The introduction of PARP inhibitors revolutionized the treatment of ovarian cancer, providing much-needed therapeutic options. However, clinical challenges remain as many patients are not candidates for PARP inhibitors and responses are often short-lived. Furthermore, biomarkers have not been established to definitively match patients with the most appropriate therapies.
Despite these challenges, ovarian cancer experts say it is an encouraging and exciting time in the field, with a multitude of combination approaches being investigated to enhance responses to therapy and identify relevant biomarkers. During the June 2 Education Session “The State of the Art in High-Grade Serous Ovarian Cancer,” three experts provided an update on the latest developments in the classification of ovarian cancer, current treatment approaches, and future directions.
Two-Tiered Classification System
Recent years have seen a growing recognition that ovarian cancer encompasses a heterogeneous group of malignancies that includes not only tumors in the ovaries but also those in nearby structures, such as the endometrium, primary peritoneum, and fallopian tubes. These malignancies encompass a variety of histologic, morphologic, and genetic subtypes, and may differ in their treatment approach.
Session speaker Elise C. Kohn, MD, of the National Cancer Institute, reminded the audience that in 2014, the World Health Organization and the International Federation of Gynecology and Obstetrics (FIGO) published revised staging classification criteria categorizing serous adenocarcinoma (SOC) into two grades—low and high—that differ in their histology and molecular characteristics. It is important for clinicians to recognize this distinction, Dr. Kohn explained, as high- and low-grade SOC respond differently to chemotherapy and thus may require different treatment approaches.
High-grade SOC accounts for approximately 70% of ovarian cancer cases. Molecular characteristics of high-grade SOC include TP53 mutations and genomic instability; serous tubal in situ carcinoma (STIC) precursors are also considered high grade. Low-grade SOC is relatively rare, occurring in fewer than 5% of cases; characteristics include KRAS and BRAFmutations.
Dr. Kohn added that high-grade SOC is considered to be highly chemosensitive. Although low-grade SOC can still respond to chemotherapy, “it just doesn’t meet expectations,” she said.
Given the clinical significance of the classification criteria, Dr. Kohn emphasized, “It is very important that [clinicians] are all on the same page that we separate [SOC] into high-grade and low-grade.” For clinicians who still receive pathology reports that include a number-based grading system, Dr. Kohn said that p53 immunostaining may help differentiate between the two subgroups. High-grade SOC is associated with null or overexpressed p53, whereas p53 expression is sporadic in low-grade SOC. A morphologic assessment can also provide useful information.
Current Therapeutic Approaches and Modifications
Dr. Kohn provided an overview of current treatment approaches for patients with ovarian cancer based on subtype. For patients with high-grade SOC, treatment may include chemotherapy, antiangiogenic therapy, DNA repair inhibition therapy, and radiation therapy. For low-grade SOC and all other subtypes (clear-cell, endometrial, and mucinous ovarian cancer), no validated type-specific treatment has been established.
Turning back to high-grade SOC, Dr. Kohn noted that the Gynecologic Cancer InterGroup (GCIG) recently published primary treatment recommendations for these patients. The consensus document notes that primary debulking surgery remains an important first-line intervention in high-grade SOC, with a goal of R0 resection. Neoadjuvant therapy may be considered for patients in whom R0 resection is not feasible; these patients should be considered for clinical trials. The standard chemotherapy regimen for high-grade SOC is intravenous carboplatin/paclitaxel administered every 3 weeks, although certain variations on this are acceptable.
Over the past year, a number of clinical trials have been presented or published evaluating different strategies in ovarian cancer treatment. The GOG-0262 trial reported no difference with the use of weekly compared with every-3-week paclitaxel except for a subset of patients who were not also receiving bevacizumab. “We should take that as interesting and provocative, but not necessarily as gospel,” Dr. Kohn concluded.
For patients with aysmptomatic CA125 relapse, GCIG guidelines note there is no proven effective therapy. For patients with platinum-sensitive recurrent disease, guidelines recommend a platinum combination with or without an antiangiogenic agent, or a platinum combination followed by a PARP inhibitor.
Several months ago, results were published from the GOG-0213 trial, which showed a nonsignificant small but persistent trend toward improved overall survival with the addition of bevacizumab to paclitaxel/carboplatin in patients with recurrent platinum-sensitive ovarian cancer. Bevacizumab received U.S. Food and Drug Administration approval for use in patients with platinum-sensitive recurrent ovarian cancer in late 2016.
