (85%) exhibited a reduction or loss of mutant ESR1 on treatment with AZD9833. Efficacy data to be presented include objective response rate and clinical benefit rate at 24 weeks. Of note, unconfirmed partial responses have been observed in Part C after the data cut-off for this abstract. Conclusions: AZD9833 continues to show an encouraging efficacy and dose-dependent safety profile as a monotherapy or in combination with palbociclib. A Phase 2 study comparing the efficacy and safety of three doses of AZD9833 versus fulvestrant (NCT04214288), and a Phase 2 pre-surgical ‘window of opportunity’ study (EUDRA-CT; 2019-003706-2) are ongoing. Citation Format: Richard Baird, Mafalda Oliveira, Eva Maria Ciruelos Gil, Manish R Patel, Begoña Bermejo de las Heras, Manuel Ruiz-Borrego, Javier García-Corbacho, Anne Armstrong, Udai Banerji, Chris Twelves, Valentina Boni, Jason Incorvati, Peter Kabos, Adam L Cohen, Bruno de Paula, Marta Capelán Rodríguez, Judy S Wang, Christina Hernando, Alejandro Falcón Gonzalez, Ivan Victoria Ruiz, Julia Lai-Kwon, Anosheh Afghani, Christos Vaklavas, Tim Brier, Steven Fox, Bistra Kirova, Teresa Klinowska, Chris Leach, Justin PO Lindemann, Richard Mather, Rhiannon Maudsley, Christopher J Morrow, Nitharsan Sathiyayogan, Andy Sykes, Li Zhang, Erika Hamilton. Updated data from SERENA-1: A Phase 1 dose escalation and expansion study of the next generation oral SERD AZD9833 as a monotherapy and in combination with palbociclib, in women with ER-positive, HER2-negative advanced breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-05.

SAR439859, a Novel Selective Estrogen Receptor Degrader (SERD), Demonstrates Effective and Broad Antitumor Activity in Wild-Type and Mutant ER-Positive Breast Cancer Models.

Primary treatment for estrogen receptor-positive (ER+) breast cancer is endocrine therapy. However, substantial evidence indicates a continued role for ER signaling in tumor progression. Selective estrogen receptor degraders (SERD), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties. Furthermore, activating mutations in the ER have emerged as a resistance mechanism to current endocrine therapies. New oral SERDs with improved drug properties are under clinical investigation, but the biological profile that could translate to improved therapeutic benefit remains unclear. Here, we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradation activities against both wild-type and mutant Y537S ER. Driven by its fluoropropyl pyrrolidinyl side chain, SAR439859 has demonstrated broader and superior ER antagonist and degrader activities across a large panel of ER+ cells, compared with other SERDs characterized by a cinnamic acid side chain, including improved inhibition of ER signaling and tumor cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models, including MCF7-ESR1 wild-type and mutant-Y537S mouse tumors, and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. These findings indicate that SAR439859 may provide therapeutic benefit to patients with ER+ breast cancer, including those who have resistance to endocrine therapy with both wild-type and mutant ER.

Selective Estrogen Receptor Degraders (SERDs): A Promising Strategy for Estrogen Receptor Positive Endocrine-Resistant Breast Cancer.

Estrogen receptor (ER) plays important roles in gene transcription and the proliferation of ER positive breast cancers. Selective modulation of ER has been a therapeutic target for this specific type of breast cancer for more than 30 years. Selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) have been demonstrated to be effective therapeutic approaches for ER positive breast cancers. Unfortunately, 30-50% of ER positive tumors become resistant to SERM/AI treatment after 3-5 years. Fulvestrant, the only approved selective estrogen receptor degrader (SERD), is currently an important therapeutic approach for the treatment of endocrine-resistant breast cancers. The poor pharmacokinetic properties of fulvestrant have inspired the development of a new generation of oral SERDs to overcome drug resistance. In this review, we describe recent advances in ERα structure, functions, and mechanisms of endocrine resistance and summarize the development of oral SERDs in both academic and industrial areas.

