TPS5115 Background: New therapies are urgently needed to treat prostate cancer, especially for patients progressing on existing drugs that inhibit the activity of the Androgen Receptor (AR) (e.g. Androgen Receptor Pathway Inhibitors (ARPIs)). Metastatic Castration-Resistant Prostate Cancer (mCRPC) is a more aggressive stage of the disease, characterized by increased AR expression and signaling. To address this unmet medical need, we have developed a Regulated Induced Proximity Targeting Chimera (RIPTAC™) Therapeutic HLD-0915. HLD-0915 is a heterobifunctional small molecule that leverages full length AR (FL-AR) expression in tumor cells to form a trimeric complex with an Essential Protein (EP) needed for cell survival. This results in EP loss of function in prostate cancer cells and a selective antitumor effect. HLD-0915 activity requires only the presence of FL-AR and retains activity regardless of whether there are AR or non-AR aberrations that may otherwise serve as drivers of disease. Preclinically, HLD-0915 treatment results in tumor shrinkage and PSA declines following oral dosing in murine models of castration-resistant and ARPI-resistant forms of the disease, while delivering a favorable therapeutic index. The Phase 1 trial in mCRPC will investigate safety and early signs of efficacy in the intended patient population. Methods: This first-in-human, multicenter, open label Phase 1/2 study evaluates the safety, tolerability, and clinical activity of HLD-0915 in patients with mCRPC. Phase 1 consists of monotherapy dose levels employing a Bayesian Optimal Interval (BOIN) design with each dose level starting with a minimum of 3 patients per cohort with the primary objectives of defining the maximal tolerated dose and/or recommended dose for expansion and characterizing safety and tolerability of HLD-0915. This study also aims to characterize the PK profile and assess clinical activity by PSA declines and objective response rate per RECIST and will explore ctDNA, tumor cell genetics, and PD biomarkers. Patients with progressive mCRPC who may or may not have received prior novel antiandrogen therapy, a taxane, or PSMA targeted radioligand will be enrolled. Cohort 1 enrollment begins in January 2025. The Phase 2 portion of the study will confirm the RP2D and clinical activity in up to 3 cohorts which will be decided in the future based on emerging data. Clinical trial information: NCT06800313 .

Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor activity.

Abstract Breast cancer is the most frequently diagnosed cancer among women and remains the second leading cause of cancer death in women. An estimated 70% of all breast cancers express estrogen receptor alpha (ERα); and endocrine therapies have validated ERα as a target for the treatment of breast cancer. Despite effective endocrine therapies, many patients eventually relapse and become resistant to standard of care treatments. Endocrine resistant tumors often remain dependent on ERα for growth and survival, as evidenced by their sensitivity to the selective estrogen receptor degrader (SERD), fulvestrant. However, fulvestrant may be limited in achieving maximal target occupancy due to pharmaceutical and pharmacokinetics properties which necessitates intramuscular route of administration. Consequently, SERDs with superior drug-like properties were sought to allow consistent and rapid achievement of maximal therapeutic exposure. GDC-0810 and GDC-0927 as first and second generation orally bioavailable SERDs were discovered through a prospective lead optimization on ERα degradation. The evolution from GDC-0810 to GDC-0927 will be described and provides new insights into ERα biology and biochemistry. By shifting away from the acrylic acid moiety in GDC-0810, GDC-0927 achieved increased potency and more consistent, complete suppression of ER signaling. Co-crystal structures of both GDC-0810 and GDC-0927 with ERα will be shared. Subsequent optimization of GDC-0927 resulting in improved pharmacokinetic properties will also be highlighted. Citation Format: Mehmet Kahraman, Steven P. Govek, Johnny Y. Nagasawa, Andiliy Lai, Celine Bonnefous, Karensa Douglas, John Sensintaffar, Nhin Lu, KyoungJin Lee, Anna Aparicio, Josh Kaufman, Jing Qian, Gang Shao, Rene Prudente, James D. Joseph, Beatrice Darimont, Daniel Brigham, Richard Heyman, Peter J. Rix, Jeffrey H. Hager, Nicholas D. Smith, Robert A. Blake, Jae Chang, Edna Choo, Anneleen Daemen, Lori S. Friedman, Jane Guan, Steven Hartman, Ellen Ingalla, James R. Kiefer, Tracy Kleinheinz, Sharada Labadie, Ciara Metcalfe, Vidhi Mody, Michelle Nannini, Deepak Sampath, Amy Young, Maia Vinogradova, Wei Zhou, Jun Liang, Xiaojing Wang. Discovery and evolution of orally bioavailable selective estrogen receptor degraders for ER+ breast cancer: From GDC-0810 to GDC-0927 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1648.

