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Capecitabine + peposertib is an investigational combination therapy studied primarily for the treatment of locally advanced rectal cancer. Capecitabine is an oral prodrug of 5-fluorouracil (5-FU), a nucleoside metabolic inhibitor that interferes with DNA synthesis and inhibits tumor cell proliferation. Peposertib (also known as M3814) is a potent, selective small molecule inhibitor of DNA-dependent protein kinase (DNA-PK), which plays a critical role in the repair of DNA double-strand breaks via non-homologous end joining. The rationale for combining these agents is to enhance radiosensitization during chemoradiotherapy by inhibiting DNA repair mechanisms in tumor cells, thereby increasing their susceptibility to radiation-induced damage. In phase Ib studies, this combination was evaluated alongside radiotherapy; however, it did not improve complete response rates at tolerable dose levels and was associated with significant gastrointestinal toxicity[1][2][4].
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