As the leading cause of death among all gynecological cancers in developed countries,1 ovarian cancer is a devastating malignancy. According to the World Health Organization, in 2018, there were an estimated 295,000 new cases of ovarian cancer and 185,000 deaths worldwide.2 Because ovarian cancer can be difficult to detect in the early stages of development, the majority of patients present with advanced stage tumors.1 In fact, 59% of ovarian cancers are metastatic at diagnosis, with an additional 21% spread to regional lymph nodes.3 For women with metastatic epithelial ovarian cancer, the 5-year relative survival rate is only 29.2%.2,4
The initial treatment of newly diagnosed advanced disease generally begins with surgery, including total abdominal hysterectomy and cytoreduction,5 followed by platinum-based chemotherapy plus antiangiogenesis therapy with a vascular endothelial growth factor (VEGF) inhibitor. Subsequently, a VEGF inhibitor or a poly ADP ribose polymerase (PARP) inhibitor—for tumors with a BRCA mutation—are given as maintenance therapy.6 For those who are poor surgical candidates or have a low likelihood of optimal cytoreduction, neoadjuvant therapy may be considered.
Despite responding well to first-line treatment, most patients with the cancer relapse less than 2 years after diagnosis. However, longer progression-free survival after first-line therapy improves the probability of response to a second line of chemotherapy after relapse.7 “Unfortunately, it is a fact that the majority of patients will relapse,” said Isabelle Ray-Coquard, MD, PhD, of Centre Leon Bérard, Professor of Medical Oncology at Université Claude Bernard, Lyon, and President of the GINECO group France. “For this reason, we should not delay providing an available option for future use in the management of ovarian cancer if it is possible to give the treatment now, because we don’t know what the future will bring.”
Although women with advanced ovarian cancer have a range of treatment options, no one choice is right for every patient.8 Therefore, treatments must be chosen with the patient’s individual tumor characteristics in mind. Richard T. Penson, MD, MRCP, Associate Professor of Medicine at Harvard Medical School and Clinical Director of Medical Gynecologic Oncology at Massachusetts General Hospital, is convinced that molecular testing is the first step to choosing the right treatment. “Every single woman with ovarian cancer has to be gene tested for the significant clinical benefit in that patient, and the potential to prevent the disease in future generations of families who carry predisposition gene mutations,” he explained.
The National Comprehensive Cancer Network (NCCN) Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian recommend that all women diagnosed with ovarian cancer receive tumor molecular testing.9 However, there are still considerable gaps in testing. A survey of oncologists in the United States and Europe on treatment practices of advanced ovarian cancer across different countries found substantial variability in genetic testing and treatment of ovarian cancer.10
For example, the survey showed that although the proportions of patients in treatment, maintenance, and remission were identical across each country, and line of treatment, at 60%, 20%, and 20%, respectively, the proportion of BRCA testing was not performed systematically, with rates ranging from 45% in Italy to 73% in the United States, raising concerns regarding access to the most appropriate treatment for patients whose BRCA status is unknown.
Recent advances in the understanding of hereditary ovarian cancer have shown that the BRCA gene plays a significant role in the development of ovarian/fallopian tube cancers. Approximately 10% to 15% of women with ovarian cancer have a germline BRCA mutation11 and about 7% have somatic BRCA gene mutations,12 as well as several other mutations unrelated to BRCA. In ovarian cancer, patients harboring BRCA 1/2 mutations have different patterns of clinical behavior and respond differently to treatment.
Because the BRCA gene also plays a role in repairing DNA via homologous recombination (HR) and mutation of this gene leads to HR deficiency (HRD), in addition to BRCA1/2 testing for patients with advanced ovarian cancer, testing for homologous recombination deficiency should also be performed and an assay for HRD is now available commercially. “We are now planning homologous recombination deficiency testing in all patients in addition to testing for BRCA mutations,” said Dr. Penson.
