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

Abstract

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

Phase I Study of Elacestrant (RAD1901), a Novel Selective Estrogen Receptor Degrader, in ER-Positive, HER2-Negative Advanced Breast Cancer

“…Response rates for studies performed in a population of patients similar to the population used in this study have ranged from 1.3% for LSZ102 to 16% for AZD9833, with activity noted in patients with ESR1 mutations for most agents. [19][20][21][22][23] Of note, direct cross-trial comparisons should be done with caution due to differences in eligibility and small patient numbers at different dose levels in these phase I studies.…”

“…50% with some SERDs 19,20 and other AEs including bradycardia, ranging from 8% to 45%, and visual disturbances in 53% of patients. 21,22,24 In conclusion, elacestrant at the RP2D of 400 mg orally once daily has an acceptable safety profile, suitability for administration as monotherapy or in combination with other targeted agents, and improved tolerability with the tablet formulation as compared with the initial capsule formulation with a safety profile characterized predominately by grade 1-2 GI events. Elacestrant demonstrated single-agent activity with confirmed partial responses in heavily pretreated postmenopausal women with advanced ER1 breast cancer, including those with prior CDK4/6i and prior fulvestrant as well as those whose tumors harbored ESR1 mutations that confer resistance to ET.…”

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

“…The dose-escalation part of the trial recommended 100 mg once daily to be explored. Results from the dose-expansion cohort included [81]: 88 patients (cohort A: giredestrant monotherapy, n = 40; cohort B: giredestrant plus palbociclib, n = 48). Patients from cohort A exhibited a median ORR of 13% (95% CI, 4-30%), and a median PFS of 7.8 months (95% CI, 5.3-11.4).…”

Endocrine resistance in breast cancer: from molecular mechanisms to therapeutic strategies

“…Mutations at LBD decreases the affinity of the receptor to tamoxifen and fulvestrant [23], necessitating the use of more potent ER antagonists [24]. In this line, next-generation oral SERMs or SERDs can target both the WT and mutant ER, such as GDC-9545 and elacestrant [30], and they showed clinical activity (NCT03332797 and NCT02338349) [31,32] with acceptable toxicity profiles in mutant ER-carrying MBC, some of which progressed on prior therapy with SERDs (Table 2).…”