After years in development, several PARP inhibitors have achieved indications in ovarian cancer treatment, while others continue in development and expanding indications.
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 and BRCA2 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.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 (gBRCA) mutations);2,4 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.
There is potential synergy between PARP inhibitors and other therapies, such as immunotherapy and angiogenesis inhibitors. Tumors with BRCA mutations or other deficits in homologous recombination may be more immunogenic than other tumors. Other strategies, such as chemoimmunoconjugates and other approaches to synthetic lethality beyond PARP inhibition—for example, targeting ataxia telangiectasia mutated (ATM) or ATM and RAD-3 related—are also on the horizon.Until recently, treating patients with advanced breast cancer and deleterious BRCA mutations was not appreciably different from treating similarly advanced patients with wild-type BRCA status. But more than a decade ago, mouse models of triple-negative breast cancer developed by the Jonkers laboratory at the Netherlands Cancer Institute in Amsterdam had clearly shown extreme sensitivity to cisplatin in these BRCA-mutated breast cancer models.9 Platinums and PARP inhibitors have been subsequently evaluated in advanced BRCA-mutated breast cancer. OlympiAD and EMBRACA were randomized phase III trials that compared olaparib and talazoparib (Talzenna), respectively, with physician’s choice chemotherapy (not including platinum chemotherapy) in patients with gBRCA mutations and metastatic HER2-negative breast cancer who had received prior chemotherapy. The primary endpoint, PFS, was significantly longer in the PARP inhibitor arms,10,11 leading to FDA approval for both of these drugs (Table 2).
The unresolved question from these trials is how to integrate platinums and PARP inhibitors into breast cancer treatment strategies, particularly for patients with gBRCA mutations. Subgroup analyses from OlympiAD, EMBRACA, and ABRAZO show that in patients who had previously received platinum chemotherapy, response rates to the olaparib and talazoparib were lower than in other subgroups; however, these drugs were still active in platinum-experienced patients.12 Early treatment of metastatic disease with PARP inhibitors, relegating treatment with platinum upon progression has been tested in a phase II trial of veliparib followed by veliparib plus carboplatin, but results were not encouraging.13 Therefore, the optimal sequence of these agents in patients with gBRCA-mutated metastatic breast cancer requires further study.
As in ovarian cancer, combinations of PARP inhibitors with immunotherapy and novel drugs targeting other mediators of DNA damage response are planned or ongoing. Assays for homologous recombination, with the goal of expanding the use of PARP inhibition to patients with breast cancer with other defects in homologous recombination beyond gBRCA mutations are also under study. Exploration of these agents in BRCA-mutated early-stage breast cancer, in the neoadjuvant setting, are in preliminary stages.14Lastly, despite the demonstrated efficacy of PARP inhibition in BRCA-mutated ovarian and breast cancers, most patients, especially if exposure occurs after many previous treatments, eventually develop resistance. Among mechanisms of PARP inhibitor resistance being studied are increased PARP inhibitor drug efflux, reversion mutations that restore homologous recombination (the most well-described mechanism to date), changes in replication fork stability, and loss of proteins that antagonize BRCA function.15,16 Strategies to circumvent PARP inhibitor resistance are a major focus of preclinical research that may require direct study of patient organoids and clinical trials.