Bioavailable Selective Estrogen Receptor Degrader Research Articles

Abstract PS15-02: A Phase Ⅰb Study of D-0502 as Monotherapy for Advanced or Metastatic ER-Positive and HER2-Negative Breast Cancer: Results from the Dose-Expansion Stage

Abstract Background: Endocrine therapy is the mainstay treatment for estrogen receptor (ER)-positive advanced breast cancer (BC). D-0502, an orally bioavailable selective estrogen receptor degrader (SERD), has previously demonstrated antitumor activity in various ER-positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer cell lines and xenograft models. The phase Ⅰ open-label study (NCT03471663) evaluated the safety, tolerability, pharmacokinetics (PK) and efficacy of D-0502 as monotherapy and in combination with palbociclib in female patients with ER+ and HER2- breast cancer. The dose escalation part of D-0502 monotherapy (phase Ⅰa) has been presented before (SABCS 2021, PS11-26 Abstract #1348). Here, we present the results of D-0502 monotherapy from the dose-expansion stage in phase Ⅰb study. Methods: In the single-agent dose-expansion stage of phase Ⅰb study, patients (n=60) received D-0502 (400 mg QD) in 28-day cycles. Eligible patients included females with confirmed ER+, HER2- locally advanced, or metastatic BC; ECOG 0-1; measurable disease (RECIST v1.1); premenopausal or postmenopausal status; adequate hematologic, hepatic and renal functions. The primary objectives are to characterize the safety of D-0502. The secondary objectives are to evaluate the preliminary anti-tumor activity and the PK characteristic. Results: As of April 07, 2023, 60 female patients were enrolled and treated with 400mg single-agent D-0502. Median age was 57 (range: 32-82) years, 55.0% had an ECOG PS of 1. Disease progression resulting in treatment discontinuation occurred in 66.7% (40/60) of patients, and 6.7% (4/60) of patients discontinued treatment because of AEs. Treatment-related adverse events (TRAEs) were reported in 57 pts (95.0%), most of which were grade 1-2. No grade 4/5 TRAE has been reported. The incidence of serious adverse events was 6.7% (4/60). The most common (≥ 15%) TRAEs included vomiting, dizziness, nausea, increased aspartate aminotransferase and alanine aminotransferase, anaemia, decreased appetite, diarrhoea, and malaise. In the 51 efficacy evaluable patients, 8 patients had partial response (PR) and 27 had stable disease (SD); objective response rate (ORR) and disease control rate (DCR) were 15.7% (8/51) and 68.6% (35/51), respectively. The clinical benefit rate (CBR: CR + PR + SD ≥24 weeks) was 47.1% (24/51). The median PFS was 5.6 months (95% Cl: 2.0, 10.0). Conclusion: D-0502 monotherapy showed promising antitumor activity and tolerable toxicity in female patients with ER+ and HER2- locally advanced or metastatic BC. Currently this treatment is being evaluated in a phase Ⅲ study for patients with ER+ and HER2- locally advanced or metastatic BC in China. Citation Format: Jiayu Wang, Tao Sun, Qingyuan Zhang, Yanxia Shi, Xu Wang, Yiding Chen, Quchang Ouyang, Kunyan Li, Manojkumar Bupathi, w. Jeffery Edenfield, Andrea L.M. Silber, Hong Zong, Erika Hamilton, Dejan Juric, Kate Lathrop, Yihong Zhang, Kathryn Stazzone, Zhe Shi, Yaolin Wang, Ling Zhang, Binghe Xu. A Phase Ⅰb Study of D-0502 as Monotherapy for Advanced or Metastatic ER-Positive and HER2-Negative Breast Cancer: Results from the Dose-Expansion Stage [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS15-02.

Abstract 474: Preclinical development of an oral selective estrogen receptor degrader (SERD) TFX06 for the treatment of ER+HER2− breast cancer

Abstract Breast cancer (BC) has recently surpassed lung cancer to become the most commonly diagnosed cancer in women worldwide. Approximately 70% of BC was ER+, in which estrogen receptor α (ERα, encoded by ESR1 gene) drives dysregulated cell proliferation. In clinic, ER+ BC has been effectively treated by endocrine therapy targeting estrogen or ER. As the first approved ERα degrader, fulvestrant has proven to be effective for locally advanced or metastatic BC. However, its clinical utilization is hampered by inconvenience of intramuscular injection, as well as its poor PK/PD profile and limited efficacy, especially in the patient population that developed ESR1 mutation-conferring drug resistance after the earlier line of treatment with an aromatase inhibitor. Thus, developing an oral and more effective therapy for ER+ BC remains an unmet medical need. We report herein discovery and preclinical investigation of a novel orally bioavailable SERD TFX06. TFX06 demonstrated potent binding affinity to ERα with a Ki of 0.10 nM and preferably antagonized ERα to ERβ with an IC50 value of 0.086 nM and 2.83 nM, respectively. TFX06 potently induced ERα degradation in ER+ BC cells and substantially inhibited cell proliferation in BC cell lines with ER wild type (WT), and MCF-7 cells expressing Y537S or D538G mutants. Oral administration of TFX06 demonstrated impressive antitumor efficacy in ER WT (TGI = 101%) and ER D538G-expressing (TGI = 99%) MCF-7 cell line-derived xenograft (CDX) models in mice. Similarly, in an ER+ BC patient-derived xenograft (PDX) model (HCI-013) with ER Y537S mutation, TFX06 also exerted excellent antitumor activity (TGI = 99%). Furthermore, TFX06 in combination with palbociclib achieved synergistic activity in MCF-7 CDX model. Moreover, TFX06 exhibited an excellent correlation between systemic/local drug exposure, pharmacodynamic modulation (i.e., ERα downregulation) and antitumor activity. Collectively, these findings demonstrate that TFX06 is a novel, orally bioavailable SERD. TFX06 demonstrates substantial antitumor activity in both in vitro and in vivo preclinical tumor models, including those expressing ESR1 mutations, through downregulation of ERα. The preclinical data warranted the clinical evaluation of TFX06 in human with an IND application submitted to the China NPMA. Citation Format: Jinping Wu, Ke An, Douglas D. Fang, Jianyu Lu, Lihong Hu, Jing Wang, Kaili Zhang, Yuanfeng Xia, Charles Ding, Shuhui Chen, Sha Wei. Preclinical development of an oral selective estrogen receptor degrader (SERD) TFX06 for the treatment of ER+HER2− breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 474.

