Role of PARP Inhibitors in BRCA-Related Malignancies

Sana Iqbal, PharmD; Mohammad A. Rattu, PharmD, BCOP, BCPS, BCGP; Neal Shah, PharmD


US Pharmacist. 2018;43(9):HS10-HS17. 

In This Article

Abstract and Introduction


Poly (ADP-ribose) polymerase (PARP) inhibitors target an important enzyme involved in DNA repair. The agents olaparib, rucaparib, and niraparib are currently indicated for ovarian, fallopian tube, and primary peritoneal cancers. Olaparib is also indicated for breast cancer. PARP inhibitors have demonstrated statistically significant improvements in progression-free survival. Most adverse effects have been related to the gastrointestinal tract and the blood. Major limitations to the long-term use of PARP inhibitors include the development of bone marrow disorders and drug resistance. There are several more PARP inhibitors and combination strategies under investigation for solid and hematologic malignancies.


In recent years, target-specific chemotherapies and biotherapies have gained prominence in the field of oncology. One pertinent drug class is poly ADP ribose polymerase (PARP) inhibitors, which target a key enzyme involved in DNA repair. When a single-strand break (SSB) occurs in DNA, it is typically remedied through base excision repair via various PARP enzymes.[1,2] PARP-1 is recruited/activated by SSBs, and it transfers ADP ribose moieties from cellular nicotinamide-adenine-dinucleotide (NAD+) to acceptor proteins, a process known as PAR-ylation.[1,3] This eventually restores genomic integrity and normal cell function.[1] In the absence of PARP enzymes, alternate DNA repair mechanisms still exist.[1,2] An SSB can progress to a double-strand break (DSB), which can then be repaired via a precise process called homologous recombination.[1–3] Wild-type BRCA1 and BRCA2 are part of the complex that permits homologous recombination.[1,2] On the other hand, if DSBs cannot be repaired via homologous recombination (e.g., due to BRCA deficiencies mutations), there will be irreversible DNA damage and subsequent cell death.[1,2] PARP inhibitors promote the progression of SSBs to DSBs, and can induce synthetic lethality in cells with impaired homologous recombination mechanisms.[1–3] An overactivation of PARP-1 can also deplete NAD+ and lead to apoptosis (Figure 1).[1,3]

Figure 1.

Schematic mechanism of PARP inhibitors
SSBs in DNA recruit PARP. With a PARP inhibitor, more DSBs occur. In normal cells, SSBs and DSBs can be repaired. In BRCA-mutated cells, DSBs are not repaired effectively. DSB: double-strand break; HR: homologous recombination; PARP: Poly (ADP-ribose) polymerase; SSB: single-strand break. Source: References 1, 2.

PARP inhibitors have demonstrated clinical activity in somatic and/or germline BRCA-mutated malignancies (gBRCAm). Collectively, they are indicated for breast, ovarian, fallopian tube, and primary peritoneal cancers.[4–6] This drug class remains under investigation for its potential utility in solid and hematologic malignancies.