Ribociclib (RIB) vs. palbociclib (PAL) in patients (pts) with hormone receptor-positive/HER2negative/HER2-enriched (HR+/HER2-/HER2-E) advanced breast cancer (ABC): A head-to-head phase III study-HARMONIA SOLTI-2101/AFT-58

TPS1125 Background: RIB and PAL are CDK4/6 inhibitors with demonstrated efficacy in terms of progression-free survival (PFS) and similar tolerability in pts with HR+/HER2- ABC when combined with endocrine therapy (ET). Only RIB has demonstrated a consistent, statistically significant, and clinically meaningful overall survival (OS) benefit across the MONALEESA (ML) phase III trials, while PALOMA trials failed to achieve similar outcome. Given effective treatments (Tx) may change underlying tumor biology (TB), it is hypothesized that RIB changes TB, enabling a better response to subsequent therapy and thus improving OS. RNA-based intrinsic subtyping reflects differences in TB and has strong prognostic and predictive value in HR+/HER2- ABC. Non-Luminal subtypes, as HER2-E and basal-like (BL), are relatively endocrine-resistant and have poorer prognosis than luminal. Tumors can switch subtypes over time to a more aggressive and less endocrine-responsive biology, which may also be reversed by effective Tx. A retrospective analysis of pooled data from ML 2/3/7 trials showed that HER2-E tumors had surprising benefit from RIB, while BL tumors did not. Pre/clinical data and indirect comparisons suggest that RIB may outperform PAL in HER2-E. Thus, choosing pts with HER2-E tumors as a means of a well defined TB with relative endocrine resistance provides the right setup for HARMONIA study to explore likely differential re-sensitization to endocrine therapy with RIB vs. PAL and ultimately testing which CDK4/6i prepares best for continued response and OS benefit. In addition, HARMONIA explores the value of earlier Tx with chemotherapy (paclitaxel) + anti PD-1 (tislelizumab) in pts with BL tumors to leverage learnings from treating ET-insensitive triple-negative BC. Methods: This is an international, multicenter, randomized, open-label, phase III study, using prospective pre-selection based on TB in pts with HR+/HER2- ABC, with HER2-E tumors (main cohort) and with BL tumors (exploratory cohort). HER2-E cohort will randomized pts 1:1 to RIB+ET (letrozole or fulvestrant) or PAL+ET. As per recent protocol amendment, BL cohort pts will be treated with paclitaxel plus tislelizumab, an anti PD-1 monoclonal antibody, pts may be offered to try RIB + ET first, and will remain eligible for paclitaxel + tislelizumab upon progression. Primary endpoint (EP): PFS per RECIST v1.1. Secondary EP: OS, PFS2, clinical benefit rate, duration and time to response, quality of life, and exploratory EP, including subtype switching between primary and metastatic tumor, and after trial Tx. Interim and primary EP analysis will be performed after 224 and 310 PFS events are observed (~80% power using one-sided 5% α). HARMONIA will recruit in Spain (55 sites), Portugal (5), and US (35) within SOLTI & AFT network. Clinical trial information: NCT05207709 .