New Strategies and Novel Agents Transform Ovarian Cancer Into a Chronic Condition

Maurie Markman, MD

Approximately 20 years ago, findings from a landmark ovarian cancer study demonstrated the favorable impact associated with adding paclitaxel to cisplatin (compared with cyclophosphamide plus cisplatin) as first-line chemotherapy.¹ Remarkably, other than the substitution of carboplatin for cisplatin, which improved the toxicity profile of the regimen but not its efficacy, there has been essentially no change in the primary cytotoxic management of the malignancy since that time.

Despite this sobering state of affairs, the therapeutic landscape and clinical outcomes for the malignancy have improved rather substantially. In the primary treatment setting, several phase III randomized trials have revealed equivalent efficacy and reduced treatment-related morbidity associated with the neoadjuvant approach of using systemic chemotherapy followed by surgery after confirmation of malignant disease² and the potential clinical utility of regional (intraperitoneal) as well as hyperthermic intraperitoneal drug delivery.^1,3

During this time, a number of single antineoplastic agents and combination regimens also have received regulatory approval or have been considered as a therapeutic option in second-line or later settings based on the results of clinical trials published in high-quality, peer-reviewed oncology journals.¹

The antiangiogenic agent bevacizumab (Avastin) has been examined in multiple clinical trials in ovarian cancer and has achieved regulatory approval in the United States on the basis of favorable progression-free survival (PFS) results when employed as a component of therapy (along with cytotoxic therapy) in the primary, platinum-sensitive recurrent and platinum-resistant settings.⁴ In each of these situations, bevacizumab is also continued as a maintenance approach.

Of particular note are data from a phase III trial that examined the combination of bevacizumab with investigator’s choice of single cytotoxic agents commonly employed in platinum-resistant ovarian cancer.⁴ The study results revealed an impressive improvement in both PFS and objective response rates when the antiangiogenic agent was added to any of 3 cytotoxic drugs. It is uniquely relevant that this was the first—and, to date, only—randomized phase III trial to reveal an improvement in survival outcome in platinum-resistant ovarian cancer. Over the past several years, ovarian cancer care has been transformed by the impressive activity of PARP inhibitors in several clinical settings.⁵ Currently, the FDA has approved 3 PARP inhibitors for use in ovarian cancer as second-line or later maintenance therapy following a response to platinum-based therapy.

Although it is not surprising that these agents have shown their greatest activity in the setting of BRCA mutations (germline or somatic), there is also solid evidence for clinical utility even in the absence of this important biomarker, such that the FDA decided not to require BRCA testing when a PARP inhibitor is considered for the second-line or later maintenance setting.

Recently, phase III trial results have shown that olaparib (Lynparza) can substantially improve PFS when employed as a first-line maintenance strategy in women with a known BRCA mutation (germline or somatic).⁶ Ongoing trials are exploring the utility of several biomarkers that may be capable of defining non-BRCA—mutant ovarian cancers that have a clinically meaningful probability of responding to PARP inhibition.

The immediate future of clinical investigation in ovarian cancer is remarkably exciting, with a number of novel agents and combination strategies (eg, PARP inhibitors combined with checkpoint inhibitors or antiangiogenic agents) currently being examined in multiple clinical trials.

Unfortunately, we must acknowledge that the overall percentage of patients with advanced ovarian cancer who are “cured” of their malignancy—defined as those whose disease does not recur during their lifetime—has not changed substantially over the past 2 decades. However, during this time, epithelial ovarian cancer has been transformed in an increasing percentage of individuals into a serious, unfortunately still likely fatal, but more chronic condition in which extended survival of satisfactory quality (as defined by an individual patient) may be measured in years. In fact, it is estimated that as many as 200,000 women in the United States are currently living with this malignancy. With these important facts in mind, it becomes even more essential that the oncology research community focus as much attention on the overall impact of antineoplastic therapy on the quality of life of the patient undergoing treatment as on the duration of survival.

References

1. Markman. Drugs. 2008;68(6):771-789.
2. Vergote et al. N Engl J Med. 2010;363(10):943-953.
3. van Driel et al. N Engl J Med. 2018;378(3):230-240.
4. Rossi et al. Oncotarget. 2017;8(7):12389-12405.
5. Markman. Womens Health (Lond). 2018;14:1745505717750694
6. Moore et al. N Engl J Med. 2018;379(26):2495-2505.