PARP Inhibitors Show Promise in Ovarian Cancer Treatment
Marilyn Huang, M.D.,
Sylvester Comprehensive Cancer Institute
About 23,000 cases of epithelial ovarian cancer (EOC), which includes fallopian tube and primary peritoneal carcinoma, are diagnosed annually,
They account for approximately 14,000 deaths, making it the fifth leading cause of cancer death among women.
Over the past 5 years, the treatment for EOC has been rapidly changing.
The standard frontline treatment for EOC consists of a combination of platinum-based chemotherapy regimen and cytoreductive surgery. While this approach achieves clinical remission, 70% of patients will develop recurrence within the first two years, at which time cure is no longer possible.
The unique molecular signatures among different types of EOC has been a particulaary important discovery. By identifying hereditary BRCA germline mutations and recognizing homologous recombination deficiency (HRD), we have new treatments as well as opportunities for prevention. Homologous recombination (HR) is critical to double-strand DNA repair and is lost in approximately 30% of patients with high-grade serous EOC.
What do PARP inhibitors do?
Poly (adenosine diphosphate-ribose) polymerase, or PARP, is a protein that helps damaged cells repair themselves.
PARP inhibitors trap PARP on DNA such that tumors with defects in HRD (patients with germline BRCA mutations) cannot repair and die. Based on this concept, PARP inhibitors were explored in recurrent ovarian cancer.
PARP inhibitors are another tool to battle recurrent ovarian cancer and may extend survival rates by months, but ovarian cancer remains a deadly disease.
Thus, strategies were undertaken to incorporate new therapies aimed at extending progression-free survival, which is the time from treatment completion until disease recurrence, and by proxy, overall survival.
Clinical trials are critical to advancing scientific knowledge to establish novel therapeutics in our pursuit to curing cancer.
Olaparib is a PARP inhibitor that gained FDA approval in 2014. In frontline EOC, a study evaluated the efficacy of maintenance Olaparib therapy in women carrying germline BRCA mutation after a complete or partial clinical response to platinum-based chemotherapy. The results from this study, published late 2018, changed the standard for EOC treatment forever. Use of maintenance Olaparib resulted in a dramatic, 70% lower risk of disease progression or death compared to placebo.
Olaparib has brought us a giant step closer to curing more women diagnosed with EOC.
Afterward, three trials (PRIMA, VELIA, and PAOLA-1) were completed in newly diagnosed women. The goal was to determine if women without a BRCA mutation or HRD would also benefit from PARP inhibitor therapy.
In PRIMA, women considered high risk for relapse, those with stage IV disease, received neoadjuvant chemotherapy or with residual disease following primary cytoreductive surgery that achieved complete or partial response with platinum-based chemotherapy were randomized to niraparib or placebo. While not an inclusion factor, the study assesses HR status on patient tumor samples. This study, reported results in 2019, demonstrating benefit in all groups of women. Specifically, women with BRCA mutations had the most benefit with reduction in death or progression of disease by 60%, women with HRD in their tissue 50% and in women with neither BRCA or HRD in germline DNA or tissue 32%. Based on this study, niraparib was granted FDA approval for use in the frontline maintenance setting.
We were fortunate at Sylvester Comprehensive Cancer Center to offer both the PRIMA and VELIA trials to women in South Florida. Based on these trials, niraparib was approved for frontline maintenance therapy in women with a partial or complete response to platinum-based chemotherapy.
I am thrilled to have patients on both trials that remain cancer-free.
While PARP inhibitors have dramatically changed the landscape of EOC. But patient selection remains a challenge. Not all patients benefit from this treatment and response is not definitive (development of drug resistance).
More research is warranted. We need to better understand the landscape of PARP inhibitor response mechanisms and to identify novel strategies to enrich the scope of PARP inhibitors through innovative combinations. In addition to PARP inhibitors, combinations with anti-angiogenic therapy (drugs that stop tumors from growing their own blood vessels), immuno-oncology (checkpoint inhibitors), DNA damage response (DDR) inhibitors, and epigenetic or chromatin modifiers are all being investigated in various stages of clinical trials.
At Sylvester, we offer multiple ovarian cancer clinical trials, including a trial combining checkpoint inhibitor (immunotherapy) with standard chemotherapy. This study aims to assess the pathologic response with the combination therapy.
I have dedicated my career to identifying both new agents and new combinations of therapy.
In addition to these trials, specimen collection and banking will allow us to gain further insight of markers in responders and non-responders that may serve as biomarkers that may predict response. Other trials are for women with recurrent EOC exploring different combination therapies.