Design, synthesis and biological evaluation of fluorinated selective estrogen receptor degraders (FSERDs) --- A promising strategy for advanced ER positive breast cancer

Although endocrine therapies involving pharmaceuticals, such as tamoxifen and aromatase inhibitors, had initially demonstrated good responses in patients with estrogen receptor-positive (ER+) breast cancer, they often led to drug resistance. ER plays a vital role in the progression of metastatic diseases. Fulvestrant, a first generation selective estrogen receptor degrader (SERD), can effectively downregulate the ER protein and inhibit its downstream signaling pathways. However, as the drug needs to be intramuscularly injected, its widespread use is limited owing to poor patient compliance. Herein, we described a novel class of orally bioavailable fluorine-substituted SERDs that exhibit improved pharmacokinetic profiles. We substituted the hydroxyl group of clinical SERD candidate 6 with a fluorine atom to diminish phase II metabolism. The subsequent structure–activity relationship (SAR) investigation identified 22h and 27b, which can effectively degrade ER in a dose-dependent manner and exhibit considerable antiproliferative potency and efficacy in vitro and in vivo. The excellent pharmacokinetic profiles of 27b render it promising candidate of clinically useful oral SERD.

Abstract P6-10-06: A preoperative window-of-opportunity study of imlunestrant in estrogen receptor-positive, HER2-negative early breast cancer: Results from the EMBER-2 study

Abstract Background: Imlunestrant is a novel, orally bioavailable selective estrogen receptor degrader (SERD) with pure antagonistic properties that result in sustained inhibition of estrogen receptor (ER)-dependent gene transcription and cell growth. In a phase 1 study, imlunestrant monotherapy showed favourable safety, pharmacokinetics (PK) and preliminary efficacy in heavily pre-treated ER-positive (ER+) advanced breast cancer patients (Jhaveri ASCO 2022). Here, we present pharmacodynamic (PD) data from the preoperative window of opportunity (WOO) study (EMBER-2, NCT04647487), evaluating the biological activity of imlunestrant monotherapy in ER+, HER2-negative (HER2-) early breast cancer (EBC). Methods: Post-menopausal women with stage I–III operable ER+ (>50%) or Allred score >5, HER2- untreated EBC ≥1 cm in diameter were randomized 1:1 to imlunestrant 400 mg once daily (QD) or imlunestrant 800 mg QD for 15 days (treatment window of -2 to +7 days) up to the surgery date. Pre- and on-treatment tumor samples were compared for changes in PD biomarkers. Primary study objective was change in ER expression (measured by IHC and quantified by H-score). Secondary objectives were change in progesterone receptor (PR) expression (measured by IHC and quantified by H-score) and Ki-67 (measured by IHC and expressed by percentage positive scoring) along with evaluation of safety and tolerability. Results: From Apr 28, 2021, to Mar 11, 2022, 58 patients were enrolled of which 54 were biomarker-evaluable for ER expression (400 mg: n = 28; 800 mg: n = 26). Patient demographics and tumor characteristics for all enrolled patients were similar across cohorts, with a median age of 64 years (50-83), 72% invasive ductal carcinoma (IDC), 28% invasive lobular carcinoma (ILC), 59% stage I, 36% stage II and 5% stage III disease. 91% of the patients had a compliance rate higher than 80%. Among biomarker evaluable patients, relative reduction in PD biomarkers after a median of 15 days (range 13 to 23 days) of treatment are presented in Table 1. There was no significant difference in PD biomarker modulation noted between the two imlunestrant doses (400 mg vs 800 mg) or based on tumor histology (IDC, ILC). Imlunestrant was well tolerated. There were no discontinuations due to adverse events (AEs). Treatment-related AEs (TRAEs) were mainly grade 1, most commonly: fatigue (10%), diarrhea (9%), hot flushes (7%), and nausea (5%). There were no TRAEs of diarrhea and nausea observed at the 400 mg dose. No grade 3 or higher TRAEs were reported. Conclusion: Imlunestrant demonstrated evidence of target engagement along with consistent biological activity across all evaluated dose levels and was well tolerated in an EBC population, further supporting continued adjuvant development in the ongoing EMBER-4 study. Additional biomarker analyses for the EMBER-2 study are also planned. Table 1. Relative reduction in PD biomarkers from Baseline to Day 15 Citation Format: Patrick Neven, Nicole Stahl, Maria Vidal, Miguel Martín, Nadia Harbeck, Peter A. Kaufman, Francois-Clement Bidard, Peter A. Fasching, Philippe Aftimos, Erika Hamilton, Stacey Carter, Peter Schmid, Duncan Wheatley, Manali Bhave, Kelly K. Hunt, Swati A. Kulkarni, Roohi Ismail-Khan, Claudia Karacsonyi, Shawn T. Estrem, Umut Ozbek, Bastien Nguyen, Eva Ciruelos. A preoperative window-of-opportunity study of imlunestrant in estrogen receptor-positive, HER2-negative early breast cancer: Results from the EMBER-2 study. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-06.

Abstract OT1-01-02: EMBER-4: A phase 3 adjuvant trial of imlunestrant vs standard endocrine therapy (ET) in patients with ER+, HER2- early breast cancer (EBC) with an increased risk of recurrence who have previously received 2 to 5 years of adjuvant ET