Design, syntheses and evaluations of novel indole derivatives as orally selective estrogen receptor degraders (SERD)

Most estrogen receptor positive (ER +) breast cancers depend on ER signaling pathway to develop. Clinical application of SERD fulvestrant effectively degraded ER, blocked its function and prolonged progression free survival of ER + breast cancer patients. However, current SERD suffers from limited bioavailability, therefore is given as intramuscular (IM) injection. In this paper, we report herein a novel indole series compounds with nanomolar range ER degradation potencies and oral systemic exposures. Selected compounds suppressed tumor growth in vivo in ER + MCF7 breast cancer CDX model via p.o. administration. All those data supported further optimizations of this analog to develop preclinical candidate as oral SERD for ER + breast cancer’s treatment.

A phase 1b study evaluating the effect of elacestrant treatment on estrogen receptor availability and estradiol binding to the estrogen receptor in metastatic breast cancer lesions using 18F-FES PET/CT imaging

BackgroundElacestrant is an oral selective estrogen receptor (ER) degrader. This phase 1b open-label, non-randomized study (RAD1901-106) was initiated to determine the effect of elacestrant on the availability of ER in lesions from postmenopausal women with ER+ advanced breast cancer (ABC) using 16α-18F-fluoro-17β-estradiol positron emission tomography with low-dose computed tomography (FES-PET/CT).MethodsEligible patients were postmenopausal women with ER+, HER2− ABC; tumor progression after ≥ 6 months of 1–3 lines of endocrine treatment for ABC; and measurable or evaluable disease. Two 8-patient cohorts were enrolled: one treated with 400 mg elacestrant once daily (QD) and one treated with 200 mg elacestrant QD with dose escalation to 400 mg QD after 14 days. Elacestrant was dosed continuously until progressive disease, toxicity, or withdrawal. FES-PET/CT was performed pre-dose at baseline and 4 h post-dose on day 14. The primary endpoint was the percentage difference in FES uptake in tumor lesions (maximum 20) after 14 days of treatment compared to baseline. Overall response was investigator-assessed by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1.ResultsPatients (n = 16; median age, 53.5 years) had ABC with a median 2.5 prior lines of endocrine therapy. Median reduction in tumor FES uptake from baseline to day 14 was 89.1% (Q1, Q3: 75.1%, 94.1%) and was similar in both cohorts (89.1% [Q1, Q3: 67.4%, 94.2%], 200/400 mg and 88.7% [Q1, Q3: 79.5%, 94.1%], 400 mg). Residual ER availability (> 25% persistence in FES uptake) on day 14 was observed in 3 patients receiving 200/400 mg (3/78, 37.5%) and 1 patient receiving 400 mg (1/8, 12.5%). The overall response rate (ORR) was 11.1% (1 partial response), and clinical benefit rate (CBR) was 30.8%. Median percentage change in FES uptake did not correlate with ORR or CBR. Adverse events occurring in > 20% of the patients were nausea (68.8%), fatigue (50.0%), dyspepsia (43.8%), vomiting (37.5%), and decreased appetite, dysphagia, and hot flush (31.3% each). Most events were grade 2 in severity.ConclusionElacestrant 200 mg and 400 mg QD greatly reduced ER availability measured by FES-PET/CT. In a heavily pretreated population, elacestrant was associated with antitumor activity.Trial registrationClinicalTrials.gov, NCT02650817. Registered on 08 January 2016

277MO SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), in ER+/ HER2- metastatic breast cancer (mBC): Biomarker analyses from a phase I/II study