The introduction of PARP inhibitors has transformed the management of ovarian cancer and changed the course of disease for many patients.13 In 2014, the U.S. Food and Drug Administration (FDA) approved the first PARP inhibitor for use in women with deleterious germline BRCA-mutated advanced ovarian cancer who had been treated with three or more prior lines of chemotherapy.14 Three PARP inhibitors are now approved by the FDA for the treatment of ovarian cancer,15–17 and an indication was recently added for its use as first-line maintenance therapy in patients with BRCA1/2 mutations in complete clinical or partial remission.15
The most advantageous characteristic of PARP inhibitors is the mechanism of action, which targets cancer cells and exploits their inherent deficiencies while avoiding normally functioning cells.18 Tumors with a deficiency in the homologous recombination repair pathway are highly vulnerable to the effects of PARP inhibition. Because homologous deficiency prevents the tumor cells from repairing the damage inflicted when PARP is suppressed, genomic instability and cell death results.13,19 This is often seen in BRCA-mutated tumors, since functioning BRCA proteins have a major role in preserving the complex DNA repair pathway.19 Other mechanisms apart from BRCA mutations can also result in homologous recombination repair pathway alterations and lead to a clinical benefit from PARP inhibitors.19
Approximately 50% of high-grade serous ovarian tumors are estimated to have a degree of homologous recombination repair deficiency, either germline or somatic mutations, and are likely to benefit from PARP inhibitors.20 Studies show among women with BRCA1/2 mutations, maintenance PARP inhibitor therapy for those with disease recurrence has led to a nearly fourfold prolongation of progression-free survival compared with placebo.21 Additionally, women with BRCA1/2 mutations who respond to first-line chemotherapy and receive a maintenance PARP inhibitor have a 70% lower risk of disease progression or death than with placebo.22 However, tumors that become platinum resistant—an inevitable consequence of recurrence—rarely respond to PARP inhibitors.19
Impressive results from several important phase III studies of three PARP inhibitors in front-line maintenance therapy for patients with newly diagnosed advanced ovarian cancer—and not just those with BRCA mutations— presented at the European Society for Medical Oncology (ESMO) Congress 2019 show the potential these therapies have to reshape the treatment landscape of this cancer.
“All three phase III trials reported positive, statistically significant results for PARP inhibitors in the first-line setting for advanced ovarian cancer,” said Dr. Ray-Coquard. “Based on this data, PARP inhibitors should be considered beyond BRCA status as first-line treatment.” In one study, women with advanced ovarian cancer and visible residual disease after debulking surgery received a PARP inhibitor as first-line treatment after responding to platinum-based chemotherapy. The greatest benefit was seen in patients with homologous recombination–deficient disease, with a progression-free survival more than twice as long in patients receiving the PARP inhibitor compared with placebo (22.1 vs 10.9 months, respectively).23 Although homologous recombination–proficient tumors had a statistically significant benefit in terms of progression-free survival, “the improvement was only 2.7 months,” explained Dr. Penson. “This is not a clinically meaningful benefit. However, we do expect the FDA to approve this PARP inhibitor in homologous recombination–deficient tumors, because the data was significant and substantial in patients with homologous recombination–deficient tumors.”
Another highlighted trial was the first phase III study to evaluate the efficacy and safety of a PARP inhibitor in combination with a VEGF inhibitor, compared with placebo plus a VEGF inhibitor, as first-line maintenance in advanced ovarian cancer. Overall, the combination improved median progression-free survival from 16.6 months to 22.1 months.24 “In this study, patients were not randomized until 7 months after the first cycle of chemotherapy,” said Dr. Ray-Coquard, principal investigator of the study. “So, the intent-to-treat population had close to 30 months of progression-free survival, which we have never seen before. Additionally, this study did not restrict patient selection based on surgical outcome or BRCA mutation status, so the study population was representative of the majority of patients with advanced ovarian cancer.”
In patients with tumors positive for homologous recombination–deficiency—including those with a tumor BRCA mutation—the combination increased progression-free survival by 19 months compared with the VEGF inhibitor alone (17.7 months vs 37.2 months, respectively).
“This study supports the combination of a PARP inhibitor and VEGF inhibitor, for patients who can receive a VEGF inhibitor, for all patients in first-line therapy,” said Dr. Ray-Coquard. However, Dr. Penson had a different interpretation of the study’s results.￼ “This study suggested little benefit from a VEGF inhibitor,” he explained. “Although there is added benefit, the greatest benefit in patients with a BRCA mutation is from the PARP inhibitor. We haven’t yet defined the relative contribution of VEGF inhibition versus PARP inhibition in tumors with homologous recombination–deficiency, as there is no clear biomarker for antiangiogenic benefit.
The final study evaluated a PARP inhibitor given simultaneously with platinum-based chemotherapy and continued as maintenance therapy. Patients were randomly assigned to one of three treatment arms: chemotherapy plus placebo followed by placebo maintenance; chemotherapy plus PARP inhibitor followed by placebo maintenance; or chemotherapy plus PARP inhibitor followed by PARP inhibitor maintenance. Progression-free survival was significantly longer in the women who received the PARP inhibitor plus chemotherapy and PARP inhibitor maintenance compared with the other treatment arms, and an even greater benefit was seen in patients with the BRCA1/2 mutation and in patients with homologous recombination–deficiency.25 No benefit was observed for patients who were given a PARP inhibitor plus chemotherapy only.
