Vepdegestrant is an oral proteolysis-targeting chimera (PROTAC) estrogen receptor (ER) degrader that directly utilizes the ubiquitin–proteasome system. It was compared to fulvestrant in patients who had received one prior line of hormonal therapy with a CDK4/6 inhibitor. Among patients with ESR1 mutations, Vepdegestrant demonstrated a median progression-free survival (PFS) of 5.0 months versus 2.1 months with fulvestrant. In the overall population, the median PFS was 3.8 months for Vepdegestrant and 3.6 months for fulvestrant, indicating that the drug showed particular efficacy in tumors harboring ESR1 mutations.
Vepdegestrant is an oral proteolysis-targeting chimera (PROTAC) estrogen receptor (ER) degrader that directly harnesses the ubiquitin–proteasome system.
In this phase 3, open-label, randomized trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer who had received one previous line of cyclin-dependent kinase 4 and 6 inhibitor therapy plus one line of endocrine therapy (and up to one additional line of endocrine therapy). Patients were randomly assigned in a 1:1 ratio to receive vepdegestrant at a dose of 200 mg orally once every day of each 28-day cycle or fulvestrant at a dose of 500 mg, administered intramuscularly, on day 1 and day 15 of cycle 1 and on day 1 of subsequent cycles, with randomization stratified according to ESR1-mutation status and presence or absence of visceral disease. The primary end point was progression-free survival as assessed by blinded independent central review among the patients with ESR1 mutations and among all the patients who underwent randomization. Progression-free survival was estimated with Kaplan–Meier methods and hazard ratios with a stratified Cox proportional-hazards model. Research Summary Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Breast Cancer
A total of 624 patients underwent randomization; 313 were assigned to receive vepdegestrant, and 311 to receive fulvestrant. Among the 270 patients with ESR1 mutations, the median progression-free survival was 5.0 months (95% confidence interval [CI], 3.7 to 7.4) with vepdegestrant and 2.1 months (95% CI, 1.9 to 3.5) with fulvestrant (hazard ratio, 0.58 [95% CI, 0.43 to 0.78]; P
Among patients with ER-positive, HER2-negative advanced breast cancer, vepdegestrant was associated with significantly longer progression-free survival than fulvestrant in the subgroup with ESR1 mutations but not in the full patient population. (Funded by Pfizer and Arvinas Estrogen Receptor; VERITAC-2 ClinicalTrials.gov number, NCT05654623.)
Our site participated in this study, where patients were tested for ESR1 mutations via circulating tumor DNA (ctDNA). Those who tested positive were switched to camizestrant (Cami), which demonstrated improved progression-free survival.
Elinzanitant, a neurokinin-targeted therapy, has been shown to reduce vasomotor symptoms compared to placebo. These symptoms are one of the reasons some of my patients discontinue aromatase inhibitor (AI) therapy, so Elinzanitant presents a promising alternative to help manage these side effects. Additionally, Fezolinetant is already approved and available on the market.
The INAVO120 trial evaluated inavolisib + palbociclib–fulvestrant vs placebo + palbociclib–fulvestrant in patients with PIK3CA-mutated, HR+/HER2– advanced breast cancer progressing on or shortly after adjuvant endocrine therapy (ET). Inavolisib significantly improved overall survival (OS) (34.0 vs 27.0 mo) and progression-free survival (PFS) (17.2 vs 7.3 mo), with a higher objective response rate (ORR) (62.7% vs 28.0%) and longer DoR (19.2 vs 11.1 mo). Toxicities were manageable but included more hyperglycemia (63.4%), stomatitis (55.3%), GI, and ocular AEs. Bottom line: this triplet sets a new bar for first-line PIK3CA-mutant HR+ MBC, but we’ll need to stay vigilant about metabolic and mucosal side effects as we bring it into practice.
Adding Palbociclib did not help, revealing that there is no need to continue with different hormonal therapy than the one used in first line. It also added more toxicity.
DON’T omit, there is still a benefit, especially in 6-10% patients.