SAR439859 has antitumor activity in patients (pts) with wild type (WT) and mutated ESR1 mBC. Here we describe tumor molecular features and evidence of on target activity in SAR439859-treated pts. Plasma circulating cell-free DNA (cfDNA) and paired biopsies were collected at baseline (BL), on treatment (OT) and end of treatment (EOT: cfDNA only) from heavily pretreated postmenopausal pts with ER+/HER2- mBC who received SAR439859 monotherapy (Part A: dose range 20–600 mg QD; Part B: 400 mg QD) in a phase I/II study (NCT03284957). In cfDNA at BL and EOT, mutation (mut) analysis was performed on a next generation sequencing panel of 77 genes. ESR1 muts in cfDNA at BL and OT were assessed by droplet digital polymerase chain reaction (ddPCR). In tumor tissue, ER and progesterone receptor (PgR), Ki67 and Bcl-2 expression over time were assessed by immunohistochemistry; changes in ER signaling pathway activation were assessed by gene set variation analysis (RNA sequencing). Response was assessed in pts who received SAR439859 ≥150 mg QD. At BL, in cfDNA from 63 pts, 95% had ≥1 mut, 52% had ≥1 ESR1 mut, 92% had ≥1 non-ESR1 mut and 49% had concurrent ESR1 and other muts. Most prevalent BL non-ESR1 muts were in PIK3CA (44% of pts), EGFR (33%), TP53 (30%) and MET (25%). ESR1 muts most commonly detected at BL and EOT were D538G, Y537S and Y537N. ESR1 muts tended to decrease OT; of 14 pts with ESR1 muts at BL, 2 had WT ESR1 OT. In 8 paired biopsies (7 were highly proliferative luminal B tumors), ER, PgR and Ki67 decreased (median relative change from BL: -58%, -88% and -33%), while Bcl-2 increased (24%). ER activation score decreased in 3/5 paired biopsies tested (median change from BL -0.38). SAR439859 showed clinical benefit (complete response + partial response [PR] + stable disease ≥24 weeks) in 40% (12/30) of WT ESR1 pts and 32% (9/28) of mutated ESR1 pts, per ddPCR. Of the 5 pts with PRs, 4 had WT ESR1 and 1 had 2 ESR1 muts, at BL. Common genomic alterations, including in ESR1 and PIK3CA, were detected in most mBC pts. SAR439859 showed clinical benefit irrespective of ESR1 mut status and resulted in ER degradation and pathway inhibition in heavily pretreated pts.

Correction to: Pharmacokinetic and Pharmacodynamic Studies of Elacestrant, A Novel Oral Selective Estrogen Receptor Degrader, in Healthy Post-Menopausal Women

Authors would liketo correct the errors in table2.

Abstract 4373: Discovery of ZN-c5, a novel potent and oral selective estrogen receptor degrader

Abstract Majority of breast cancers express the estrogen receptor alpha (ERα) and the two major strategies for therapeutic targeting of ER-alpha positive breast cancer are aromatase inhibitors (which deprives estrogen) and inhibition of the estrogen receptor alpha. Although these strategies can be effective, many patients develop resistance which ultimately leads to disease progression which continues to rely on estrogen receptor signaling. One of the resistance mechanisms is the acquisition of activating mutations in the ER gene (ESR1) that allow tumors to proliferate without depending on estrogen. One approach to overcome resistance is to develop high affinity small molecules that degrade the estrogen receptor and effectively shut down ER signaling. Fulvestrant, an ER antagonist and a selective estrogen receptor degrader (SERD) is the only small molecule that is approved for the treatment of ER+/HER2− metastatic breast cancer. However, fulvestrant's limitation include low oral bioavailability and administration via intramuscular injection, which limits its exposure and leads to sub-optimal estrogen receptor degradation. The poor pharmacokinetic properties of fulvestrant has fueled the interest in developing an orally bioavailable small molecule estrogen receptor antagonist and degrader that could potentially benefit breast cancer patients. Here we describe the discovery of Zn-c5 a novel, small molecule with potent antagonism and degradative properties against the estrogen receptor both in vitro and in vivo. ZN-c5 showed a high oral bioavailability across several preclinical species as compared to other SERDs. To test if the high oral bioavailability can be translated to potent efficacy in vivo, we evaluated the anti-tumor activity of ZN-c5 in MCF-7 orthotopic tumor xenograft model. Oral ZN-c5 treatment at 5 mg/kg and 10 mg/kg resulted in 89% and 102% tumor growth inhibition respectively. Combination of ZN-c5 with cell cycle inhibitors such as CDK4/6 inhibitors or PI3K inhibitors results in enhanced antitumor activity. In addition to MCF-7 model, we evaluated the activity of ZN-c5 in ER mutant models including WHIM20, a Y537S ESR1 patient derived xenograft model. Treatment with ZN-c5 at 40 mg/kg induced 64% tumor growth inhibition while fulvestrant at 200 mg/kg (exposures 8-fold higher than that achieved in the clinic) resulted in 13% tumor growth inhibition. These data indicate that ZN-c5 has improved antitumor activity over fulvestrant in human tumor xenograft models. Zn-c5 is currently in clinical trials as a single agent and in combination studies. The PK profile of ZN-c5 in breast cancer patients indicates that Zn-c5 has greater than 5-fold exposure than fulvestrant. We believe that the high exposure of ZN-c5 coupled with its potency and degradative properties could therapeutic benefit estrogen receptor positive breast cancer patients. Citation Format: Ahmed A. Samatar, Jiali Li, Sayee Hegde, Peter Huang, Jianhui Ma, Kevin Bunker, Robert Winkler, Fernando Donate, Masha Sergeeva. Discovery of ZN-c5, a novel potent and oral selective estrogen receptor degrader [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4373.

