Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

SIMPLE SUMMARY: DNA damage induces genome instability, which may elicit cancer development. Defects in the DNA repair machinery further enhance cancer predisposition, but can also be exploited as a therapeutic target. Indeed, targeted agents against specific components of DNA repair, such as PARP inhibitors, are employed in various tumor types, while others, such as ATR, CHK1 or WEE1 inhibitors, are in clinical development. Even though these molecules have proven to be effective in different settings, they display several on- and off-target toxicities, shared by the whole pharmacological class or are drug specific. Among these effects, hematological and gastrointestinal toxicities are the most common, while others are less frequent but potentially life-threatening (e.g., myelodysplastic syndromes). Particular caution is needed in the case of combinatorial therapeutic approaches, which are currently being developed in clinical trials. In any case, it is necessary to recognize and properly manage adverse events of these drugs. This review provides a comprehensive overview on the safety profile of DDR-targeting agents, including indications for their management in clinical practice. ABSTRACT: Targeting the inherent vulnerability of cancer cells with an impaired DNA Damage Repair (DDR) machinery, Poly-ADP-Ribose-Polymerase (PARP) inhibitors have yielded significant results in several tumor types, eventually entering clinical practice for the treatment of ovarian, breast, pancreatic and prostate cancer. More recently, inhibitors of other key components of DNA repair, such as ATR, CHK1 and WEE1, have been developed and are currently under investigation in clinical trials. The inhibition of DDR inevitably induces on-target and off-target adverse events. Hematological and gastrointestinal toxicities as well as fatigue are common with all DDR-targeting agents, while other adverse events are drug specific, such as hypertension with niraparib and transaminase elevation with rucaparib. Cases of pneumonitis and secondary hematological malignancies have been reported with PARP inhibitors and, despite being overly rare, they deserve particular attention due to their severity. Safety also represents a crucial issue for the development of combination regimens incorporating DDR-targeting agents with other treatments, such as chemotherapy, anti-angiogenics or immunotherapy. As such, overlapping and cumulative toxicities should be considered, especially when more than two classes of drugs are combined. Here, we review the safety profile of DDR-targeting agents when used as single agents or in combination and we provide principles of toxicity management.