Fiona Garner

RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models

Agents that inhibit estrogen production, such as aromatase inhibitors or those that directly block estrogen receptor (ER) activity, such as selective estrogen receptor modulators and selective estrogen receptor degraders, are routinely used in the treatment of ER-positive breast cancers. However, although initial treatment with these agents is often successful, many women eventually relapse with drug-resistant breast cancers. To overcome some of the challenges associated with current endocrine therapies and to combat the development of resistance, there is a need for more durable and more effective ER-targeted therapies. Here we describe and characterize a novel, orally bioavailable small-molecule selective estrogen receptor degrader, RAD1901, and evaluate its therapeutic potential for the treatment of breast cancer. RAD1901 selectively binds to and degrades the ER and is a potent antagonist of ER-positive breast cancer cell proliferation. Importantly, RAD1901 produced a robust and profound inhibition of tumor growth in MCF-7 xenograft models. In an intracranial MCF-7 model, RAD1901-treated animals survived longer than those treated with either control or fulvestrant, suggesting the potential benefit of RAD1901 in the treatment of ER-positive breast cancer that has metastasized to the brain. Finally, RAD1901 preserved ovariectomy-induced bone loss and prevented the uterotropic effects of E2, suggesting that it may act selectively as an agonist in bone but as an antagonist in breast and uterine tissues. RAD1901 is currently under clinical study in postmenopausal women with ER-positive advanced breast cancer.

Elacestrant (RAD1901), a selective estrogen receptor degrader (SERD), has anti-tumor activity in multiple ER+ breast cancer patient-derived xenograft models

Purpose: Estrogen receptor–positive (ER+) breast cancers are typically treated with endocrine agents, and dependence on the ER pathway is often retained even after multiple rounds of antiestrogen therapy. Selective estrogen receptor degraders (SERD) are being developed as a strategy to more effectively target ER and exploit ER dependence in these cancers, which includes inhibiting both wild-type and mutant forms of ER. The purpose of this study was to evaluate the efficacy of a novel orally bioavailable SERD, elacestrant (RAD1901), in preclinical models of ER+ breast cancer. Experimental Design: Elacestrant was evaluated as a single agent and in combination with palbociclib or everolimus in multiple ER+ breast cancer models, including several patient-derived xenograft models. Results: Elacestrant induces the degradation of ER, inhibits ER-mediated signaling and growth of ER+ breast cancer cell lines in vitro and in vivo, and significantly inhibits tumor growth of multiple PDX models. Furthermore, we demonstrate that elacestrant in combination with palbociclib or everolimus can lead to greater efficacy in certain contexts. Finally, elacestrant exhibits significant antitumor activity both as a single agent and in combination with palbociclib in two patient-derived breast cancer xenograft models harboring ESR1 mutations. Conclusions: These data underscore the potential clinical utility of elacestrant as a single agent and as a combination therapy, for both early- and late-stage ER+ disease. Clin Cancer Res; 23(16); 4793–804. ©2017 AACR.

Abstract OT2-01-10: A phase 1 study of RAD1901, a novel, orally available, selective estrogen receptor degrader, for the treatment of ER positive advanced breast cancer

The current NCCN treatment guidelines for ER+ breast cancer involves the use of approved agents such as fulvestrant, tamoxifen and aromatase inhibitors that either inhibit estrogen production or block estrogen receptor binding. While the initial treatment regimens with these selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) is often successful, many women eventually relapse with more aggressive forms of endocrine-resistant disease. To begin to overcome some of the challenges associated with current therapies including exposure limitations and intramuscular administration, we have developed RAD1901, a novel, non-steroidal, orally available SERD. Preclinical studies with RAD1901 have demonstrated potent dose dependent ER degradation consistent with a SERD mechanism of action, as well as potent inhibition of proliferation in vitro in breast cancer cell lines. RAD1901 also demonstrated significant anti-tumor efficacy in vivo, and notably single agent regressions in both MCF7 and a primary patient derived xenograft models harboring an ESR1 mutations. A phase 1 monotherapy study conducted in healthy postmenopausal female volunteers evaluated forty four subjects treated once daily with RAD1901 with doses ranging from 200 mg/day up to 1000 mg/day for 7 days. All dose levels were generally well tolerated and pharmacokinetic analysis demonstrated plasma exposures consistent with preclinical efficacy in ER+ breast cancer models. Furthermore, 18F-estradiol positron emission tomography (FES-PET) was also performed at baseline and after 7 days of RAD1901 treatment, to evaluate estrogen receptor engagement. Standardized uptake values (SUV) pre- and post-treatment with RAD1901 demonstrated complete attenuation of FES-PET signal in ER+ tissues such as the uterus from the 200 mg/day dose level. Taken together, these results provide strong preclinical and clinical rationale for the development of RAD1901 as a potent and selective oral SERD for the treatment of hormone driven and hormone resistant ER + metastatic breast cancers. RAD1901-005 is a Phase 1 study currently enrolling ER+ advanced metastatic breast cancer patients. The study consists of two parts: a monotherapy dose escalation followed by a safety expansion at the maximum tolerated dose (MTD). The dose escalation will follow a standard 3+3 design with once daily dosing to establish, safety, tolerability, and PK. Once the MTD for RAD1901 has been established, the safety expansion will further evaluate the safety, tolerability, biomarkers and preliminary efficacy at the recommended phase 2 dose (RP2D) following a continuous once daily schedule. Key inclusion criteria include post-menopausal women aged 18 years or older, with advanced ER positive, HER2 negative breast cancer, who have received ≤ 2 prior chemotherapy regimens in the metastatic setting and > 6 months of prior endocrine therapy. Patient enrollment started in early 2015, and is currently ongoing. ClinicalTrials.gov identifier: NCT02338349. Citation Format: Harb W, Garner F, McDermott J, Zimmerman T, Williams G, Hattersley G, Purandare D. A phase 1 study of RAD1901, a novel, orally available, selective estrogen receptor degrader, for the treatment of ER positive advanced breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-10.

