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Bevacizumab and PARP Inhibitors in Ovarian Cancer
My Thoughts on the Expanding Roles of Bevacizumab and PARP Inhibitors in Ovarian Cancer Treatment

Released: September 11, 2017

Expiration: September 10, 2018

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Recent new approvals and indications are transforming management strategies and improving outcomes for patients with ovarian cancer. Bevacizumab is commonly used for recurrent disease, and PARP inhibitors are an increasingly important strategy, but planning the optimal treatment sequence can be a challenge. In this commentary, I share my thoughts on recent clinical data and how clinicians can optimize the use of both bevacizumab and PARP inhibitors in treating their patients with ovarian cancer.

Bevacizumab
The FDA has approved bevacizumab for the treatment of recurrent ovarian cancer, both in the platinum-resistant and platinum-sensitive settings. In Europe, bevacizumab is more broadly approved for treating advanced high-risk ovarian cancer, that is, FIGO stage III/IV disease. I do not use bevacizumab for women with newly diagnosed ovarian cancer because it does not (yet) have an FDA approval in this setting, but I often use bevacizumab for recurrent disease. Let’s discuss the data behind these decisions.

Front Line: In the phase III GOG-0218 trial of newly diagnosed stage III/IV ovarian cancer, median PFS was improved by approximately 4 months with the addition of bevacizumab to every-3-week carboplatin/paclitaxel followed by bevacizumab maintenance vs chemotherapy alone. In the phase III ICON7 trial, a European study that used a reduced dose of bevacizumab (7.5 mg/kg vs 15.0 mg/kg in the GOG trial) in combination with carboplatin/paclitaxel followed by bevacizumab maintenance for patients with stage I-IV disease, the PFS improvement vs carboplatin/paclitaxel alone was deemed statistically significant but was only a 2.4-month improvement. No OS improvement was seen in either trial.

Platinum-Resistant Recurrence: The phase III AURELIA trial assessed single-agent chemotherapy with or without bevacizumab in patients with platinum-resistant ovarian cancer. Results showed a doubling in median PFS, from 3.4 months with chemotherapy alone to 6.8 months with addition of bevacizumab (P < .0001). Median OS improved from 13.3 months to 16.6 months. Of note, both chemotherapy and bevacizumab were continued until progression or unacceptable toxicity.

In a subsequent analysis by chemotherapy cohort, of the 3 chemotherapy regimens included in this trial, the most pronounced benefit was seen with weekly paclitaxel plus bevacizumab, which improved median PFS by 5.7 months vs paclitaxel alone, from 3.9 months to 10.4 months (HR: 0.47). Lesser benefit was noted with pegylated liposomal doxorubicin (median PFS: 3.5 vs 5.1 months) and topotecan (median PFS: 2.1 vs 6.2 months). There was no significant difference in OS between treatment arms in any of the chemotherapy cohorts, but there was a trend toward improvement in the weekly paclitaxel cohort (unadjusted HR: 0.65; median 22.4 vs 13.2 months).

For platinum-resistant ovarian cancer, if a patient is symptomatic, has rapid growth, or concern exists about near-future progression, it makes sense to add bevacizumab to single agent chemotherapy. However, the potential benefit of any therapy must be weighed against the adverse events associated with this agent, mostly hypertension, proteinuria, and risk of perforation. Hypertension is the most common and can be controlled with medication but must be closely monitored. Proteinuria is also a concern, and physicians must monitor kidney function using the UPC ratio. Gastrointestinal perforation is uncommon but is a risk with bevacizumab therapy. A phase II study of single-agent bevacizumab in patients with platinum-resistant disease showed a higher incidence of gastrointestinal perforations in patients with 3 or more lines of chemotherapy, thickening of the bowel on CT, and/or evidence of bowel obstruction. So, bevacizumab should be avoided in patients with a current diagnosis of a bowel obstruction, signs and symptoms possibly related to bowel dysfunction, or an impending small bowel obstruction.

Platinum-Sensitive Recurrence: Next, 2 trials examined the combination of bevacizumab with platinum-based chemotherapy for the treatment of platinum-sensitive, recurrent ovarian cancer. The phase III OCEANS study looked at the addition of bevacizumab to carboplatin/gemcitabine followed by bevacizumab maintenance as second-line therapy for patients with epithelial ovarian, primary peritoneal, or fallopian tube cancer. In this study, the addition of bevacizumab provided a 4-month median PFS improvement vs chemotherapy alone (12.4 vs 8.4 months), albeit with no OS improvement.