About 75% of breast cancers are estrogen receptor alpha (ER-α) positive, and women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, but resistance often emerges. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and shows some activity in patients who have progressed on antihormonal agents. However, fulvestrant must be administered by intramuscular injections that limit its efficacy. We describe the optimization of ER-α degradation efficacy of a chromene series of ER modulators resulting in highly potent and efficacious SERDs such as 14n. When examined in a xenograft model of tamoxifen-resistant breast cancer, 14n (ER-α degradation efficacy = 91%) demonstrated robust activity, while, despite superior oral exposure, 15g (ER-α degradation efficacy = 82%) was essentially inactive. This result suggests that optimizing ER-α degradation efficacy in the MCF-7 cell line leads to compounds with robust effects in models of tamoxifen-resistant breast cancer derived from an MCF-7 background.

The further optimization of ER-α degradation efficacy of a series of ER modulators by refining side-chain substitution led to efficacious selective estrogen receptor degraders (SERDs). A fluoromethyl azetidine group was found to be preferred and resulted in the identification of bis-phenol chromene 17ha. In a tamoxifen-resistant breast cancer xenograft model, 17ha (ER-α degradation efficacy = 97%) demonstrated tumor regression, together with robust reduction of intratumoral ER-α levels. However, despite superior oral exposure, 5a (ER-α degradation efficacy = 91%) had inferior activity. This result suggests that optimizing ER-α degradation efficacy leads to compounds with robust effects in a model of tamoxifen-resistant breast cancer. Compound 17ha (GDC-0927) was evaluated in clinical trials in women with metastatic estrogen receptor-positive breast cancer.

4548 Background: ARN-509 is a novel small molecule AR antagonist that impairs AR nuclear translocation and binding to DNA, inhibiting tumor growth and promoting apoptosis, with no partial agonist activity. (Clegg et al., 2012) We conducted a phase I trial to assess safety, pharmacokinetics (PK), and determine the recommended phase II dose (RP2D). Methods: Eligible patients with mCRPC received ARN-509 orally on a continuous daily dosing schedule. Seven doses (30, 60, 90, 120, 180, 240, and 300 mg) were tested using standard 3x3 dose escalation criteria. Once drug concentrations were achieved that met or exceeded optimal levels predicted preclinically, an additional 2 dose levels were tested to further confirm the safety margin of ARN-509 (390 and 480 mg). Anti-tumor activity was assessed by PSA, radiographic responses, and FDHT-PET imaging. Results: Thirty patients were enrolled. The most common grades 1-2 treatment-related adverse events were fatigue (38%), nausea (29%), and pain (24%). There was only 1 t...

ER-targeted therapeutics provide valuable treatment options for patients with ER+ breast cancer, however, current relapse and mortality rates emphasize the need for improved therapeutic strategies. The recent discovery of prevalent ESR1 mutations in relapsed tumors underscores a sustained reliance of advanced tumors on ERα signaling, and provides a strong rationale for continued targeting of ERα. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (SERD), which was identified by prospectively optimizing ERα degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ERα conformation, relative to that induced by currently approved therapeutics, suggesting a unique mechanism of action. GDC-0810 has robust in vitro and in vivo activity against a variety of human breast cancer cell lines and patient derived xenografts, including a tamoxifen-resistant model and those that harbor ERα mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer.

