PARP enzymes are involved in a number of DNA repair processes. Tumors with pathogenic 

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 

 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 (

). 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 

mutations. FDA approval followed a phase II trial that showed a compelling objective response rate (ORR) of 34% for women with germline 

mutations and recurrent advanced ovarian cancer who progressed after 3 lines of therapy and were treated with single-agent olaparib.

 In this trial and other similar ones, patients with platinum-sensitive disease had a better response to olaparib than patients with platinum- resistant disease.

 Olaparib also showed activity in platinum-resistant ovarian cancer (in patients with germline 

 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

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

 mutation status, but a better response is expected in patients with germline 

 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.

 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,

 with a trend toward improved overall survival in one trial,

 it is an alternative to PARP inhibitor maintenance, especially for patients without pathogenic 

 mutations or other deficiencies in homologous recombination.

Table 1. Indications for PARP Inhibitors in Ovarian Cancer

There is potential synergy between PARP inhibitors and other therapies, such as immunotherapy and angiogenesis inhibitors. Tumors with 

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&mdash;are also on the horizon.

Until recently, treating patients with advanced breast cancer and deleterious 

 mutations was not appreciably different from treating similarly advanced patients with wild-type 

 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 

 Platinums and PARP inhibitors have been subsequently evaluated in advanced 

-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 

mutations and metastatic HER2-negative breast cancer who had received prior chemotherapy. The primary endpoint, PFS, was significantly longer in the PARP inhibitor arms,

 leading to FDA approval for both of these drugs (

The unresolved question from these trials is how to integrate platinums and PARP inhibitors into breast cancer treatment strategies, particularly for patients with 

 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.

 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.

Therefore, the optimal sequence of these agents in patients with 

-mutated metastatic breast cancer requires further study.

Table 2. Indications for PARP Inhibitors in Breast Cancer

An Eye Toward the Future: Better Definition of PARP Inhibitor Resistance

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 

 mutations are also under study. Exploration of these agents in 

-mutated early-stage breast cancer, in the neoadjuvant setting, are in preliminary stages.

Lastly, despite the demonstrated efficacy of PARP inhibition in 

-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.

 Strategies to circumvent PARP inhibitor resistance are a major focus of preclinical research that may require direct study of patient organoids and clinical trials.

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2010;376(9737):245-251. doi: 10.1016/S0140-6736(10)60893-8.

Kaufman B, Shapira-Frommer, R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.

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Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer.

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Litton JK, Rugo HS, Ettl J, et al. A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician’s choice of therapy in patients with advanced breast cancer and a germline BRCA-mutation. Presented at: San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS6-07.

Turner NC, Balmaña J, Fasching PA, et al. A phase 2 study (2-stage, 2-cohort) of the oral PARP inhibitor talazoparib (BMN 673) in patients with germline BRCA mutation and locally advanced and/or metastatic breast cancer (ABRAZO). 

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Articles

After years in development, several PARP inhibitors have achieved indications in ovarian cancer treatment, while others continue in development and expanding indications. 

Integrating PARP Inhibitors Into the Treatment of Women

Franco M. Muggia, MD, professor, Department of Medicine, NYU Langone Medical Center, discusses the current challenges oncologists are facing in the treatment landscape of ovarian cancer.

PARP inhibitors are effective agents in low-grade serous ovarian cancer, for which the major target is estrogen receptors, Muggia explains. Additionally, bevacizumab (Avastin) targets the vascular endothelial growth factor receptor.

Although the drugs in this field (which are mainly taxanes and platinum-based agents) have been effective, researchers need to improve upon increasing the cure rates for these patients. The challenge with this population is that resistance to these therapies often develop. There is also a high recurrence rate, he adds.

Videos

Dr. Muggia on Challenges in Ovarian Cancer Treatment

Franco M. Muggia, MD, professor, Department of Medicine, NYU Langone Medical Center, discusses combination treatments currently being tested for the treatment of patients with ovarian cancer.

Muggia summarizes 1 study that looked at platinum-resistant patients who received intraperitoneal carboplatin with intraperitoneal bortezomib (Velcade), a proteasome inhibitor. Though this was a small study of approximately 20 patients, there were quite a few positive responses, says Muggia.

He also discusses combinations involving PARP inhibitors, which are quickly becoming a major element of the overall ovarian cancer treatment landscape, with 3 particular agents at the forefront. Olaparib (Lynparza) was approved in 2014 for women with 

-positive advanced ovarian cancer following treatment with ≥3 prior lines of chemotherapy. In August 2016, the FDA granted a priority review to rucaparib for patients with 

-positive advanced ovarian cancer who have received ≥2 prior lines of chemotherapy. Finally, an application was recently submitted to the FDA for niraparib as a maintenance treatment for women with recurrent platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer.

Overall, Muggia says the intraperitoneal route appears to naturally lend itself for retreatment in this setting.

Dr. Muggia on Combination Treatments in Ovarian Cancer

Franco M. Muggia, MD, The Anne Murnick Cogan and David H. Cogan Professor of Oncology, 

 Medical Center, discusses using Doxil to treat ovarian cancer.

Muggia says Doxil is a special formulation of doxorubicin, a very toxic drug that was used in ovarian cancer when the drug first came out. Doxorubicin can only be used up to a certain limit and can cause cardiac and acute toxicities. It is currently only used in endometrial cancer, Muggia says.

Muggia says Doxil eliminates acute toxicities, though there are some delayed side effects associated with the drug. Muggia says he conducted a phase I trial of Doxil that showed remarkable response in ovarian cancer. Now, he is working on combining Doxil with other agents in phase II trials. Muggia says Doxil combines well with other drugs, especially those that have acute effects.

Muggia says physicians are researchers are now looking at combining Doxil with agents that have multiple acute effects in an effort to control the acute effects.

Franco M. Muggia, MD, professor of oncology, New York University, director, Division of Medical Oncology, New York University Medical Center, discusses using Doxil to treat ovarian cancer.

Dr. Muggia on Doxil in Ovarian Cancer

Franco M. Muggia, MD, Franco M. Muggia, MD, The Anne Murnick Cogan and David H. Cogan Professor of Oncology, 

 Medical Center, discusses the challenge of developing targeted therapies to treat ovarian cancer.

Muggia says drug development in ovarian cancer has not been easy, resulting in a lack of targeted therapies. Physicians rely on a chemotherapy regimen to treat patients with ovarian cancer that eliminates advanced disease about 80-90% of the time. However, Muggia says, the disease eventually comes back.

Muggia says there is a need to improve treatment for ovarian cancer. 

 and PARP targets have proven to be good targets to develop further.

Franco M. Muggia, MD, professor of oncology, New York University, director, Division of Medical Oncology, New York University Medical Center, discusses the challenge of developing targeted therapies to treat ovarian cancer.

Franco M. Muggia, MD

Articles

Integrating PARP Inhibitors Into the Treatment of Women

Dr. Muggia on Challenges in Ovarian Cancer Treatment

Dr. Muggia on Combination Treatments in Ovarian Cancer

Dr. Muggia on Doxil in Ovarian Cancer

Dr. Muggia on Targeted Therapies in Ovarian Cancer