Abstract Background: Adjuvant ET has been the standard of care for patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) EBC. A significant proportion of patients with increased risk still experience disease relapse despite available ET and more optimum ET is needed to prevent patients developing incurable metastatic cancer. Distant recurrence risk ranges from 20% to 40% after 5 years of adjuvant ET, depending on clinicopathological (clin-path) features at diagnosis. Consequently, there is a need to further optimize adjuvant treatment, particularly in those patients who are at increased risk of recurrence. Imlunestrant is an orally bioavailable selective estrogen receptor degrader (SERD) with pure antagonistic properties and the potential to overcome ET resistance. In early phase trials, imlunestrant monotherapy showed favorable safety with pharmacokinetic (PK) exposures exceeding fulvestrant and preliminary efficacy in ER+, HER2- advanced breast cancer patients (EMBER, Jhaveri 2022) along with robust biological/pharmacodynamic activity and tolerability in EBC (EMBER-2, Neven). Trial Design: EMBER-4 is a randomized, open-label, global phase 3 study comparing imlunestrant versus physicians’ choice of ET, in patients who are at an increased risk of recurrence based on clin-path features and who have received 2 to 5 years of standard adjuvant ET. Approximately 6,000 patients will be randomized 1:1 to receive imlunestrant (400 mg daily) for 5 years or physicians’ choice of adjuvant ET (tamoxifen or an aromatase inhibitor, AI, dosed per label). Study treatment duration is 5 years. Males and pre-/peri-menopausal women will receive concomitant treatment with a GnRH agonist if receiving imlunestrant or an AI. Stratification factors include time from initial adjuvant ET, use of prior adjuvant cyclin dependent kinase 4/6 inhibitors, nodal status, menopausal status, and geographic region. Eligibility criteria: Eligible patients are adult males and females (pre-, peri- or postmenopausal) with ER+, HER2- EBC who have completed definitive locoregional therapy and have received 2 to 5 years of prior adjuvant ET without disease recurrence, but who are at increased risk of recurrence based on clin-path features at diagnosis. Prior (neo) adjuvant chemotherapy and/or targeted therapy with a CDK4/6- or PARP- inhibitor is permitted. Study endpoints: The primary endpoint is invasive disease-free survival (IDFS), excluding second non-breast primary invasive cancers. Key secondary endpoints include distant relapse-free survival, overall survival, IDFS including second non-breast primary invasive cancers, safety, PK and patient reported outcomes. Recruitment for EMBER-4 begins globally in Q4 2022. Citation Format: Komal Jhaveri, Joyce O’Shaughnessy, Fabrice Andre, Matthew P. Goetz, Nadia Harbeck, Miguel Martín, Francois-Clement Bidard, Zachary M. Thomas, Suzanne Young, Roohi Ismail-Khan, Lillian M. Smyth, Michael Gnant. EMBER-4: A phase 3 adjuvant trial of imlunestrant vs standard endocrine therapy (ET) in patients with ER+, HER2- early breast cancer (EBC) with an increased risk of recurrence who have previously received 2 to 5 years of adjuvant ET [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-01-02.

Abstract PD13-12: PD13-12 Imlunestrant, an oral selective estrogen receptor degrader, in combination with abemaciclib with or without an aromatase inhibitor, in estrogen receptor-positive advanced breast cancer: Results from the phase 1a/b EMBER study

Abstract Background: Imlunestrant is a novel, orally bioavailable selective estrogen receptor degrader (SERD) with pure antagonistic properties that result in sustained inhibition of estrogen receptor (ER)-dependent gene transcription and cell growth. Preclinically, imlunestrant has favorable efficacy and pharmacokinetic (PK) properties, including antitumor activity in ESR1-mutant models, along with enhanced efficacy when combined with abemaciclib. In dose escalation (Phase 1a) and dose expansion (Phase 1b) in the EMBER study, imlunestrant monotherapy was well tolerated with favorable safety, PK and encouraging antitumor activity in heavily pre-treated ER+, HER2- advanced breast cancer (aBC) patients (Jhaveri, ASCO 2022); imlunestrant recommended phase 2 dose (RP2D) was determined as 400mg QD. Here, we present the phase 1b dose expansion of imlunestrant with abemaciclib ± aromatase inhibitor (AI) in EMBER (NCT04188548). Methods: Phase 1b enrolled patients with ER-positive (ER+), HER2-negative (HER2-) aBC [shown prior endocrine therapy (ET) sensitivity or untreated de novo aBC; ≤1 prior therapies for aBC but must not have received a prior CDK4/6 inhibitor]. Patients were randomized, based on menopausal status and presence of visceral metastases, to receive imlunestrant + abemaciclib OR imlunestrant + abemaciclib + AI. Men and premenopausal women received a concomitant GnRH agonist. Serial plasma samples were obtained for PK and ctDNA analysis. Key endpoints included safety and tolerability, PK, objective response rate (ORR) per RECIST v1.1 (ORR: complete response [CR] or partial response [PR]) in patients with measurable disease), and clinical benefit rate (CBR: CR or PR, or stable disease ≥24 weeks) in patients enrolled ≥24 weeks prior to data cut. Results: As of 26 May 2022, 85 patients have received imlunestrant [n=80 at 400 mg (RP2D); n=5 at 800 mg] in combination with abemaciclib (150mg twice daily) ± AI. Forty-eight (56%) patients had visceral disease and 9% had at least 1 ESR1 mutation detected in ctDNA at baseline. Patients were predominantly (75%) ET pre-treated, 51% with an AI; and 8% and 5%, respectively, had received prior chemotherapy or fulvestrant, for aBC. The most common treatment-emergent adverse events were diarrhea (87%), nausea (58%), fatigue (45%), neutropenia (39%) and abdominal pain (34%). The majority of treatment-related AEs (TRAEs) were Grade 1 or 2, with Grade ≥3 TRAEs occurring in 36% of patients. Most common TRAEs at RP2D (400mg) were diarrhea (81%), nausea (45%), fatigue (33%) and neutropenia (35%). No patient discontinued treatment due to an AE. Dose reductions were required of both imlunestrant and abemaciclib in 6 (7%) patients and of either imlunestrant in 3 (4%) or abemaciclib in 22 (26%) patients. Preliminary efficacy is presented in Table 1. Conclusion: Imlunestrant in combination with abemaciclib ± AI showed acceptable safety and tolerability, comparable to the MONARCH 2 trial of fulvestrant + abemaciclib, along with evidence of clinical activity in ER+, HER2- aBC patients. These data suggest no additive toxicity of imlunestrant when administered in combination with abemaciclib, along with comparable clinical benefit to that observed in MONARCH 2. Further data will be presented at the meeting. The phase 3, EMBER-3 study is ongoing; evaluating imlunestrant, investigator’s choice ET, and imlunestrant + abemaciclib in ET pre-treated ER+, HER2- aBC patients (NCT04975308). Table 1. Preliminary efficacy in combination therapies in EMBER Citation Format: Komal Jhaveri, Hwei-Chung Wang, Cynthia Ma, Elgene Lim, Jessica J. Tao, Luis Manso, Jean-Yves Pierga, Ritesh Parajuli, Yolanda Jerez Gilarranz, Yen-Shen Lu, Muralidhar Beeram, Tim Larson, Ajay Dhakal, Roohi Ismail-Khan, Claudia Karacsonyi, Shanshan Cao, Cynthia Osborne, Shawn T. Estrem, Bastien Nguyen, Yujia Li, Eunice Yuen. PD13-12 Imlunestrant, an oral selective estrogen receptor degrader, in combination with abemaciclib with or without an aromatase inhibitor, in estrogen receptor-positive advanced breast cancer: Results from the phase 1a/b EMBER study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-12.