Abstract 1042: Preclinical pharmacokinetic and metabolic characterization of the next generation oral SERD AZD9833

Abstract AZD9833 is a potent, orally delivered, non-steroidal selective estrogen receptor degrader (SERD) that both antagonizes and degrades ERα. It is currently in clinical testing for the treatment of ER+ metastatic breast cancer (SERENA-1; NCT03616587). While ER is a clinically validated target, sustained inhibition of the target via oral delivery has proven an elusive goal. Despite intensive research, no oral SERD options are currently approved. Poor pharmacokinetic (PK) properties and/or short half-life (t ½) are often underlying features that limit oral SERD candidates from once or twice daily dose regimens. AZD9833 is a clinical stage next generation oral SERD that may overcome these challenges. The pre-clinical PK properties of AZD9833 are consistent with once daily oral dosing in patients and are reported herein. AZD9833 is a low molecular weight (<500 Da), low lipophilicity (logD <3) base with good permeability characteristics. High volume of distribution (6-13 L/kg) and high bioavailability were observed in preclinical species. The in vitro hepatic metabolic clearance (CLint) for AZD9833 varied across species and were found to be nonlinear as a function of concentration. This nonlinear behaviour most strongly manifested in dog where in vivo bioavailability was <2 or 95 %F depending on dose. To explain these observations, detailed in vitro mechanistic studies were conducted and physiologically based PK (PBPK) models were created. Cytochrome P450 phenotyping studies suggest dog clearance is mediated by CYP2D15 whereas CYP3A is the dominant P450 isoform responsible for clearance in human. In vitro CLint vs. concentration studies exhibited a low Km in dog (0.2 μM) relative to human (2 μM) and other species. To further our understanding, we constructed PBPK models which demonstrated that the dose dependent exposures in dog were predictable. The human model suggests that nonlinear behaviour will manifest well above predicted efficacious doses. Modeling also allowed us to assess the potential for drug-drug interactions with likely co-medications such as CDK 4/6 inhibitors. The PBPK predictions of good human exposure and long t ½ are being explored in the ongoing clinical trial. Citation Format: Eric T. Gangl, Roshini Markandu, Pradeep Sharma, Andy Sykes, Petar Pop-Damkov, Pablo Morentin Gutierrez, James S. Scott, Dermot F. McGinnity, Adrian J. Fretland, Teresa Klinowska. Preclinical pharmacokinetic and metabolic characterization of the next generation oral SERD AZD9833 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1042.

Abstract 4369: Preclinical mechanistic PK/PD-efficacy modeling for AZD9833, a novel next generation oral SERD, to support dose selection during early clinical development