Abstract P3-05-07: RAD1901, a novel oral, selective estrogen receptor degrader (SERD) with single agent efficacy in an ER+ primary patent derived ESR1 mutant xenograft model

Despite advances in the treatment of metastatic breast cancer, many women eventually relapse with more aggressive forms of endocrine-resistant disease. Mutations in the ESR1 gene encoding the estrogen receptor (ER) have recently emerged as a potential mechanism for the development of clinical resistance to conventional anti-estrogen therapies, such as fulvestrant. To overcome some of the pharmacokinetic limitations and intramuscular administration challenges associated with fulvestrant endocrine therapy and to combat the development of resistance, there is a significant need for the development of more durable and more effective ER-targeted therapies. Here, we begin to describe and characterize the preclinical efficacy of RAD1901, a novel, orally bioavailable small-molecule SERD, with significant therapeutic potential for treatment of breast cancer. RAD1901 selectively binds to and degrades the ER and is a potent antagonist of ER-positive breast cancer cell proliferation. Importantly, RAD1901 demonstrated profound tumor growth inhibition in MCF-7 xenograft models when compared to fulvestrant and tamoxifen. Importantly, RAD1901 also demonstrated marked single agent efficacy in a primary patient-derived xenograft (PDx) model harboring the ESR1 Y537S mutation indicating the utility of this SERD against clinically relevant ER mutants. Further biochemical binding studies and co-crystallization experiments of RAD1901 bound to the ER further confirms the ability of RAD1901 to bind to both mutant and wild type forms of the ER. RAD1901 is currently undergoing clinical testing in postmenopausal women with ER-positive advanced breast cancer. Citation Format: Garner F, Brown J, Katzenellenbogen J, Lyttle CR, Hattersley G. RAD1901, a novel oral, selective estrogen receptor degrader (SERD) with single agent efficacy in an ER+ primary patent derived ESR1 mutant xenograft model. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-07.

Abstract P4-04-14: Anti-tumor activity of elacestrant (RAD1901) in combination with alpelisib (BYL-719) in patient-derived xenograft models of ER+ breast cancer

Estrogen-receptor positive (ER+) breast cancers make up approximately 70% of all breast cancers diagnosed. While patients with ER+ breast cancer have a better prognosis than other subtypes of breast cancer, the majority of those with advanced metastatic disease will eventually relapse. This has been attributed, in part, to mutations in the ER gene that result in constitutive activation of ER and contribute to aromatase inhibitor treatment resistance. As a strategy to deliver a more durable response in this setting, the use of selective estrogen receptor degraders (SERDs) that target and inhibit both wild-type and mutant ER has gained widespread attention. Indeed, fulvestrant, the only approved SERD on the market, is currently used as a second-line therapy in the metastatic setting, however, the intramuscular route of administration and pharmacokinetic properties of fulvestrant have fueled the development of orally bioavailable SERDs. We have previously described elacestrant (RAD1901), a novel and orally bioavailable selective estrogen receptor degrader (SERD) as an inhibitor of ER+ breast cancer growth in preclinical models, including those that harbor ER mutations and those that are insensitive to fulvestrant. In addition to ER mutations, the activation of parallel oncogenic pathways can also drive endocrine resistance, with the PI3K/Akt/mTOR pathway chief among those driving growth and treatment resistance to endocrine therapy. Consistent with these above-mentioned findings, recent clinical strategies to treat advanced ER+ disease have involved combining SERDs with PI3K inhibitors. Alpelisib (BYL-719) is a PI3K-alpha specific inhibitor that is being developed in combination with endocrine agents for the treatment of ER+ breast cancer. Here, we examined the effect of elacestrant in combination with alpelisib, in two ER+ breast cancer PDX models (one harboring wild-type ER and one harboring a Y537S mutation in the ER gene). The combination of elacestrant (10mg/kg) and alpelisib (35mg/kg) was well tolerated and resulted in significant tumor growth inhibition in both PDX models. Interestingly, in the mutant ER PDX model, the combination resulted in significantly greater growth inhibition relative to either compound alone. These data suggest the dual inhibition of the ER and PI3K signaling pathways with elacestrant and alpelisib produces significant anti-tumor activity in clinically-relevant PDX models, including those harboring ER mutations. Citation Format: Sankaran B, Garner F, Hattersley G, Purandare D, Bihani T. Anti-tumor activity of elacestrant (RAD1901) in combination with alpelisib (BYL-719) in patient-derived xenograft models of ER+ breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-14.