A phase 1a/b trial of imlunestrant (LY3484356), an oral selective estrogen receptor degrader (SERD) in ER-positive (ER+) advanced breast cancer (aBC) and endometrial endometrioid cancer (EEC): Monotherapy results from EMBER.

1021 Background: Imlunestrant is a novel, orally bioavailable SERD with pure antagonistic properties that result in sustained inhibition of ER-dependent gene transcription and cell growth. In dose escalation, imlunestrant showed favorable safety, pharmacokinetics (PK) and preliminary efficacy in patients with ER+, HER2- aBC and ER+ EEC (Phase 1a EMBER, Jhaveri 2021). Here we present updated data from the dose escalation (Phase 1a) and dose expansion (Phase 1b) of imlunestrant monotherapy in EMBER (NCT04188548). Methods: Phase 1a/1b enrolled patients with ER+ aBC (prior ET sensitivity; ≤3 prior therapies for aBC in Phase 1a following protocol amendment and ≤2 in Phase 1b) and ER+ EEC (prior platinum therapy; no prior fulvestrant or aromatase inhibitor). Premenopausal women received a concomitant GnRH agonist. Serial plasma samples were obtained for PK and ctDNA analysis. Key endpoints included recommended phase 2 dose (RP2D) determination, safety and tolerability, PK, objective response rate per RECIST v1.1 (ORR: complete response [CR] or partial response [PR]) in patients with measurable disease and ≥1 post-baseline tumor assessment or discontinued prior to tumor assessment, and clinical benefit rate (CBR: CR or PR, or stable disease ≥24 weeks) in patients enrolled ≥24 weeks prior to data cut. Results: As of January 14, 2022, 138 patients (n = 114 aBC, n = 24 EEC) received imlunestrant monotherapy at doses ranging from 200-1200 mg QD. Median age was 62.0 years (range 32-95). Median number of prior therapies for aBC and EEC was 2 (range 0-8) and 1 (0-5), respectively. aBC patients had received a prior ET (94.7%), CDK4/6 inhibitor (92.1%), fulvestrant (50.9%) and chemotherapy (26.3%). No dose-limiting toxicities were observed. Most treatment-emergent adverse events (TEAEs) were grade 1. At the RP2D (400 mg QD, n= 69), the most common all grade TEAE’s were nausea (33.3%), fatigue (27.5%), and diarrhea (23.2%). Across all doses, the incidence of treatment-related grade 3 AEs was low (3.6%). No patient discontinued due to a TEAE. In evaluable aBC patients, ORR was 8.0% (6/75) and CBR was 40.4% (42/104). In evaluable EEC patients, ORR was 5.0% (1/20 had a PR- ongoing pending confirmation) and CBR was 47.1% (8/17). Clinical benefit was observed regardless of baseline ESR1 mutation status as determined by ctDNA sequencing. Additional biomarker analyses will be presented at the meeting. Conclusions: Imlunestrant continues to demonstrate a favorable side effect profile, with no cardiac or opthalmic safety signals, and has continued evidence of clinical activity in heavily pre-treated ER+ aBC and EEC patients. Clinical trial information: NCT04188548.

Abstract OT2-11-01: EMBER-3: A randomized phase 3 study of LY3484356, a novel, oral selective estrogen receptor degrader vs investigator’s choice of endocrine therapy of either fulvestrant or exemestane, in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer previously treated with endocrine-based therapy

Abstract Background: The estrogen receptor (ER) is the key therapeutic target for ER-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. Novel degraders of ER may overcome resistance to available endocrine therapy (ET) while providing consistent oral bioavailability and convenience of administration. LY3484356 is a novel, orally bioavailable selective estrogen receptor degrader (SERD) with pure antagonistic properties resulting in sustained inhibition of ER-dependent gene transcription and -cell growth. In the phase 1a/b EMBER trial, LY3484356 monotherapy demonstrated a favorable safety profile with pharmacokinetic (PK) exposures that exceeded fulvestrant. LY3484356 also showed single agent efficacy in patients with ER+, HER2- metastatic breast cancer (MBC), including in patients with baseline ESR1 mutations and fulvestrant- and/or CDK4/6 inhibitor- refractory disease1. Trial Design: EMBER-3 is a randomized, open-label, global phase 3 study comparing LY3484356 versus investigator’s choice of ET (fulvestrant or exemestane), in patients with ER+, HER2- locally advanced or MBC. Approximately 500 patients will be randomized 1:1 to receive LY3484356 (400 mg PO QD continuously in 28-day cycles) or investigator’s choice of ET (dosed per label). Males and pre-menopausal women will receive concomitant treatment with a GnRH agonist. Eligibility criteria: Eligible patients are adult males and females (pre- or post-menopausal) with ER+, HER2- locally advanced or MBC who have received prior treatment with an aromatase inhibitor, alone or in combination with a CDK4/6 inhibitor. No other prior therapy for advanced disease is permitted. Patients must have evaluable disease (measurable or non-measurable bone only). Study endpoints: The primary endpoint is investigator-assessed progression-free survival (PFS) per RECIST v1.1. Secondary endpoints include BIRC-assessed PFS, overall survival, objective response rate, duration of response, clinical benefit rate, safety and tolerability, PK and patient reported outcomes. Recruitment for the EMBER-3 study begins in Q3 2021. Reference: 1Jhaveri et al. J Clin Oncol 2021 39:15_suppl, 1050 Citation Format: Komal Jhaveri, Nadia Harbeck, Philippe Aftimos, Sung-Bae Kim, Xavier Pivot, Cristina Saura, Giuseppe Curigliano, Monica Casalnuovo, Xuejing Aimee Wang, Suzanne R.L. Young, Lillian Smyth, Joyce O'Shaughnessy. EMBER-3: A randomized phase 3 study of LY3484356, a novel, oral selective estrogen receptor degrader vs investigator’s choice of endocrine therapy of either fulvestrant or exemestane, in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer previously treated with endocrine-based therapy [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 OT2-11-01.

