PRIMA Clinical Trial
Bradley J. Monk, MD, Medical Director, Florida Cancer Specialists and Research Institute, West Palm Beach, and Founder of GOG Partners, discusses the clinical advances in the treatment of ovarian cancer, including research using PARP inhibitors, which can change standard of care for women with certain tumor types.
Over the past 25 years, the incidence of ovarian cancer has fallen significantly, and the prevalence has increased dramatically—the result of a greater focus on prevention, better characterization of tumor types, and more effective treatments.
For patients newly diagnosed with advanced or metastatic ovarian cancer, the standard of care is surgery and adjuvant first-line platinum-based chemotherapy (or combined with the antiangiogenesis agent bevacizumab). Patients who respond to first-line treatment are given maintenance therapy with poly(ADP)-ribose polymerase (PARP) inhibitors, possibly in combination with bevacizumab.
Niraparib is a PARP inhibitor that was the subject of the double-blind, randomized, placebo-controlled, multicenter trial (also known as the PRIMA study), which evaluated its efficacy as first-line maintenance therapy in patients with newly diagnosed, advanced ovarian cancer. This trial evaluated the effect of niraparib in patients with homologous recombination deficient (HRd) tumors or in the overall study population.
Seven hundred thirty-three patients with advanced ovarian cancer were randomized 2:1 to receive niraparib or placebo once daily after completion of platinum-based chemotherapy. All patients were treated until the emergence of intolerable toxicity or disease progression, with an intended treatment duration of 3 years. If the investigator believed the patient was benefiting from treatment, the niraparib therapy could continue.
In the final analysis of the PRIMA trial, mean patient follow-up duration was 73.9 months. In the earlier, primary study, researchers found an improvement in median progression-free survival (PFS) in the overall study population (13.8 mo for the niraparib group vs. 8.2 mo for the placebo group; hazard ratio, 0.62; P < .001) and in the HRd-tumor study population (21.9 mo vs. 10.4 mo, respectively; hazard ratio 0.43; P < .001). In the extended, final study analysis, the researchers confirmed the durability of this benefit, with a hazard ratio for disease progression of 0.66 in the overall population and 0.67 in the HRd-tumor cohort. However, overall survival was not differentiated among the overall population (hazard ratio, 1.01) and HRd cohorts (hazard ratio, 0.95). An improvement in overall survival was noted in one subgroup with HRd and BRCAm tumors (hazard analysis 0.89), though the study was not designed to detect these subgroup differences. No new safety signals were seen in the extended analysis, and there was no decrement in the patients’ quality of life.
The investigators concluded that first-line maintenance therapy with the PARP inhibitor niraparib in patients with advanced ovarian cancer resulted in no significant difference in overall survival but a greater 5-year PFS compared with placebo, especially in those with HRd tumors.
PARP Inhibitors
Paul DiSilvestro, MD, Director, Program in Women’s Oncology, Women & Infants Hospital of Rhode Island, Providence, and Division Director for Gynecologic Oncology, Department of Obstetrics and Gynecology at The Warren Alpert Medical School of Brown University, discusses how PARP inhibitors are dramatically improving clinical outcomes for certain women with advanced ovarian cancer.
In breast cancer and colorectal cancer, physicians are very good at preventing and diagnosing early-stage disease. This is not the case with ovarian cancer. Most patients with ovarian cancer receive their initial diagnosis only after the disease has spread, mainly because of a lack of useful screening tools and the relative lack of notable early symptoms.
Despite the typical late diagnosis, women with ovarian cancer are seeing far better improvements in long-term survival; in years past, overall survival was only 20%, but today its approximately 50%, with the majority of women experiencing long-term survivals (with data up to 7 years from diagnosis). It is not a cure, but it is a far better story today for women with advanced ovarian cancer.
This improved survival is directly related to the critical utility of tumor testing (1) for germline BRCA mutations and (2) somatic homologous recombination deficiency (HRd) and BRCA mutations. Upon diagnosis, germline and somatic genetic testing are now considered the standard of care.
According to Dr. DiSilvestro, in patients with advance ovarian cancer, homologous recombination repair is key. He explained that DNA consists of two parallel strands, like a railroad track. The four nucleic acids are like railroad ties between the strands. If one strand bends or breaks, one strand is still intact. Ordinarily, the body will try to repair the DNA and restore its twin helix structure through the use of poly(ADP-ribose) polymerase or PARP enzyme.
In the case of most cancers, including ovarian cancer, if one DNA strand breaks, you don’t want that repair to occur; you want the other strand to break as well. In other words, “the idea is to drive single-stranded breaks to double-stranded breaks.” That requires inhibiting the action of PARP, to “force the cancer tumor growth off the track.”
PARP inhibitors (e.g., niraparib, olaparib) are used in combination as first-line therapy and as maintenance therapy after platinum-based chemotherapy for patients with BRCA variants. Of women with advanced ovarian cancer, approximately 15% have a BRCA germ-line mutation and 7% have a somatic BRCA mutation. This group of patients generally have HRd-positive tumors as well.
The results of recent studies highlight the importance of testing for both germline and somatic BRCA mutations and providing first-line maintenance therapy with PARP inhibitors to all patients with advanced ovarian cancer who have BRCA mutations. Study evidence now indicates that withholding PARP-inhibitor therapy in the maintenance setting until the patient suffers disease progression or relapse is no longer optimal. In patients with HRd-positive tumors, PARP inhibitors are used as first-line maintenance therapy in combination with bevacizumab.