According to Dr. Penson, the data presented at ESMO do not make a strong enough case for universally treating women upfront with PARP inhibitors. “Patients are dividing out into three groups. One-quarter have a BRCA mutation, another quarter have homologous recombination deficiency, and the remainder of the patients are homologous recombination–proficient,” said Dr. Penson. “My strong bias is that PARP inhibitors should be available to twice the number of patients than previously, including those with BRCA mutations and other homologous recombination deficiencies, but should be limited to biomarker-driven homologous recombination deficiency tumors.” Dr. Ray-Coquard pointed out, however, that testing for these deficiencies may have room for improvement. “In these trials, the results of the homologous recombination deficiency assay were inconclusive for 15%-18% of enrolled patients. Until a more accurate test is developed, the best option for these patients will remain uncertain,” she said.
How will the introduction of PARP inhibitors earlier in treatment affect its use in recurrent disease? “We just don’t know the answer to that,” said Dr. Penson. “We suspect, based on Canadian and Australian data, that one-third of patients who have prior PARP exposure will develop resistance and lose the advantage of their BRCA mutation or homologous recombination deficiency positivity. However, two-thirds will still respond.”
Dr. Ray-Coquard noted that the reintroduction of a VEGF inhibitor at relapse after receiving it earlier in treatment can improve progression-free survival in ovarian cancer, but it is not known if this applies to PARP inhibitors. “An ongoing study is evaluating this question, but until recently, very few patients received re-treatment with a PARP inhibitor,” said Dr. Ray-Coquard.
Although women with ovarian cancer may initially be hesitant to begin maintenance therapy immediately following chemotherapy, according to Dr. Ray-Coquard, if patients understand the complete treatment plan from the beginning of therapy includes maintenance treatment they are likely to be more comfortable with the protocol.
“If a PARP inhibitor is likely to be introduced as maintenance therapy, the patient should understand that the end of chemotherapy is not the end of treatment,” said Dr. Ray-Coquard. “We have to personalize our consultation and adapt the discussion to the patient. In advanced disease where survival is very short, providing plenty of information is essential.”
Also important is ensuring that patients are educated regarding expectations of side effects when PARP inhibitors are introduced. “Unlike with chemotherapy, where nausea, fatigue, and anemia increase with each treatment cycle, the majority of side effects with PARP inhibitors happen at the beginning of therapy,” said Dr. Ray-Coquard. “If we don’t explain the timing of the side effects, patients may want to discontinue the PARP inhibitor in the first 2 weeks.” Dr. Penson agreed that educating patients about nausea and fatigue is what allows patients to stay on the optimal dose of treatment. “Many patients are dose-reduced unnecessarily because the nausea and fatigue peaks at 2 weeks and then improves. If you stop the medication for 3 days and give antiemetics, the patient can often tolerate the same treatment dose.” For this reason, “we generally wait 2 months to start a PARP inhibitor after chemotherapy is completed; this ‘treatment holiday’ is really appreciated by patients,” said Dr. Ray-Coquard.
“Going forward, we need to practice biomarker-driven medicine,” said Dr. Penson. “We are seeing advantages for patients with oral treatments that extend survival, which is very exciting.” Despite the positive results from the recent phase III clinical trials described here, many questions remain about how best to use PARP inhibitors in the treatment of advanced ovarian cancer and in whom. Should all patients receive PARP inhibitors or should they be restricted to patients with BRCA mutations and HRD positivity? How will first-line use of PARP inhibitors affect their use in the relapsed setting? And, how best should PARP inhibitors be used in combination with other therapies to increase their effectiveness?
Currently, ongoing trials are underway that may provide the answers to these questions, including studies evaluating immunotherapy combined with a PARP inhibitor and triplet therapy of a PARP inhibitor, immunotherapy, and VEGF inhibition.26 The results of these studies, and others, will continue to shape and impact the future treatment of women with advanced ovarian cancer and provide optimism about the integration of novel therapies.
Dr. Ray-Coquard disclosed that she has received honoraria from AstraZeneca, Clovis, Tesaro and PharmaMar; consulting or advisory board fees from AstraZeneca, Roche, Clovis, Tesaro, Genmab, PharmaMar, MSD and Pfizer; research funding from MSD, GSK, and Pharmamar; and travel expenses from AstraZeneca and Roche, MSD, Tesaro and Clovis.
Dr. Penson disclosed that he has served on scientific advisory boards for AbbVie, Amgen Inc., AstraZeneca, Baxalta Oncology, Care4ward (unpaid), Clovis Oncology, Eisai Inc., Genentech, Inc., Merck & Co., Mersana Therapeutics, Inc., Sutro Biopharma, Tesaro, and Vascular Biogenics Ltd; he has received research funding from Array BioPharma Inc., AstraZeneca, Cerulean Pharma Inc. Eisai Inc., Genentech, Inc., Regeneron, Sanofi-Aventis, US LLC, Tesaro Inc., and Vascular Biogenics Ltd; and has received royalties from BMJ, Blackwell Publishing Medicine at a Glance, UpToDate, Advance Medical, Best Doctors, and Grand Rounds: Second Medical Opinions.
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