Abstract P1-17-02: ZN-c5, an oral selective estrogen receptor degrader (SERD), in women with advanced estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer

Abstract Background: Hormone receptor+/HER2- breast cancer is the most common subtype of breast cancer. Resistance to endocrine therapy is a major clinical challenge. Although fulvestrant binds and degrades the ER and shows anti-tumor activity in patients with advanced breast cancer, intramuscular injection is inconvenient and precludes achievement of higher and potentially more efficacious exposure. ZN-c5 is a novel, orally bioavailable SERD with high potency and has demonstrated activity in estrogen-dependent tumor models. Methods: This Phase 1/2, open-label, multicenter study is evaluating the safety, pharmacokinetics and preliminary anti-tumor activity of ZN-c5 as monotherapy or in combination with palbociclib. In the Phase 1 portion evaluating ZN-c5 as monotherapy, participants were adult, post-menopausal (or receiving a gonadotropin-releasing hormone agonist) women with advanced adenocarcinoma of the breast, ER+/HER2- disease, and sensitive to endocrine therapy for metastatic disease (partial response [PR], complete response or stable disease [SD] lasting > 6 months or disease recurrence after at least 24 months of adjuvant endocrine treatment). ZN-c5 was administered orally and continuously in 28-day cycles until disease progression or unacceptable toxicity. Dose escalation cohorts of subjects were enrolled at several dose levels of ZN-c5, based on a modified 3+3 design. Enrollment in the Phase 1 ZN-c5 monotherapy dose escalation and expansion has been completed and results are presented. Phase 1 testing of ZN-c5 in combination with palbociclib and Phase 2 testing in monotherapy are ongoing and will be presented at a future meeting. Results: In Phase 1 monotherapy, a total of 56 female subjects were enrolled to receive ZN-c5 at dose levels of 50 mg once daily (QD, n=16), 75 mg QD (n=3), 100 mg QD (n=3), 75 mg twice daily (BID, n=6), 150 mg QD (n=15), 150 mg BID (n=3), or 300 mg QD (n=10). Median age was 58.5 years (range, 38 - 89) and ECOG performance status was 0 (55%) or 1 (45%). Subjects had a median of 2 prior therapies for advanced/metastatic disease (range, 0 - 9), with a median of 2 prior hormonal-based therapies (range, 0 - 6) and a median of 0 prior chemotherapies (range, 0 - 3). Twenty-six subjects (46%) received prior fulvestrant and 38 (68%) received a prior CDK4/6 inhibitor. Twenty subjects (38%) had a baseline ESR1 mutation. The cut-off date for this analysis was 11 May 2021. There was no increase in severity of treatment-emergent adverse events (TEAEs) with increase in dose level. No dose-limiting toxicities were reported. The most common TEAEs were nausea (30%), fatigue (25%), and arthralgia (20%). Grade 3 TEAEs reported in > 1 subject were gamma-glutamyltransferase (GGT) increased and hyponatremia (2 subjects each); no Grade 4 TEAEs were reported. Among treatment-related events, the most common were hot flushes and nausea (14% each); the only Grade 3 events were GGT increased and hypersensitivity in 1 subject each. ZN-c5 was rapidly absorbed, with a median Tmax of 2 to 4 hours. AUC and Cmax on Days 1 and 15 were less than dose proportional. No ZN-c5 accumulation after 15 days of dosing was observed. Confirmed PRs have been observed in 2 subjects (at 150 and 300 mg QD, respectively), and 14/45 (31%) evaluable subjects have experienced clinical benefit (PR or SD ≥ 24 weeks). Five of the 14 subjects with long SD received prior fulvestrant. Median progression-free survival (PFS) was 3.8 months (95% CI: 3.2, 5.3). Conclusions: In this first-in-human study, ZN-c5 monotherapy was well tolerated and showed clinical benefit, including confirmed PRs, in subjects with advanced ER+/HER2- breast cancer. These data warrant further evaluation of ZN-c5 as monotherapy and in combination with palbociclib. Citation Format: Kevin Kalinksy, Vandana Abramson, Pavani Chalasani, Hannah M. Linden, Jasmina Alidzanovic, Rachel M. Layman, Živko Vranješ, Julie R. Nangia, Katherine D. Crew, Zoran Andric, Marijana Milovic-Kovacevic, Jasna Trifunovic, Jose Suarez, Matt Suster, Mieke Ptaszynski, Joanne Mortimer. ZN-c5, an oral selective estrogen receptor degrader (SERD), in women with advanced estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer [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 P1-17-02.

Species-dependent hepatic and intestinal metabolism of selective estrogen receptor degrader LSZ102 by sulfation and glucuronidation

1. LSZ102 is an orally bioavailable selective estrogen receptor degrader in clinical development for the treatment of breast cancer. Preclinical studies showed efficacy in xenograft models on oral dosing. However, oral bioavailability was relatively low in several preclinical species (7-33%), and was associated with first-pass metabolism, particularly intestinal first-pass. 2. To investigate metabolism and first-pass effects, metabolites were analysed in human plasma samples after oral dosing of LSZ102 to patients, rat plasma samples after oral dosing of [14C]LSZ102, and in vitro incubations of [14C]LSZ102 with human and rat hepatocytes and intestinal S9 fractions. The kinetics of human sulfotransferase enzymes potentially involved in metabolism of LSZ102 were characterized. 3. Sulfate metabolites were found to be the major components in human plasma, as well as in human hepatocytes and intestinal S9 fractions. Contrastingly, glucuronidation was predominant in rat plasma, hepatocytes and intestinal S9. LSZ102 was found to be metabolized by several human sulfotransferases expressed in liver and intestine. The combined metabolism data in rat and human provide supporting evidence for an extensive intestinal first-pass metabolism effect via sulfation in human but glucuronidation in rat. 4. As LSZ102 is metabolized by a number of different sulfotransferases, drug-drug interactions resulting from the inhibition of one sulfotransferase are unlikely. 5. Despite the observed species difference in metabolism, the major human metabolites of LSZ102, sulfate M5, glucuronide M4, and secondary glucuronide/sulfate metabolite M12, have no or weak pharmacological activity and are not considered a toxicity risk as they are phase II conjugative metabolites.

Accelerating drug access from advanced to early breast cancer: the special case of oral selective estrogen receptor degraders.