Abstract P2-08-06: A phase 1 study of RAD1901, a novel, oral selective estrogen receptor degrader, for the treatment of ER-positive advanced breast cancer

Background: The majority of breast cancers are defined as estrogen receptor positive (ER+) breast cancer. Despite availability of standard therapies, such as aromatase inhibitors, many women eventually relapse with aggressive disease due to acquisition of endocrine resistance, including ESR1 mutations. To help address some of the challenges associated with current therapies including exposure limitations and intramuscular administration, we have developed RAD1901, a novel, non-steroidal, oral selective estrogen receptor degrader (SERD). Preclinical studies with RAD1901 have demonstrated a dose dependent degradation of ER consistent with a SERD mechanism of action. In multiple in vivo models of breast cancer, including patient-derived xenograft models that are sensitive or resistant to standard endocrine therapies, RAD1901 has anti-tumor efficacy both as a single agent and in combination with palbociclib and everolimus. Importantly, RAD1901 has shown superior efficacy compared to fulvestrant in a number these models including those harboring and ESR1 mutation. Methods: RAD1901-005 is a Phase 1 study currently enrolling ER+ advanced metastatic breast cancer patients (ClinicalTrials.gov identifier: NCT02338349) with a dose escalation cohort based on a standard 3+3 design followed by a safety expansion cohort at a tolerated dose. Key inclusion criteria include postmenopausal women aged 18 years or older, with advanced ER+, HER2-negative breast cancer, who have received ≤ 2 prior chemotherapy regimens in the metastatic setting and > 6 months of prior endocrine therapy. In addition, circulating tumor DNA (ctDNA) was evaluated to determine ESR1 mutation status and to correlate it with clinical response. Results: As of the cut-off date in March, 13 patients were enrolled in the dose escalation part of the study (3+3 design) at doses of 200 mg qd, 400 mg qd and 600 mg qd. RAD1901 exposure was dose dependent and the PK profile was comparable to PK data from a previous study in healthy volunteers. RAD1901 was well tolerated with the most common adverse events being low-grade nausea and dyspepsia. No DLTs were observed. A safety expansion cohort (Part B, n=20) was opened. At the cut-off date 4 of the 13 patients had been on study 4 or more months. Updated outcomes and biomarker data, including ctDNA, will be presented at the meeting. Conclusion: RAD1901, a novel, non-steroidal, oral SERD, is well-tolerated with manageable adverse effects, and is associated with preliminary evidence of clinical activity in patients with advanced ER+ advanced postmenopausal breast cancer, including patients with ESR1 mutant tumors. Citation Format: Kaklamani VG, Kabos P, Elledge R, Harb W, Purandare D, O9Neill A, Garner F, Bardia A. A phase 1 study of RAD1901, a novel, oral selective estrogen receptor degrader, for the treatment of ER-positive advanced breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-08-06.

Abstract 1814: RAD1901, an orally available SERD, as an effective combination partner in ER+ breast cancer