Abstract Objectives: The estrogen receptor alpha (ERα) is highly expressed in breast cancers and is a clinically validated target in oncology. AZD9833 is a novel potent oral selective estrogen receptor degrader (SERD) currently being tested in the clinic [SERENA-1 (NCT03616587)]. We present here the preclinical PK/PD modeling work used to understand the required target modulation and concentration required to see anti-tumor efficacy and therefore help support the dose selection during the early clinical development of AZD9833. Methods: We developed a novel mechanistic mathematical model applied to mouse in both a xenograft ESR1 wild-type (MCF-7) and a PDX model harboring an ESR1 D538G mutation (CTC-174) linking the compound pharmacokinetics with the magnitude of target modulation expressed as relative levels of estrogen (ER) or progesterone receptor (PR) both measured by Western Blotting. These changes at the biomarker level were subsequently linked to inhibition of tumor cell proliferation, via a Hill-Langmuir relationship resulting in macroscopic dynamic effects on tumor size. All model parameters were derived from internal studies; some were estimated using Non-Linear Mixed Effect modeling of individual longitudinal PK, PD biomarker and tumor size data taken from several studies. Results: The model described well the relationship between plasma concentration of AZD9833 and modulation of PR (MCF-7) and ER (CTC-174). In vivo AZD9833 concentration required to see 50% of the maximal target modulation in both animal models (1.6 and 0.4 nM respectively) was in very good agreement with in vitro values when accounting for the different levels of estradiol in both animal models. Population tumor size patterns, for all treatment regimens ranging from 0 to 100% Tumor Growth Inhibition (TGI) across both tumor models were very well described with the model proposed. 75% reduction of ER levels and 45% reduction of PR levels were required to slow the tumor growth rate by one half in the CTC-174 and MCF-7 models respectively. This quantitative relationship was further validated with another SERD (Fulvestrant) in both animal models. Conclusions: This study provides quantitative mechanistic insights into the links between key biomarker modulation (ER and PR) and anti-tumor responses, supporting our understanding of the required high target modulation needed (>70% modulation of PR in MCF-7 and >85% modulation of ER in CTC-174) for maximal anti-tumor effects in these two animal tumor models. This basic mechanistic understanding is valuable to contextualize compound-induced PD modulation in patients, for given doses and schedules and helps to support dose selection decisions. Citation Format: Pablo Morentin Gutierrez, Christopher Morrow, Natalie Cureton, Mandy Lawson, Dawn Trueman, Eric Gangl, Joanne Wilson, Aaron Smith, James Scott, Teresa Klinowska. Preclinical mechanistic PK/PD-efficacy modeling for AZD9833, a novel next generation oral SERD, to support dose selection during early clinical development [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4369.

Abstract 5674: Discovery of AZD9833, an oral small molecule selective degrader of the estrogen receptor (SERD)

Abstract The estrogen receptor alpha (ERα) is expressed in >70% of breast cancers and is a clinically validated target in oncology. Anti-hormonal therapies that block ER function directly (e.g. tamoxifen) or therapies that block the production of estrogen itself (e.g., aromatase inhibitors) have proven to be effective treatments of the disease. Further advances in disease control have been made with the development of the Selective Estrogen Receptor Degrader (SERD) fulvestrant, which both antagonizes ERα-driven tumor cell growth and causes degradation of the ERα receptor. The first-generation oral SERDs, including AZD9496, showed full ER degradation in MCF-7 cells but incomplete ER degradation in other cell lines, and partial agonism. Building on that learning, extensive structure-enabled chemical optimization has resulted in the identification of a next generation oral SERD AZD9833, a potent degrader and antagonist of the ERα receptor (both EC50 <1 nM in MCF7 cells) with favorable physicochemical properties (logD7.4 <3). AZD9833 delivers maximal ERα degradation equivalent to fulvestrant in all ER+ cell lines tested, including MCF7, CAMA1, T47D and BT474. In addition, and in contrast to AZD9496, AZD9833 does not cause ER agonism in the endometrial carcinoma cell line Ishikawa in vitro and does not cause an increase in the thickness of the endometrium in juvenile rats. In several patient-derived and cell line xenograft models, including models with clinically relevant ESR1 mutations, AZD9833 completely suppresses tumor growth and gives equivalent pharmacodynamic activity to supra-clinical levels of fulvestrant. Furthermore, in an ESR1 wild-type and an ESR1 D538G PDX model, AZD9833 demonstrated combinatorial benefit with palbociclib. Based on this preclinical data AZD9833 has progressed into a multi-stage monotherapy and palbociclib combination First Time in Patient clinical trial, SERENA-1 (NCT03616587). Citation Format: James S. Scott, Thomas Moss, Steve Stokes, Willem M. Nissink, Christopher J. Morrow, Mandy Lawson, Natalie Cureton, Eric Gangl, Pablo Morentin Gutierrez, Richard Mather, Justin P. Lindemann, Andrew Sykes, David Fisher, Radoslaw Polanski, Danielle Carroll, Aisling Barton Twomey, Teresa Klinowska. Discovery of AZD9833, an oral small molecule selective degrader of the estrogen receptor (SERD) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5674.