For hormone receptor positive breast cancer, the development of endocrine resistance commonly occurs, presenting as either disease progression in the metastatic setting or recurrence during or following adjuvant endocrine therapy. Various mechanisms of resistance have been described. In order to reduce or overcome endocrine resistance, there has been substantial interest in developing potent and orally bioavailable selective estrogen receptor degraders (SERDs) for metastatic disease and select patients with early-stage estrogen receptor positive breast cancer. At least 11 oral SERDs have entered clinical development. We review current studies in both the metastatic and neoadjuvant/adjuvant setting and present the available evidence of benefit and toxicity for these novel agents. Further characterization of changes to tissue-based biomarkers such as estrogen receptor, progesterone receptor and Ki67 expression and blood-based biomarkers such as ctDNA and estrogen receptor 1 mutation may help to refine therapeutic strategies, combinations, and patient selection to identify women who are most likely to benefit from these novel endocrine agents. Although SERDs have clear therapeutic potential based on nonclinical studies and have demonstrated early signs of activity in phase I and II studies in the metastatic setting, ongoing research is needed to clarify when and in whom these agents may have greatest clinical benefit.

A New Era in ER+ Breast Cancer: Best-in-Class Oral Selective Estrogen Receptor Degrader (SERD) Designed as an Endocrine Backbone Treatment

There has been intense interest in developing orally bioavailable SERDs, energized by the recent discovery of treatment-resistant ESR1 mutations. Overcoming the two decades long challenge of combining all the desirable activities and properties into one molecule, GDC-9545 (giredestrant) was identified with an exceptional preclinical profile. This Viewpoint seeks to place this molecule in the historical context of previously reported oral SERDs and highlights the exciting clinical potential for a best-in-class oral SERD.

Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical Perspective.

Estrogen receptor-positive (ER+) is the most common subtype of breast cancer. Endocrine therapy is the fundamental treatment against this entity, by directly or indirectly modifying estrogen production. Recent advances in novel compounds, such as cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), or phosphoinositide 3-kinase (PI3K) inhibitors have improved progression-free survival and overall survival in these patients. However, some patients still develop endocrine resistance after or during endocrine treatment. Different underlying mechanisms have been identified as responsible for endocrine treatment resistance, where ESR1 gene mutations are one of the most studied, outstanding from others such as somatic alterations, microenvironment involvement and epigenetic changes. In this scenario, selective estrogen receptor degraders/downregulators (SERD) are one of the weapons currently in research and development against aromatase inhibitor- or tamoxifen-resistance. The first SERD to be developed and approved for ER+ breast cancer was fulvestrant, demonstrating also interesting activity in ESR1 mutated patients in the second line treatment setting. Recent investigational advances have allowed the development of new oral bioavailable SERDs. This review describes the evolution and ongoing studies in SERDs and new molecules against ER, with the hope that these novel drugs may improve our patients’ future landscape.

Abstract 1236: Preclinical characterization of LY3484356, a novel, potent and orally bioavailable selective estrogen receptor degrader (SERD)

Abstract Nearly 70% of newly diagnosed breast cancers are estrogen receptor alpha (ERα) positive, for which endocrine therapy is a primary treatment. However, approximately 40% of those patients on endocrine therapy develop resistance, which includes mutations in ERα (ESR1) that drive constitutive activation of the receptor. One approach to overcome this resistance is to develop a potent degrader and pure antagonist of the estrogen receptor, which can effectively suppress estrogen receptor signaling. Fulvestrant, a pure antagonist and selective estrogen receptor degrader (SERD) is approved for the treatment of HR+/HER2- metastatic breast cancer. However, fulvestrant is limited by poor pharmacokinetics properties, limited exposure and sub-optimal in vivo estrogen receptor degradation. Here we describe the preclinical profile of LY3484356, an oral SERD and pure estrogen receptor antagonist, with potent activity against the wild type and mutant estrogen receptor. LY3484356 has Ki values of 0.64 nM and 2.8 nM against wild type ERα and Y537S mutant ERα proteins, respectively. It is a potent and highly efficient degrader of wild type ERα and Y537N mutant ERα proteins in cells, with IC50 values 3.0 nM and 9.6 nM, respectively. LY3484356 is also a potent inhibitor of ERα-mediated transcription in vitro and in vivo. It inhibits cell proliferation in wild type ERα and ESR1 Y537N mutant breast cancer cell lines, with average IC50 values of 3 nM and 17 nM, respectively. In a panel of breast cancer cell lines, 11 out of 12 ER+ breast cancer cell lines were sensitive to LY3484356 (IC50 less than 100 nM), whereas all ER- cell lines tested were insensitive. LY3484356 has demonstrated sustained and prolonged target inhibition (>75% inhibition of PGR transcription up to 96h after last dose) in ESR1 wild type (MCF7) and ESR1 Y537S mutant (ST941/C) xenograft tumors. Consistent with its profile as a pure antagonist, immature rat studies demonstrated no significant effect on uterine wet weight. LY3484356 demonstrated significant tumor growth inhibition and tumor regressions in wild type ESR1 breast cancer xenograft models such as MCF7, T47D and ZR-75-1, as well as ESR1 mutant breast cancer PDX models. LY3484356 has shown synergy or additivity in combination with CDK4/6 inhibitor abemaciclib, mTOR inhibitor everolimus and PIK3CA inhibitor alpelisib in inhibiting cell proliferation in ER+ breast cancer cell lines in vitro and tumor growth inhibition in relevant xenograft or PDX models in vivo. The first-in-human Phase 1/2 clinical trial of LY3484356 (EMBER, ClinicalTrials.gov NCT04188548) is currently ongoing and a window-of-opportunity study evaluating the pharmacodynamic effects of LY3484356 in early stage breast cancer is expected to begin early 2021. Citation Format: Shripad V. Bhagwat, Baohui Zhao, Weihua Shen, Cecilia Mur, Robert Barr, Lisa J. Kindler, Almudena Rubio, Jolie A. Bastian, Jeffrey D. Cohen, Brian E. Mattioni, Eunice Yuen, Thomas K. Baker, Mark A. Castanares, Dongling Fei, Jason R. Manro, Maria Jose Lallena, Sheng-Bin Peng, Alfonso de Dios. Preclinical characterization of LY3484356, a novel, potent and orally bioavailable selective estrogen receptor degrader (SERD) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1236.