Abstract Background: Modulation of estrogen activity and/or synthesis is the mainstay therapeutic strategy in the treatment of estrogen receptor (ER)+ breast cancer (BC). However, many patients (pts) relapse or develop resistance to available hormonal agents via estrogen-dependent and estrogen-independent mechanisms. Furthermore, mutations in ESR1 affecting the ER ligand binding domain that drive ER-dependent transcription and proliferation in the absence of estrogen can mediate resistance. Therefore, next generation ER targeting agents with robust activity in both wild type and mutant ER tumors are needed. GDC-0810 is a novel, potent, non-steroidal, orally bioavailable, selective ER antagonist/ER degrader that induces tumor regression in tamoxifen-sensitive and resistant ER+ BC xenograft models. Methods: A phase I dose escalation study with 3+3 design was conducted in postmenopausal women with ER+ (HER2-) locally advanced or metastatic BC (progressing after ≥ 6 months on endocrine therapy; ≤ 2 prior chemotherapies) to determine the safety, pharmacokinetic (PK) and recommended phase II dose (RP2D) of GDC-0810. Pharmacodynamic (PD) activity was assessed with [18F]-fluoroestradiol (FES)-PET scans. Plasma PK samples, CT scans, and when feasible, paired pre and on-study tumor biopsies were obtained. Results: Forty-one pts (median # of prior therapies: 4) were enrolled at 5 total daily dose levels (100-800 mg) and 2 regimens: once (QD) or twice (BID) daily given orally with and without fasting. Increases in GDC-0810 exposure were dose-dependent. The common treatment-related adverse events (AEs) were grade 1/2 diarrhea (63%), fatigue (46%), nausea (44%), flatulence (24%), vomiting (22%), and anemia (22%). Diarrhea was mostly Grade 1, intermittent in nature, and manageable with dose modifications, dietary adjustments, and treatment with PRN loperamide. There was one dose limiting toxicity of Grade 3 diarrhea at 800 mg QD (fasting). 600 mg QD given with food was determined to be single agent R2PD. Complete/near complete (>90%) suppression of FES uptake was observed in 90% of pts with FES-PET scans, including 5 pts with known ESR1 mutations. Evidence of reduced ER levels and Ki67 staining was observed in on-study biopsies. At a median follow-up of 8 months 13 of 31 (42%) pts on study achieved stable disease > 6 months while 10 pts remain active on study with followup < 6 months. Conclusions: GDC-0810 has a tolerable safety profile to date, with predictable PK, evidence of robust PD target engagement, and encouraging anti-tumor activity in heavily pretreated patients with advanced or metastatic ER+ BC. A phase IIa study of GDC-0810 is ongoing in postmenopausal women with ER+ (HER2-) advanced or metastatic BC who have been previously treated with an aromatase inhibitor, including tumors with ESR1 mutations (clinicaltrials.gov NCT01823835). Citation Format: Maura Dickler, Aditya Bardia, Ingrid Mayer, Eric Winer, Peter Rix, Jeff Hager, Meng Chen, Iris Chan, Edna Chow-Maneval, Carlos Arteaga, Jose Baselga. A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with estrogen receptor+ HER2-, advanced/metastatic breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT231. doi:10.1158/1538-7445.AM2015-CT231