The phase III GOG-0213 study similarly evaluated the addition of bevacizumab to carboplatin/paclitaxel followed by bevacizumab maintenance in patients with recurrent, platinum-sensitive ovarian cancer. In the bevacizumab arm, there was a 4.4-month PFS improvement and a 5-month improvement in median OS compared with chemotherapy alone. Based on these results, the FDA approved bevacizumab in combination with chemotherapy for platinum-sensitive ovarian cancer.

Clinicians considering the use of bevacizumab to treat their patients with recurrent, platinum-sensitive ovarian cancer should consider factors such as the patient’s goals of therapy, underlying comorbidities (including preexisting hypertension or renal insufficiency), and if the patient is experiencing abdominal symptoms that could increase her risk of a gastrointestinal perforation. At this time, I do not tend to use bevacizumab often in the platinum-sensitive setting because even with effective treatment, patients will progress and are likely to become platinum resistant. Patients with platinum-sensitive recurrence can do quite well with carboplatin/paclitaxel, carboplatin/gemcitabine, or carboplatin/pegylated liposomal doxorubicin with consideration of a PARP inhibitor for maintenance therapy. Bevacizumab can then be combined with paclitaxel in the platinum-resistant setting to extend efficacy.

PARP Inhibitors
In addition to treatment options with bevacizumab, PARP inhibitors are an exciting new treatment option for patients with ovarian cancer. Cells with mutated BRCA proteins rely on other pathways to repair DNA damage, notably the PARP pathway. PARP inhibitors cause apoptosis through double-stranded breaks and interference with DNA repair due to a process called “synthetic lethality.” Multiple PARP inhibitors have now been approved for use in ovarian cancer. The first approved PARP inhibitor in this setting was olaparib in 2015, followed by rucaparib in 2016, both for the treatment of BRCA1/2-mutated ovarian cancer after multiple lines of chemotherapy. Olaparib was approved for germline BRCA1/2 ovarian cancer after 3 or more lines of previous therapy whereas rucaparib was approved for germline or somatic BRCA1/2 ovarian cancer after 2 or more lines of previous therapy. In 2017, the FDA approved niraparib and then olaparib as maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer who have completed and are in response to platinum chemotherapy. Based on these indications, there is some question as to the best way to sequence treatment with bevacizumab and the PARP inhibitors for recurrent disease.

It is important to remember that, although the initial approvals for olaparib and rucaparib included only patients with BRCA1/2 mutations (whether germline or somatic), the indications for maintenance PARP inhibitors include all patients with platinum-sensitive recurrence. Although PARP inhibitors have demonstrated the greatest efficacy in patients with mutations in BRCA genes, the main factor for this is the level of underlying DNA repair deficiency the cancer cell possesses. PARP inhibitor efficacy can extend to patients with other clinical characteristics such as those with platinum sensitivity or certain histologies, such as high grade serous cancers. Therefore, a patient with a prolonged platinum-free interval may benefit greatly from maintenance with a PARP inhibitor.

How I Use Bevacizumab and PARP Inhibitors in My Clinical Practice
As mentioned in the discussion of bevacizumab, there are multiple treatment approaches clinicians can consider for recurrent disease. In my clinical practice, I typically save bevacizumab-based therapy for patients with platinum-resistant disease and use platinum-based chemotherapy followed by maintenance with a PARP inhibitor for platinum-sensitive recurrence. Multiple clinical trials are also under way evaluating combinations of anti-angiogenic agents, like bevacizumab, with PARP inhibition as well as with immunotherapy agents. However, we are waiting on the data to mature before considering this combination approach. For now, it remains unclear which patients benefit most from which maintenance therapy approaches: PARP inhibition after chemotherapy or chemotherapy plus bevacizumab followed by bevacizumab maintenance.

For a different perspective, please review the recent CME-certified activity by Bradley J. Monk, MD, FACS, FACOG where he discusses the key data supporting treatment advances in ovarian cancer in more detail.

This is an ongoing debate, so please add a comment below to let us know your approach for patients in this setting. Please share your thoughts or any questions on current management approaches for patients with ovarian cancer in the comment box below.