Abstract 406: Development of a gene signature assessing ER modulation by SERMs and SERDs as a target engagement biomarker for endocrine therapy in breast cancer

Abstract Hormone or endocrine therapy is the primary treatment for estrogen receptor-positive (ER+) breast cancer. Selective Estrogen Receptor Modulators (SERMs) have been used for women with ER+ invasive cancer in the adjuvant setting. However, they do not fully inhibit ER transcriptional activity. Therefore, selective estrogen receptor degraders (SERDs) such as fulvestrant have been developed to overcome the partial modulation of ER transcriptional activity by SERMs. However, the clinical benefit of fulvestrant is limited by its pharmaceutical properties, and burden of intramuscular administration. We developed amcenestrant (SAR439859), a novel, orally bioavailable SERD to improve drug properties and is under clinical investigation.To assess the relative ER modulating activity, we developed a gene signature by transcriptional profiling of multiple ER+ cell lines. We identified 87 genes that were either up- or down-regulated by estradiol and reversed by SERM and SERD compounds or differentially expressed between a SERM/SERD compound and estradiol. We assessed ER activity scores by applying Gene Set Variation Analysis (GSVA) method to the ER gene signature and evaluated the effect of 6 SERD compounds. Amcenestrant and fulvestrant illuminated a deeper inhibition of ER activity compared to the other compounds. In addition, these ER activity scores could potentially be utilized in clinics as pharmacodynamic (PD) biomarker to assess target engagement. We applied this ER signature to RNA-seq data from paired pre- and post-treatment tumor biopsies from patients of NCT03284957 study (AMEERA-1), an open-label, phase 1/2 study of amcenestrant in postmenopausal women with ER+/HER2- metastatic breast cancer. The results of our analysis showed that ER activity is down-regulated by amcenestrant (oral SERD) for 3 out of 5 patients, in parallel with clinical benefit. Validation in a larger patient cohort is needed. Citation Format: Joon Sang Lee, Maysoun Shomali, Monsif Bouaboula, Emma Wang, Wilson Dos-Santos-Bele, Colette Dib, Eric Boitier, Vasiliki Pelekanou, Nils Ternes, Alice Gosselin, Patrick Cohen, Marina Celanovic, Christopher Soria, Alexei Protopopov, Jack Pollard. Development of a gene signature assessing ER modulation by SERMs and SERDs as a target engagement biomarker for endocrine therapy in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 406.

Abstract 739: Preclinical and clinical activity of SAR439859, Amcenestrant, a next generation SERD

Abstract Primary treatment for estrogen receptor-positive (ER+) breast cancer is endocrine therapy. 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. Here we describe the discovery of SAR439859 (Amcenestrant), 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 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 mutant-Y537S mouse tumors and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. Importantly, in these mutant ESR1 models, we demonstrate that the efficacy of SAR439859 was increased when coadministered with palbociclib, an inhibitor of cyclin-dependent kinase 4 and 6. In the clinical setting, SAR439859 also demonstrated a high level of target engagement, ER degradation and inhibition of ER signaling as well as encouraging anti-tumor activity in heavily pretreated patients with advanced or metastatic ER-positive breast cancer. These findings indicate that SAR439859 would provide therapeutic benefit to patients with ER+ breast cancer, including those who are resistant to endocrine therapy with both wild-type and mutant ER. Citation Format: Maysoun Shomali, Fangxian Sun, Laurent Besret, Anne Caron, Joon Sang Lee, Youssef El-Ahmed, Laurent Schio, Jack Pollard, Vasiliki Pelekanou, Patrick Cohen, Marina Celanovic, Christina Herold, Chris Soria, Laurent Debussche, Monsif Bouaboula. Preclinical and clinical activity of SAR439859, Amcenestrant, a next generation SERD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 739.

Dynamics-Based Discovery of Novel, Potent Benzoic Acid Derivatives as Orally Bioavailable Selective Estrogen Receptor Degraders for ERα+ Breast Cancer.

The estrogen receptor α (ERα) is identified as an effective target for the treatment of ERα+ breast cancer; thus, discovery of novel selective estrogen receptor degraders (SERDs) are developed as an effective method to overcome the resistance of breast cancer. Herein, the hot-spot residues for protein-ligand interaction between SERDs and ERα are analyzed by molecular dynamic simulation technology, focusing on the hot-spot residues for four series of designed and synthesized SERDs. SAR studies revealed that while the acrylic acid moiety of AZD9496 is scaffold hopping into benzoic acid, compound D24 exhibits potent binding affinity with ERα, good degradation efficacy of ERα, and inhibitory effect against the MCF-7 breast cancer cell line. Besides, D24 also displays good antitumor efficacy in the MCF-7 human breast cancer xenograft model in vivo, favorable pharmacokinetic properties, excellent druggability, and good safety property, making D24 as a promising drug candidate of SERD for further evaluation.

From Pure Antagonists to Pure Degraders of the Estrogen Receptor: Evolving Strategies for the Same Target.

Pure antiestrogens, or selective estrogen receptor degraders (SERDs), have proven to be effective in treating breast cancer that has progressed on tamoxifen and/or aromatase inhibitors. However, the only FDA-approved pure antiestrogen, fulvestrant, is limited in efficacy by its low bioavailability. The search for orally bioavailable SERDs has continued for nearly as long as the clinical history of the injection-only fulvestrant. Oral SERDs that have been developed and tested in patients ranged from nonsteroidal ER binders containing an acrylic acid or amino side chain to bifunctional proteolysis-targeting chimera (PROTAC) pure ER degraders. Structural evolution in the development of oral SERD molecules has been closely associated with quantifiable ER-degrading potency, as seen in the structural comparison analysis of acrylic acid and basic amino side-chain-bearing SERDs. Failure to improve on fulvestrant in the clinical trials by numerous acidic SERDs and early basic SERDs is blamed on tolerability and/or insufficient efficacy, which will likely be overcome by the new-generation basic SERD molecules and PROTAC ER degraders with improved oral bioavailability, low toxicity, and superior efficacy of receptor degradation.

