A clinical triall is testing Lartesertib and Tuvusertib, both taken orally, in men with mCRPC, particularly those with ATM mutations.

Lartesertib and Tuvusertib work by attacking the DNA damage response (DDR) system, a network cancer cells use to repair DNA and survive treatments like chemotherapy or radiation. Lartesertib blocks ATM (ataxia telangiectasia mutated), a protein that fixes double-strand DNA breaks, while Tuvusertib targets ATR (ataxia telangiectasia and Rad3-related), which handles DNA damage during cell division.

About 20–30% of mCRPC cases carry mutations in DDR genes like ATM, BRCA1, or BRCA2, making these tumors vulnerable to such targeted therapies. By shutting down these repair pathways, the drugs aim to make cancer cells unable to fix DNA damage, leading to their destruction.

Preclinical studies show that ATM-deficient tumors are highly sensitive to ATR inhibitors like Tuvusertib, and combining them with ATM inhibitors like Lartesertib may amplify this effect, creating a “double hit” that overwhelms cancer cells’ repair capabilities. The rationale for targeting both ATM and ATR stems from how cancer cells adapt. In ATM-mutated tumors, cells often rely on ATR or other pathways to compensate, allowing them to survive despite DNA damage. Tuvusertib disrupts this backup system, while Lartesertib ensures any residual ATM function is blocked, even in patients with partial ATM loss.

Early data suggests they’re well-tolerated, though side effects like anemia, a known issue with DDR inhibitors, are being closely monitored. The drugs’ oral delivery is a plus, offering convenience over intravenous options. This synergy mirrors successes in other cancers, like ovarian, where ATR inhibitors overcame PARP resistance.

Clinical trial.