Abstract 4379: Not all selective estrogen receptor degraders are equal - Preclinical comparison of AZD9833, AZD9496 and fulvestrant

Abstract Anti-hormonal therapy has been the mainstay treatment for estrogen receptor (ER) +ve breast cancer for >40 years. The selective ER degrader (SERD) fulvestrant has demonstrated clinical benefit over aromatase inhibitors and the selective ER modulator tamoxifen. However, fulvestrant's efficacy may be limited by the intramuscular route of administration. To overcome this, AstraZeneca has developed orally bioavailable SERDs, the first generation compound AZD9496 and the next generation oral SERD AZD9833. Here we report the preclinical comparison of fulvestrant, AZD9496 and AZD9833. All three compounds induced equal ERα degradation in the ER+ breast cancer cell line MCF7. Importantly, analysis of other ER+ cell lines revealed AZD9833 phenocopied ERα degradation induced by fulvestrant, while AZD9496 only reduced ERα levels to 54% of that achieved by fulvestrant. Activity in the endometrial Ishikawa cell line demonstrated induction of progesterone receptor, an ER target gene, by AZD9496 but not AZD9833. RNAseq analysis of ER+ breast cancer cell lines treated with the three agents with and without estradiol did not reveal differences between the compounds; all estradiol-induced gene expression changes were completely reversed by the SERDs and no ER agonism was detected. By contrast, AZD9833 and fulvestrant produced an equivalent maximal anti-proliferative effect in MCF-7 and CAMA-1 cells, while AZD9496 induced a significantly inferior anti-proliferative effect. The pure anti-estrogen nature of AZD9833 and the partial agonist potential of AZD9496 was confirmed in vivo in a juvenile rat uterine assay. Like fulvestrant, AZD9833 caused a significant reduction in uterine weight and endometrial thickness, while AZD9496 produced a significant increase in both parameters. In MCF7 xenografts, both oral SERDs caused equivalent anti-tumour and pharmacodynamic effects to a supraclinical exposure of fulvestrant. However, in the patient derived xenograft CTC174 harbouring an ESR1 D538G mutation, AZD9833 caused equivalent anti-tumour and ERα degradation effects to supraclinical fulvestrant. By contrast, AZD9496 produced significantly poorer maximal anti-tumour and pharmacodynamic effects in this model compared to fulvestrant. These data demonstrate that AZD9833 phenocopied fulvestrant preclinically, as a SERD and pure anti-estrogen. It is, therefore, a suitable candidate to test the hypothesis that increasing the exposure of a SERD above what is achieved with fulvestrant can provide additional patient benefit. AZD9496, on the other hand, demonstrated inferior ERα degradation in several ER+ breast cancer cell lines and partial agonism. This may explain the result of the clinical window of opportunity study, comparing AZD9496 to fulvestrant, in which AZD9496 failed to demonstrate superior degradation of ERα, downregulation of PR expression and reduction in Ki67 positivity. Citation Format: Mandy Lawson, Natalie Cureton, Michelle DuPont, Oona Delpuech, Dawn Trueman, Pei Zhang, Azadeh Cheraghchi-Bashi-Astaneh, Sladjana Gagrica, Gareth Maglennon, Daniel Sutton, Bairu Zhang, Jonathan Cairns, Jamie Scott, Teresa Klinowska, Christopher J. Morrow. Not all selective estrogen receptor degraders are equal - Preclinical comparison of AZD9833, AZD9496 and fulvestrant [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4379.

A phase Ib study to evaluate the oral selective estrogen receptor degrader GDC-9545 alone or combined with palbociclib in metastatic ER-positive HER2-negative breast cancer.