Abstract PS12-20: A dose escalation study of the novel oral SERD-ZN-c5 in women with ER-positive, HER2-negative advanced/metastatic breast cancer

Abstract Background: ZN-c5 is an orally bioavailable selective estrogen receptor degrader (SERD) that binds potently to the estrogen receptors alpha and beta. It shows improved activity over fulvestrant in human tumor xenograft models and activity in tumor models that are resistant to tamoxifen. This is a Phase 1/2, open-label, multicenter, dose-escalation and expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), and clinical activity of ZN-c5 in subjects with advanced/metastatic estrogen receptor (ER) positive/ human epidermal growth factor receptor (HER2) negative breast cancer, both as monotherapy and in combination with palbociclib. The results from the ongoing monotherapy dose escalation are reported. Methods: Single agent ZN-c5 is being evaluated at sequentially escalating doses starting at 50 mg/day, administered orally, once daily (QD). The endpoints are to determine a maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D), preliminary clinical activity and to characterize the PK profile. Subjects must be intolerant to or have breast cancer refractory to established therapies and to have received up to 2 prior lines of chemotherapy for the treatment of advanced breast cancer. Subjects must have a documented prior response to endocrine therapy for advanced/metastatic disease (SD, PR, or CR) lasting > 6 months or disease recurrence after at least 24 months of adjuvant endocrine treatment. Results: A total of 15 female subjects (median age 57 years, range 51 - 89 years) were enrolled across 5 cohorts (3 subjects/dose level). The dose levels were 50, 75, 100, 150, and 300 mg/day. The subjects had a median of 4 prior therapies for advanced/metastatic disease, with a median of 3 prior hormonal-based therapies and a median of 1 prior chemotherapy. Eleven of 15 subjects (73%) received prior fulvestrant. The cut off-date for this analysis was 30 June 2020. There was no increase in incidence or severity of TEAEs with increase in dose level. The most frequent TEAEs reported in > 1 subject were nausea (33%), arthralgia, cough, musculoskeletal pain and vomiting (20% each), alanine aminotransferase increased, anemia, back pain, blood alkaline phosphatase increased, breast pain, diarrhea, fatigue, gamma-glutamyl transferase increased, headache, hypophosphatemia, myalgia and skin mass (13% each). Grade 3 events were COVID-19, hypercalcemia, arthralgia, back pain musculoskeletal chest pain, pain in extremity and hypertension, none were deemed related to ZN-c5. Grade 4 events were not reported. No bradycardia was observed. A single subject reported a Grade 1 visual field defect, not deemed related to ZN-c5. No DLTs were reported. ZN-c5 demonstrated a best response of stable disease (SD) in 10/15 subjects (66.5%), while progression of disease (PD) was reported in 5/15 subjects (33.5%). The clinical benefit rate (CBR, SD ≥ 24 weeks) was 40%. In addition, the progression free survival (PFS) was a median of 3.8 months (95% [CI], 1.6 to 6.3). The preliminary PK was characterized by fast absorption with median Tmax values of 1 - 2 hrs. The exposures were approximately dose-proportional at the dose levels of 50 - 100 mg and less than dose-proportional between 100 - 300 mg. No ZN-c5 accumulation after 15 days of QD dosing was observed. The estimated mean elimination half-lives ranged between 11 - 18 hrs. Conclusion: This monotherapy dose escalation study demonstrates that ZN-c5 is very well-tolerated and has promising clinical activity in patients with ER+/HER2-negative advanced breast cancer who have disease that progressed on standard therapies. The trial with ZN-c5 in monotherapy and with palbociclib is ongoing and the RP2D has not been determined yet. Citation Format: Pavani Chalasani, Vandana Abramson, Joanne Mortimer, Julie R Nangia, Jose Suarez, Matt Suster, Mieke Ptaszynski, Kevin Kalinsky. A dose escalation study of the novel oral SERD-ZN-c5 in women with ER-positive, HER2-negative advanced/metastatic 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 PS12-20.

Abstract PS11-26: A phase 1 study of D-0502, an orally bioavailable SERD, for advanced or metastatic HR-positive and HER2-negative breast cancer

Abstract Background: Targeting the estrogen receptor (ER) has proven to be one of the most successful strategies in treating HR+ (ER+ and PR+) and HER2- breast cancer. Selective estrogen receptor degraders (SERD) can be used as single agents or in combination with CDK4/6 inhibitors such as palbociclib. Fulvestrant is currently the only approved agent in its class and is limited by poor oral bioavailability necessitating monthly intramuscular injections. D-0502 is an orally bioavailable SERD with potent activity in various HR+ and HER2- breast cancer cell lines and xenograft models. Its combination with palbociclib in both MCF-7 xenograft models and ESR-1 mutated (Y537S) patient derived breast cancer xenograft models resulted in further tumor growth inhibition or regression. Drug metabolism and pharmacokinetic studies both in vitro and in vivo demonstrated that D-0502 exhibits favorable PK profiles suitable for clinical development. Methods: A first-in-human phase 1 study was conducted to evaluate D-0502 in women with advanced or metastatic HR+, HER2- breast cancer (MBC) (NCT03471663). The primary objective is to characterize the safety and tolerability of D-0502 and D-0502 in combination with palbociclib, to identify an MTD and/or RP2D. The secondary objectives are to evaluate the PK properties and the preliminary anti-tumor activities. Patients received D-0502 orally once daily in 28-day cycles. The study has completed dose escalation (phase 1a), and dose expansion and combination studies (phase 1b) are ongoing. In phase Ia, patients were enrolled and evaluated using conventional 3+3 dose-escalation to identify the MTD of D-0502 as a single agent. The phase 1b was divided into 2 stages. In Stage 1, D-0502 was evaluated with palbociclib at a dose below the MTD first before escalating to the MTD. Stage 1 also included patients in China treated at a dose below and at the MTD as single agent as well as in combination with palbociclib. Stage 2 will further evaluate the MTD for both single agent and combination of D-0502 with palbociclib. Results: At the time of this abstract submission, phase 1a dose escalation is completed, R2PD has been identified, and no DLTs were observed. PK analysis of D-0502 indicates a dose proportional increase in exposure as the dose increases, and the exposure has exceeded the potential therapeutic exposure level based on preclinical studies. The Phase Ib Stage 1 portion has also completed enrollment and the study is currently enrolling patients into phase Ib Stage 2. D-0502 as a single agent or in combination has been well tolerated with radiological tumor response and clinical benefit response (CBR) observed. Safety, PK and preliminary efficacy data will be reported at the meeting presentation. Conclusion: A first-in-human phase 1 study of D-0502 has been initiated in women with advanced or metastatic HR-positive and HER2-negative breast cancer. D-0502 has been well tolerated and achieved significant exposure and preliminary clinical activity in patients. Further results will be presented at the meeting. Citation Format: Cynthia Osborne, Donald A Richards, Sharon T Wilks, Sami Diab, Dejan Juric, Kate Lathrop, Andrea Silber, William Edenfield, Amardeep Aulakh, Ben Cho, Binghe Xu, Tao Sun, Quchang Ouyang, Yanxia Shi, Kathryn Stazzone, Zhe Shi, Ling Zhang, Yaolin Wang, Erika P Hamilton. A phase 1 study of D-0502, an orally bioavailable SERD, for advanced or metastatic HR-positive and HER2-negative 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 PS11-26.