Abstract The majority of breast cancers express estrogen receptor alpha (ERα) and thus are treated with anti-hormonal therapies that directly block ER function (e.g.Tamoxifen) or hormone synthesis (Aromatase Inhibitors). While these therapies are initially effective, acquired resistance emerges and disease progression ensues. Importantly, the majority of these tumors continue to depend on ERα for growth and survival via both ligand-dependent and ligand-independent pathways. The emerging evidence that ERα can be activated in the absence of estrogens via point mutations in ERα or cellular signaling pathways supports the development of agents that are not only competitive ERα antagonists but also reduce steady state levels of the receptor and thus limit both ligand dependent and independent signaling. Here we disclose the discovery of ARN-810, also known as GDC-0810. ARN-810 is an oral, potent antagonist of ER that also induces degradation of ERα at picomolar concentrations. ARN-810 treatment results in significant reduction in steady state ERα protein levels in breast cancer cell lines. Using peptide-based conformational profiling, we show ARN-810 induces ERα conformations that are distinct from both fulvestrant and tamoxifen indicating novel mechanism of action. In vitro, ARN-810 is active on wild-type and the constitutively active ERα mutants found in endocrine resistant breast cancer patients. Importantly, ARN-810 is active in cell-line and in vivo models of ESR1 wild-type and mutant, primary and endocrine-resistant breast cancers including patient derived xenograft (PDX) models. These preclinical data indicate that ARN-810, a novel Selective Estrogen Receptor Degrader (SERD), holds promise as a next generation therapy for the treatment of ER+ breast cancer as monotherapy, as well as in combination with agents that target other pathways involved in both intrinsic and acquired endocrine resistance. ARN-810 is in clinical development for the treatment of ER+ breast cancer. Citation Format: James Joseph, Steven Govek, Beatrice Darimont, Daniel Brigham, Anna Aparicio, Eric Bischoff, Mehmet Kahraman, Michelle Nannini, Joshua Kaufman, Andily Lai, Kyoung-Jin Lee, Jason Oeh, Nhin Lu, Wei Zhou, Michael Moon, Jing Qian, John Sensintaffar, Gang Shao, Deepak Sampath, Lori S. Friedman, Peter Rix, Richard A. Heyman, Nicholas Smith, Jeffrey H. Hager. Discovery of GDC-0810 a novel, non-steroidal selective estrogen receptor degrader with robust activity in pre-clinical models of endocrine-resistant breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5053. doi:10.1158/1538-7445.AM2015-5053

Background: Evidence that ER can signal in both ligand-dependent and independent manner in endocrine resistant breast cancer (BC) provides rationale for therapies that are not only functional antagonists of ER but also reduce ER levels, thus targeting both modes of signaling. Furthermore, mutations in ESR1 affecting the ligand-binding domain (LBD) that drive ER-dependent transcription and proliferation in the absence of estrogen suggest that LBD-mutant forms are involved in mediating clinical resistance and next generation ER modulators with robust activity in both wild type and mutant ER tumors are needed. ARN-810 is a novel, orally bioavailable, ER antagonist that induces proteasomal ER degradation in BC cell lines at picomolar concentrations and tumor regression in tamoxifen-sensitive and resistant BC xenograft models. Methods: ARN-810 was tested using standard 3+3 dose escalation to assess safety, PK, and Recommended Phase 2 Dose (RP2D). Key eligibility criteria included ER+ (HER2-) metastatic BC progressing ≥ 6 months (m) on endocrine therapy and ≤ 2 prior chemotherapies. Pre- and on-study tumor biopsies were obtained when feasible. Pharmacodynamics was assessed by functional imaging with [ 18 F]-fluoroestradiol (FES)-PET, tumor-based ER/PR/Ki67 IHC, and ER target gene expression. Plasma PK was assessed following a single dose and at steady-state. Anti-tumor activity was assessed by clinical benefit rate (CBR) [complete response, partial response, or stable disease ≥ 6m] and progression-free survival (PFS). Results: From April 2013 to June 2014, 32 patients (pts) (median age 61 (range 43 – 75); median number of prior therapies = 3 (range 1 – 7); visceral metastases 54%) were enrolled at 5 doses (100, 200, 400, 600, 800 mg) and 2 different regimens (once [QD] and twice daily) given orally with and without fasting. Increases in ARN-810 exposure were dose-dependent with no apparent food effect. At 4 weeks of treatment, complete reduction in FES uptake consistent with full receptor saturation and/or degradation was seen in 95% pts (21/22 scanned to date), including 2 pts with ESR1 mutations, suggesting ARN-810 exhibits greater ER occupancy than that recently reported for fulvestrant 500 mg (van Krutchen et al, ASCO 2014). Evidence of reduced ER levels and Ki67 staining was observed on treatment. To date, 19 pts (59.4%) remain on study with a preliminary CBR of 41%. RP2D, PFS and gene expression results will be provided at time of meeting. The most common adverse events were grades 1/2 nausea, diarrhea, fatigue, and abdominal pain. There was 1 dose limiting toxicity (grade 3 diarrhea) at 800 mg QD which led to expansion of that cohort, while in parallel, evaluation of the other dose regimens continues. No patients have discontinued the study due to toxicity. Conclusions: ARN-810 appears to be safe and tolerable, with predictable PK, promising anti-tumor activity, and pharmacodynamic evidence of target engagement, ER degradation and reduced tumor proliferation in heavily pre-treated metastatic ER+ BC. In Phase II, ARN-810 will be studied in patients previously treated with aromatase inhibitors and fulvestrant, including those with ESR1 mutations. Citation Format: Aditya Bardia, Maura N Dickler, Ingrid A Mayer, Eric P Winer, Umar Mahmood, Gary Ulaner, H Charles Manning, Peter Rix, Jeffrey H Hager, Debasish Roychowdhury, Edna Chow Maneval, Carlos L Arteaga, Jose Baselga. Phase I study of ARN-810, a novel and potent oral selective estrogen receptor degrader, in postmenopausal women with metastatic estrogen receptor positive (ER+), HER2- breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-13-01.