GOG-0213 did not evaluate the role of surgery in the treatment of recurrent ovarian cancer. That question was explored in the randomized AGO-OVAR DESKTOP III trial, which compared cytoreductive surgery with no surgery, followed by recommended platinum-based chemotherapy, in patients with a positive AGO-Score. Results of the AGO-OVAR study were presented at a Gynecologic Cancer Oral Abstract Session on June 2 (Abstract 5500).
PARP maintenance therapy has also been evaluated as a strategy for improving outcomes in recurrent ovarian cancer. In the randomized, double-blind, phase III NOVA trial, niraparib maintenance therapy was associated with a significant improvement in progression-free survival (PFS) regardless of patients’ germline BRCA mutation. Dr. Kohn noted that results of the randomized, phase III SOLO2 trial were recently presented showing a significant improvement in median PFS with olaparib maintenance compared with placebo in patients with platinum-sensitive ovarian cancer with germline BRCAmutations.
Finally, in the AURELIA study, the addition of bevacizumab to chemotherapy was associated with a significant improvement in PFS in patients with platinum-resistant ovarian cancer. “It’s really intriguing that bevacizumab and weekly paclitaxel were driving these results,” Dr. Kohn said. “That is something we all need to consider.”
For patients with platinum-resistant ovarian cancer, surgery is used only for organ protection, and standards of care for treatment include various chemotherapy regimens with or without bevacizumab.
Future Directions in High-Grade SOC
All three speakers addressed the frontier of ovarian cancer therapy, where the emphasis is on leveraging the DNA damage response to improve responses to therapy. One option, Dr. Kohn explained, is through epigenetic generation of homologous recombination deficiency (HRD). Research from Dr. Kohn and others has shown the importance of hypoxia, generated locally through the use of angiogenesis inhibitors, which can modulate the DNA damage response.
Based on this scientific rationale, the combination of a PARP inhibitor and a VEGFR inhibitor could be fruitful. Data from a phase II study suggested that a combination of olaparib and the antiangiogenic agent cediranib could be more effective than olaparib alone for patients with recurrent platinum-sensitive ovarian cancer. Early-phase trials in other cancers are now underway.
A variety of other combination strategies are being evaluated to leverage the DNA damage response of PARP inhibitors, including the addition of cell cycle inhibitors, other DNA repair-targeting agents, and immunotherapeutics. Although these approaches are still early in development, Dr. Kohn concluded that there is a lot of optimism about the future.
Rational Approach to Targeted Therapy
In their presentations, Gordon B. Mills, MD, PhD, of The University of Texas MD Anderson Cancer Center, and S. Percy Ivy, MD, of the National Cancer Institute, both addressed the importance of a combination approach to the treatment of ovarian cancer. Dr. Mills said that a strategy of “rational combinatorial therapy” encompassing all therapeutic modalities would be needed to fulfill the promise of targeted therapy.
He explained that tumor cells do not exist in isolation but rather are part of a “complex and robust” ecosystem that can change in response to targeted therapy. “The whole intracellular environment will adapt to the stress of targeted therapy,” he said, and switch to an alternative pathway.
Efforts are underway to develop rational combinations by studying how tumor cells act in response to targeted therapy and employing appropriate targeted therapies to account for both adaptive responses and genomic resistance. Dr. Ivy called the combination approach “synthetic lethality,” as two approaches synergize to induce tumor cell death.
PARP inhibitors, which act by inducing DNA damage, are particularly effective in tumors with HRD, as these cells cannot accurately repair cell damage. Conversely, Dr. Ivy explained, cells that lack HRD, and are instead HR-sufficient, are resistant to PARP inhibitors. This finding suggests that strategies that could restore HRD might reverse PARP resistance. The combination strategies that Dr. Kohn discussed, including administering PARP inhibitors with cell cycle inhibitors, other signaling molecule inhibitors, antiangiogenic agents, immunotherapies, and other approaches, are all in line with this goal of developing rational combinations, or synthetic lethality, to enhance the efficacy and durability of PARP inhibition.
Another key line of inquiry in ovarian cancer research relates to the identification of biomarkers to appropriately select treatments for individual patients based on molecular factors. “We have barely started [in terms of] evaluating a patient with ovarian cancer, looking at their tumor in detail, and using that to select the best treatment,” Dr. Mills said. With the explosion of combinations to explore in ovarian cancer, and the work to be done in establishing biomarkers, many clinical trials can be expected on the horizon.
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