Evaluation of RAD1901, a novel investigational, selective estrogen receptor degrader (SERD), for the treatment of ER-positive (ER+) advanced breast cancer.

Abstract

1014 Background: The treatment of advanced ER+ breast cancer remains a clinical challenge with the majority of patients eventually progressing due to resistance to endocrine therapy. RAD1901 is a novel, nonsteroidal, oral SERD that has demonstrated dose dependent degradation of ER, and ER regulated genes in preclinical studies. In multiple in vivo patient derived xenograft models of breast cancer, including those harboring ESR1 mutations, RAD1901 demonstrated significant antitumor activity. Methods: In a phase-1 Study RAD1901-005 (ClinicalTrials.gov ID: NCT02338349), patients with advanced ER+ breast cancer were enrolled in dose escalation cohorts, followed by a safety expansion cohort. Key inclusion criteria include postmenopausal women aged 18 years or older, with advanced ER+, HER2- breast cancer, who have received ≤ 2 prior chemotherapy regimens in the metastatic setting and > 6 months of prior endocrine therapy. ESR1 mutation status was determined from circulating tumor DNA (ctDNA) samples. Clinical outcomes were evaluated based on RECIST v1.1 criteria. Results: As of January 25, 2017, total of 39 patients were enrolled at the 400 mg qd dose. Patients were heavily pre-treated (median lines of prior therapy = 3), with 38% and 41% having previously received fulvestrant and palbociclib/CDK4/6 inhibitor, respectively. RAD1901 was generally well-tolerated, with the most common adverse events being low grade nausea (Grade 3/4 = 0%) and dyspepsia (Grade 3/4 = 0%). ESR1 mutations, including D538G, Y537S/N/C, L536H/P/R, S436P and E380Q, were detected at baseline in 44% of patients and dynamic changes in the allele frequency of ESR1 mutations were observed in response to treatment. Confirmed partial responses were observed in patients with ESR1 mutations, and those who had previously received fulvestrant and palbociclib. Conclusions: RAD1901 has demonstrated evidence of single agent activity, with confirmed partial responses in heavily pre-treated patients with advanced ER+ breast cancer, including those with ESR1 mutations, warranting additional clinical development. Clinical trial information: NCT02338349.

Rising Circulating Tumor DNA As a Molecular Biomarker of Early Disease Progression in Metastatic Breast Cancer

“…17,[26][27][28] The most commonly mutated gene in TNBC was TP53, whereas ESR1 mutations were commonly seen in patients with ER-positive tumors previously exposed to endocrine therapy. 22,[29][30][31][32][33] Sequencing results showed mutations in up to 15 genes (range, 0-15 genes) per analyzed specimen, many of which are potentially actionable but currently of unknown clinical significance. Given this degree of polyclonality and genomic heterogeneity frequently encountered in MBC, along with difficulties in differentiating driver from passenger No (only osseous) 20 (28.6) Abbreviations: ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor.…”

How I treat endocrine-dependent metastatic breast cancer

“…According to available data, response rate with new oral SERDs (elacestrant, AZD-9833, GDC-9545, LSZ102, LY3484356, G1T48, SAR439859) in patients progressing on previous ET ± CDK 4/5 inhibitors is around 13%-20% and the median PFS ranges between 4.5 and 7.8 months. 76 , 78 , 79 , 80 , 81 , 82 , 83 Combining these drugs with CDK 4/6 inhibitors seems feasible. 80 , 81 , 84 , 85 …”

Endocrine Resistance in Hormone Receptor Positive Breast Cancer–From Mechanism to Therapy

“…The purpose of this study was to evaluate the efficacy of a novel orally bioavailable SERD, elacestrant (RAD1901), in preclinical models of ER+ BC. Elacestrant (RAD1901) is one such SERD that inhibits cell proliferation in ER+ BC cell lines and is being studied as part of clinical trials in ER+/HER-2 negative advanced BC where partial response as an effective SERD was demonstrated in heavily pre-treated ER+/ER mutant MBC and patients (ClinicalTrials.gov Identifier: NCT03778931 and NCT02338349) (114, 115). A structurally and chemically unique SERD, GDC-0927, induces tumor regression in ER+ MBC patients including those with ER α mutations (ClinicalTrials.gov Identifier: NCT02316509) (116, 117).…”