Introduction The efficacy of nebulized sodium nitrite (AIR001) has been demonstrated in animal models of pulmonary arterial hypertension (PAH), but it was not known if inhaled nitrite would be well tolerated in human subjects at exposure levels associated with efficacy in these models.Methods Inhaled nebulized sodium nitrite was assessed in three independent studies in a total of 82 healthy male and female subjects. Study objectives included determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) under normal and mildly hypoxic conditions, and following co-administration with steady-state sildenafil, assessment of nitrite pharmacokinetics, and evaluation of the fraction exhaled nitric oxide (FENO) and concentrations of iron-nitrosyl hemoglobin (Hb(Fe)-NO) and S-nitrosothiols (R-SNO) as biomarkers of local and systemic NO exposure, respectively.Results Nebulized sodium nitrite was well tolerated following 6 days of every 8 h administration up to 90 mg, producing significant increases in circulating Hb(Fe)-NO, R-SNO, and FENO. Pulmonary absorption of nitrite was rapid and complete, and plasma exposure dose was proportional through the MTD dosage level of 90 mg, without accumulation following repeated inhalation. At higher dosage levels, DLTs were orthostasis (observed at 120 mg) and hypotension with tachycardia (at 176 mg), but venous methemoglobin did not exceed 3.0 % at any time in any subject. Neither the tolerability nor pharmacokinetics of nitrite was impacted by conditions of mild hypoxia, or co-administration with sildenafil, supporting the safe use of inhaled nitrite in the clinical setting of PAH.Conclusion On the basis of these results, nebulized sodium nitrite (AIR001) has been advanced into randomized trials in PAH patients.

Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-α and in which the ER-α degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.

Selective estrogen receptor degraders (SERDs) have shown promise for the treatment of ER+ breast cancer. Disclosed herein is the continued optimization of our indazole series of SERDs. Exploration of ER degradation and antagonism in vitro followed by in vivo antagonism and oral exposure culminated in the discovery of indazoles 47 and 56, which induce tumor regression in a tamoxifen-resistant breast cancer xenograft.