Breast cancer is subdivided into categories based on a patient9s estrogen receptor (ER), progesterone receptor (PR) or Her2 expression status. Estrogen receptor positive (ER+) breast cancer makes up approximately 70% of all breast cancers diagnosed and given the dependence on ER signaling in this disease segment, most treatment modalities focus on inhibiting some aspect of this pathway. Indeed, preventing estrogen synthesis (e.g. with aromatase inhibitors) and modulating ER pathway activity (e.g. with tamoxifen) continue to be mainstays in the standard of care for ER+ breast cancer patients. While patients typically respond well to these agents, a majority of patients will relapse, emphasizing the need to understand the specific mechanisms that can contribute to clinical resistance. One such mechanism is the activation of compensatory or concurrent signaling pathways that can stimulate growth (eg. Her2, CDK4/6) and/or confer survival (eg. PI3K, AKT, mTOR). The recent approval of palbociclib (CDK4/6i) or everolimus (mTORi) in combination with an aromatase inhibitor for the treatment of advanced ER+ disease demonstrates the effectiveness of combining anti-hormonals with targeted agents. While these combinations have superior efficacy compared to the use of aromatase inhibitors alone, alterations in ER itself, such as amplification and mutations, have been described as a second mechanism that can drive resistance to aromatase inhibitors in patients. These findings highlight the need for a selective estrogen receptor downregulator (SERD) that can degrade both wild-type and aberrant forms of ER in order to more effectively treat this patient population. We have recently demonstrated that treatment with RAD1901, an orally bioavailable SERD, results in consistent and robust tumor growth inhibition of patient derived xenograft (PDx) models, regardless of ER status. We hypothesized that combining RAD1901 with agents that inhibit compensatory signaling pathways would mitigate both mechanisms of resistance in ER+ breast cancer patients, leading to greater efficacy. We performed an efficacy screen with RAD1901 in patient derived xenograft (PDx) models with varied genetic backgrounds, allowing us to mimic clinical phenotypes and to better represent the heterogeneity within the ER+ breast cancer patient population. These models harbored a wide range of ER expression levels, in addition to other genetic alterations, which accurately represented the patients’ diverse treatment history profiles. Based on results from the screen, models were selected for additional studies to determine which targeted agent, if any, can be combined with RAD1901 to achieve maximal efficacy. By doing this, we were able to correlate response with genetic background in clinically relevant models, potentially allowing us to predict treatment strategies that have a higher likelihood of success for specific patients. Citation Format: Teeru Bihani, Jeffrey L. Brown, Dinesh M. Purandare, Gary Hattersley, Fiona Garner. RAD1901, an orally available SERD, as an effective combination partner in ER+ breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1814.

Abstract PR10: RAD1901, an orally available selective estrogen receptor downregulator, has potent anti-tumor activity in in vitro and in vivo models of ER+ breast cancer

Breast cancer is the most frequent type of cancer diagnosed in women, with over 200,000 new cases diagnosed in the US each year. Treatment strategies are typically based on the tumors receptor status; that is, whether a tumor expresses estrogen receptor (ER), progesterone receptor (PR), or Her2. Estrogen receptor positive (ER+) breast cancers comprise approximately two-thirds of all breast cancers. For decades the approach to treat ER+ disease revolved around altering the ligand interactions with the receptor; either by preventing estrogen binding (e.g., tamoxifen) or preventing estrogen biosynthesis (aromatase inhibitors). While patients typically respond well to these agents, estrogen-independent ER activity and recurrent ER mutations are increasingly being reported as contributing factors to endocrine resistance and continue to be a clinical hurdle. Given this growing unmet medical need, selective estrogen receptor downregulators, or SERDs, have gained widespread attention as new therapeutic treatment strategies for ER + disease. Indeed, fulvestrant has been shown to downregulate ER and cause tumor growth inhibition in many ER+ breast cancer models. However, in the clinic fulvestrant appears to be limited by PK exposure properties and this, combined with its intramuscular route of administration, underscores the need for novel orally available SERDs. Here, we describe RAD1901, an orally administered SERD that binds ER and targets it for degradation in a dose-dependent manner. Biochemical affinity binding studies and cocrystallization experiments revealed insights into RAD1901 complexes with both wild-type and mutant forms of ER. In addition, RAD1901 treatment resulted in decreased cell proliferation in in vitro breast cancer cell lines and had profound single agent tumor growth inhibition in in vivo xenograft models. Consistent with these findings, RAD1901 treatment resulted in decreased expression levels of ER target genes. Interestingly, the extent of tumor growth inhibition induced by RAD1901 in vivo was dependent on ER expression levels, demonstrating the specificity of RAD1901 and predicting its activity in ER-driven cancers. Importantly, RAD1901 was also able to induce significant tumor growth inhibition in clinically relevant and representative patient-derived xenograft models, at a level similar to or greater than fulvestrant. In conclusion, our preclinical data demonstrate that RAD1901 is an orally available SERD, with potent single agent antitumor activity. RAD1901 is currently under clinical investigation in post-menopausal women with advanced ER+ disease. Citation Format: Teeru Bihani, Jeffrey Brown, Gary Hattersley, Fiona Garner. RAD1901, an orally available selective estrogen receptor downregulator, has potent anti-tumor activity in in vitro and in vivo models of ER+ breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR10.