PARP Inhibitors

PARP inhibitor [poly (ADP-ribose) polymerase inhibitor] drugs make up a class of medications most typically used with breast and ovarian cancers with BRCA1, BRCA2 or PALB2 mutations. In addition, it then may have some effect in cancers in which the tumor suppressor PTEN gene is defective. PARP is a protein that repairs breaks in the DNA. When the ability to repair these DNA breaks are inhibited, it can lead to the death of the cells. Rapidly dividing cells, such as cancer cells, would be more sensitive to this than normal cells.

A study published in the journal Cancer Immunology Research, November 2015, by Higuchi, et al., “CTLA-4 Blockade Synergizes Therapeutically with PARP Inhibition in BRCA1-Deficient Ovarian Cancer” demonstrated that CTLA-4 inhibitors, but not PD-1/PD-L1 inhibitors, enhanced the anti-cancer immune response and survival in the mouse model. However, in a human study with 60 patients with ovarian cancer that was resistant to platinum therapy, 25% of the patients had a complete or partial response using the combination of the PARP inhibitor niraparib with the PD-1 inhibitor pembrolizumab (Keytruda). This was versus 5% with the PARP alone and 11% with Keytruda alone. Also of note, these patients did not have BRCA mutations, which will increase the potential of patients that can be treated with this combination.

Studies have shown that PARP inhibitors increase the expression of PD-L1, which can increase the effectiveness of PD-1/PD-L1 inhibitors (Clinical Cancer Research, Jiao, et al. Feb 2017, “PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression”). Some of the early results with human clinical trials have shown modest increase in survival time, but overall the results are still fairly lacking. Since we know that in general, for systemicimmunotherapy, a PD-1/CTLA-4 inhibitor combination (Yervoy/Opdivo or Yervoy/Keytruda) can be effective at times, those combinations of drugs with a PARP inhibitor should be somewhat promising, as well.

Reference: Jason R. Williams, 15 Oct 2019, The Immunotherapy Revolution: The Best New Hope For Saving Cancer Patients’ Lives,