Dani R. Castillo

HERTHENA-PanTumor01: a phase II study of patritumab deruxtecan (HER3-DXd) in previously treated advanced solid tumors

PARP inhibitors in gastric cancer: unlocking precision oncology

Abstract Gastric cancer (GC) demonstrates frequent alterations in homologous recombination repair (HRR) genes, and preclinical studies have demonstrated a clear synthetic lethality between HRR deficiency (HRD) and PARPi. While such preclinical synthetic lethality has translated into clinical benefits of PARPi in patients with HRD breast, ovarian, pancreatic, or prostate cancer, the therapeutic role of PARPi in GC remains unclear due to molecular heterogeneity and lack of validated biomarkers for patient selection. This review summarizes the mechanistic foundation for PARPi sensitivity in HRR-deficient GC tumors and evaluates emerging biomarkers, including genomic instability scores, RAD51 foci formation, mutational signatures, and candidate genes such as BRCA1/2, PALB2, and BARD1. We highlight key clinical trials and ongoing research aimed at refining patient selection, optimizing combination strategies, and identifying predictive biomarkers. Improving biomarkers to identify bona fide HRD is essential to optimizing PARPi as a valuable treatment option for patients with GC. We outline a pathway for biomarker-guided adoption of PARPi in GC management. Early-phase clinical trials of PARPi monotherapy in GC have yielded limited efficacy, likely due to variable HRD status and other mechanisms of primary resistance. Combining PARPi with chemotherapy, immune checkpoint inhibitors, or anti-angiogenic agents offers strategies to potentially increase the tumor susceptibility to PARPi and overcome resistance.

A Study of HER3-DXd in Subjects With Locally Advanced or Metastatic Solid Tumors

This is a proof-of-concept study designed to investigate HER3-DXd monotherapy in locally advanced unresectable or metastatic solid tumors. The study is enrolling cohorts of participants with melanoma \[cutaneous/acral\], squamous cell carcinomas of the head and neck (SCCHN), HER2-negative gastric cancer ovarian carcinoma, cervical cancer, endometrial cancer, bladder cancer, esophageal carcinoma, pancreatic carcinoma, prostate cancer, second-line gastric cancer, lung cancer, and breast cancer.