1023 Background: GDC-9545 is a potent, orally available, selective estrogen receptor degrader developed for the treatment of ER-positive (ER+) breast cancer alone or combined with CDK4/6 inhibitors. A first-in-human study evaluated 10-250 mg GDC-9545; tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and clinical results support expansion cohorts at ≥30 mg (Jhaveri et al., 2019). Methods: This study evaluated PK, PD, and efficacy of GDC-9545 alone and combined with palbociclib, ± LHRH agonist. Eligible patients (pts) had ER+ (HER2-) metastatic breast cancer (MBC) with ≤ 2 prior therapies in the advanced or metastatic setting. No prior treatment with CDK4/6 inhibitor was allowed in pts receiving palbociclib. Results: Eight-five pts were enrolled in 2 cohorts: GDC-9545 100 mg given once daily ± LHRH agonist (Cohort A), and GDC-9545 100 mg +125 mg palbociclib on a 21 day on/7 day off schedule ± LHRH agonist (Cohort B). Of the 39 pts in Cohort A, adverse events (AE) occurring in ≥10% of pts were fatigue, cough, back pain, pain in extremity, and arthralgia. Related AEs were generally Grade (G) 1-2; there were 3 related G3 AEs of fatigue, transaminase increased, and diarrhea. Two pts had GDC-9545 reduced, one due to G3 diarrhea and another due to G3 transaminitis. Of the 46 pts in Cohort B, AEs in ≥10% of pts were neutropenia, fatigue, bradycardia, diarrhea, constipation, dizziness, nausea, anemia, asthenia, thrombocytopenia, pruritus, and visual impairment. Twenty-six (57%) pts had G≥3 AEs. G≥3 neutropenia was reported in 23 (50%) pts. One pt had palbociclib reduced due to G3 febrile neutropenia. Eleven (13%) of 85 pts had G1 asymptomatic bradycardia considered related to GDC-9545. No pts in either cohort discontinued study treatment due to AEs. PK analysis and clinical data demonstrate no clinically relevant drug-drug interactions between GDC-9545 and palbociclib. Reduced ER, PR, and Ki67 levels, and an ER activity signature, were observed in paired pre- and on-treatment biopsies (n = 12). Eighteen of 33 pts in Cohort A had either confirmed partial responses or were on study 24 weeks (clinical benefit rate 55%). Clinical benefit was observed in pts with prior fulvestrant treatment and with detectable ESR1 mutations at enrollment. Clinical benefit data for both cohorts are anticipated to be mature in April 2020. Conclusions: GDC-9545 was well-tolerated as a single agent and in combination with palbociclib with encouraging PK, PD, and anti-tumor activity in ER+ MBC to support Phase III development. Clinical trial information: NCT03332797 .

A phase I dose escalation and expansion study of the next generation oral SERD AZD9833 in women with ER-positive, HER2-negative advanced breast cancer.

1024 Background: AZD9833 is an oral selective estrogen receptor (ER) antagonist and degrader (SERD) that has shown antitumor efficacy in a range of preclinical models of breast cancer. Methods: SERENA-1 (NCT03616587) is an ongoing Phase 1, open-label study in pre- and post-menopausal women, after ≥1 endocrine therapy and ≤2 prior chemotherapies for ER+ HER2- advanced breast cancer (ABC). The primary objective is to determine the safety and tolerability of AZD9833 once daily (QD), with dose-limiting toxicities (DLTs) in 28d defining the maximum tolerated dose. Secondary objectives include pharmacokinetics and anti-tumor response. Pharmacodynamic (PD) analysis includes ER modulation in paired tumor biopsies and ctDNA dynamic changes. Results: At 20 January 2020: 60 patients were treated (median prior therapies 5 (1–9); prior fulvestrant (Fv) 82%; prior CDK4/6i 68%) across five doses; 25 mg QD n=12, 75 mg QD n=12, 150 mg QD n=13, 300 mg QD n=13, 450 mg QD n=10. AZD9833 exposure was dose proportional after multiple doses, with a median terminal t1/2 of 12h. Treatment-related AEs experienced by ≥10% of patients were visual disturbances (53%; 91% G1, 6% G2, 3% G3), bradycardia/sinus bradycardia (45%; 93% G1, 7% G2), nausea (18%; 46% G1, 55% G2), fatigue (13%; 38% G1, 63% G2), dizziness (10%; 83% G1, 17% G3) vomiting (10%; 50% G1, 33% G2, 17% G3), and asthenia (10%; 67% G1, 33% G2). Three patients experienced DLTs: G3 QTcF prolongation (300 mg); G3 vomiting (450 mg); and a combination of G2 visual disturbance, G2 headache and G2 gait disturbance (450 mg). DLTs resolved with dose reduction. No G4 or 5 AEs were reported. Efficacy data are presented in the table below; objective response rate (ORR) and clinical benefit rate (CBR) at 24 weeks. Clinical trial information: NCT03616587 . ER signalling pathway modulation was observed in all dose cohorts. In patients where clinical responses occurred and paired biopsies obtained, 98% reduction in Ki67 was measured. Updated data will be presented. Conclusions: AZD9833 has an encouraging efficacy and dose-dependent safety profile. Evidence of clinical benefit and target engagement was observed at all dose levels in women with ER+ ABC, including patients pre-treated with CDK4/6i and Fv, and those with ESR1 mutations. A Phase 2 study comparing efficacy and safety of three doses AZD9833 vs Fv is planned (NCT04214288). [Table: see text]