Abstract Background: Evidence that ER can signal in both ligand-dependent and independent manner in endocrine resistant breast cancer (BC) provides rationale for therapies that are not only functional antagonists of ER but also reduce ER levels, thus targeting both modes of signaling. Furthermore, mutations in ESR1 affecting the ligand-binding domain (LBD) that drive ER-dependent transcription and proliferation in the absence of estrogen suggest that LBD-mutant forms are involved in mediating clinical resistance and next generation ER modulators with robust activity in both wild type and mutant ER tumors are needed. ARN-810 is a novel, orally bioavailable, ER antagonist that induces proteasomal ER degradation in BC cell lines at picomolar concentrations and tumor regression in tamoxifen-sensitive and resistant BC xenograft models. Methods: ARN-810 was tested using standard 3+3 dose escalation to assess safety, PK, and Recommended Phase 2 Dose (RP2D). Key eligibility criteria included ER+ (HER2-) metastatic BC progressing ≥ 6 months (m) on endocrine therapy and ≤ 2 prior chemotherapies. Pre- and on-study tumor biopsies were obtained when feasible. Pharmacodynamics was assessed by functional imaging with [18F]-fluoroestradiol (FES)-PET, tumor-based ER/PR/Ki67 IHC, and ER target gene expression. Plasma PK was assessed following a single dose and at steady-state. Anti-tumor activity was assessed by clinical benefit rate (CBR) [complete response, partial response, or stable disease ≥ 6m] and progression-free survival (PFS). Results: From April 2013 to June 2014, 32 patients (pts) (median age 61 (range 43 – 75); median number of prior therapies = 3 (range 1 – 7); visceral metastases 54%) were enrolled at 5 doses (100, 200, 400, 600, 800 mg) and 2 different regimens (once [QD] and twice daily) given orally with and without fasting. Increases in ARN-810 exposure were dose-dependent with no apparent food effect. At 4 weeks of treatment, complete reduction in FES uptake consistent with full receptor saturation and/or degradation was seen in 95% pts (21/22 scanned to date), including 2 pts with ESR1 mutations, suggesting ARN-810 exhibits greater ER occupancy than that recently reported for fulvestrant 500 mg (van Krutchen et al, ASCO 2014). Evidence of reduced ER levels and Ki67 staining was observed on treatment. To date, 19 pts (59.4%) remain on study with a preliminary CBR of 41%. RP2D, PFS and gene expression results will be provided at time of meeting. The most common adverse events were grades 1/2 nausea, diarrhea, fatigue, and abdominal pain. There was 1 dose limiting toxicity (grade 3 diarrhea) at 800 mg QD which led to expansion of that cohort, while in parallel, evaluation of the other dose regimens continues. No patients have discontinued the study due to toxicity. Conclusions: ARN-810 appears to be safe and tolerable, with predictable PK, promising anti-tumor activity, and pharmacodynamic evidence of target engagement, ER degradation and reduced tumor proliferation in heavily pre-treated metastatic ER+ BC. In Phase II, ARN-810 will be studied in patients previously treated with aromatase inhibitors and fulvestrant, including those with ESR1 mutations. Citation Format: Aditya Bardia, Maura N Dickler, Ingrid A Mayer, Eric P Winer, Umar Mahmood, Gary Ulaner, H Charles Manning, Peter Rix, Jeffrey H Hager, Debasish Roychowdhury, Edna Chow Maneval, Carlos L Arteaga, Jose Baselga. Phase I study of ARN-810, a novel and potent oral selective estrogen receptor degrader, in postmenopausal women with metastatic estrogen receptor positive (ER+), HER2- breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-13-01.

Abstract 60–75% of all breast cancers express the estrogen receptor (ER) and thus are treated with anti-hormonal therapies that directly block ER function (e.g. Tamoxifen) or hormone synthesis (Aromatase Inhibitors). While these therapies are initially effective, acquired resistance invariably emerges. Importantly, the majority of these tumors continue to express and depend on ER for growth and survival, suggesting that novel approaches to target ER signaling have tremendous potential to treat endocrine-resistant disease. We have identified novel ER antagonists that induce degradation of ER at picomolar concentrations resulting in significant reduction in steady state ER protein levels in breast cancer cell lines. These compounds yield regression in both Tamoxifen-sensitive and - resistant models of breast cancer in vivo. Based on their unique in vitro profile, good pharmacokinetics and oral bioavailability, these compounds represent a novel class of Selective Estrogen Receptor Degraders (SERDs) that hold tremendous promise as a next generation therapy for the treatment of ER+ breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A133.