Franco Muggia, MD
PARP enzymes are involved in a number of DNA repair processes. Tumors with pathogenic BRCA
mutations are associated with a deficiency in homologous recombination, a critical double-stranded DNA repair process. When patients with these tumors are treated with PARP inhibitors, the combination of DNA repair deficiencies may lead to tumor toxicity while sparing noncancerous tissue that has relatively intact BRCA function. Exploiting selective cellular susceptibilities by affecting parallel pathways has been called synthetic lethality. Applications of this concept in women’s cancers emerged more than a decade ago in the context of the vulnerabilities of BRCA1
null ovarian cancer cells when exposed to PARP inhibitors. Since this first positive signal, these drugs have eventually undergone numerous trials obtaining specific indications as monotherapy. More recently, they have sought to be integrated within emerging therapeutic strategies in not only ovarian cancer but also breast cancer.
PARP Inhibition in Ovarian Cancer
After years in development, several PARP inhibitors have achieved indications in ovarian cancer treatment, while others continue in development and expanding indications (Table 1
). The approved roles of PARP inhibitors in ovarian cancer fall into 2 main approaches: treatment of recurrent disease and maintenance after response to platinum-based chemotherapy.
In the treatment of ovarian cancer, olaparib (Lynparza) was the first PARP inhibitor approved by the FDA, with much of the initial clinical investigation efforts concentrated on women with germline BRCA
mutations. FDA approval followed a phase II trial that showed a compelling objective response rate (ORR) of 34% for women with germline BRCA
mutations and recurrent advanced ovarian cancer who progressed after 3 lines of therapy and were treated with single-agent olaparib.1
In this trial and other similar ones, patients with platinum-sensitive disease had a better response to olaparib than patients with platinum- resistant disease.2,3
Olaparib also showed activity in platinum-resistant ovarian cancer (in patients with germline BRCA
this distinguishes the drug from other PARP inhibitors that have not shown efficacy in platinum-resistant disease.
Rucaparib (Rubraca) showed a similarly compelling ORR in phase II trials. In contrast with the olaparib data, rucaparib trials expanded eligibility to patients with BRCA
somatic mutations (in addition to germline mutations) but limited evaluation to patients with platinum- sensitive disease. Adverse-effect profiles also differ slightly between the 2 drugs, affecting treatment choice. Ongoing trials will evaluate the efficacy of PARP inhibition in platinum-resistant ovarian cancer, and phase III trials will compare PARP inhibition with standard chemotherapy, which should yield important data that have been lacking from the previously mentioned single-arm phase II studies.
Niraparib (Zejula), olaparib, and rucaparib are approved for maintenance therapy of patients with platinum-sensitive, relapsed ovarian cancer, regardless of BRCA
mutation status, but a better response is expected in patients with germline BRCA
mutations compared with the general population. Niraparib and rucaparib trial data also showed that patients with deficiencies in homologous recombination, as defined by various assays, have a better response to PARP inhibitor maintenance than patients without any deficiency in DNA repair.5,6
Further validation homologous recombination deficiency assays is ongoing. Because bevacizumab (Avastin) yields improved progression-free survival (PFS) in the treatment (in combination with carboplatin and either gemcitabine or paclitaxel) and maintenance of platinum-sensitive recurrent ovarian cancer,7,8
with a trend toward improved overall survival in one trial,8
it is an alternative to PARP inhibitor maintenance, especially for patients without pathogenic BRCA
mutations or other deficiencies in homologous recombination.