PARP Inhibitors for Ovarian Cancer: Who and When, And Can We Afford It?

Ovarian cancer is diagnosed in over 22,000 women annually in the United States making it the second most common malignancy of the female genital tract cancer. With more than 14,000 deaths each year, it is also the most lethal.¹ Unfortunately, an effective screening test does not exist, and the onset of symptoms often heralds advanced disease involving sites outside the ovary, typically the omentum, upper abdomen, or pleura. 

The mainstay of first-line treatment for ovarian cancer is chemotherapy utilizing a platinum (carboplatin or cisplatin) with a taxane. The addition Avastin (bevacizumab; Genentech) was approved in this setting by the FDA in June 2018. The vast majority of women with advanced ovarian cancer will recur, and while not curable, new drugs have recently come on market expanding treatment options for women with recurrent disease. 

The poly (ADP-ribose) polymerase (PARP) inhibitors are a class of novel drugs with demonstrated efficacy in this setting. PARPs are a class of enzymes, activated by DNA damage, which facilitate repair of single-strand DNA breaks via the base excision repair pathway. PARPs were originally conceived as a targeted therapy for a subset of women with ovarian cancer associated with genomic or somatic mutations involving the BRCA genes (mBRCA), which are present in up to 25% of women with ovarian cancer and over 50% of patients with high grade serous carcinomas, the most common subtype of ovarian cancer. ^{2, 3} 

PARP inhibitors are indicated in two distinct settings: as treatment for recurrence and as maintenance therapy. Lynparza (olaparib; AstraZeneca) is approved as third-line treatment of women with recurrent ovarian cancer associated with mBRCA. Rubraca (rucaparib; Clovis) is approved as a second-line treatment of women with germline or somatic mBRCA or homologous recombination deficiencies. 

When considered for use as maintenance therapy, a patient need not have evidence of mBRCA (either somatically or genomically). Instead, the approval for maintenance PARP inhibitor treatment requires that women with recurrent disease have demonstrated platinum sensitivity (based on their response to their most recent response to treatment). Olaparib, rucaparib, and niraparib all carry this indication. The data to support this approval comes from phase III trials of each agent showing median progression-free survival (PFS) with maintenance PARP inhibition (ranging from 7 to 21 months).^4,5,6,7 Maintenance therapy has been a theoretically attractive concept in ovarian cancer because of the high recurrence rates although  clinical trials which utilized chemotherapy in this setting have demonstrated few benefits; clinical trials of maintenance therapy with taxanes, bevacizumab and tamoxifen have all failed to demonstrate improvements in overall survival.^8,9,10 Whether maintenance PARP inhibitors will impact overall survival remains unclear. A post-hoc, subgroup analysis of patients with germline BRCA-mutated ovarian cancer treated with maintenance olaparib or placebo demonstrated a 2-month overall survival advantage, this was not statistically significant (29.8 compared to 27.8 months).¹¹ 

In consideration of their use, it is important to recognize that PARP inhibitors can cause toxicity: nausea and vomiting, fatigue, and hematologic toxicities are common. In the Phase III trial of maintenance niraparib, 15% of patients to discontinued therapy because of toxicity. In a real-world setting, this rate would be expected to be higher.⁷ More serious side effects, including myelodysplastic syndrome and acute myeloid leukemia, are rare, but reported. When asked directly, women with ovarian cancer will forgo 7 months of PFS in exchange for a reduction in nausea and vomiting associated with treatment; and 5 months of PFS for reductions in peripheral neuropathy from severe to mild.¹² These person-centered considerations are important as these therapies are being prescribed to asymptomatic patients who may be less tolerant of treatment-related adverse effects and may choose to prioritize quality of life. 

Financial toxicity, direct costs related to out-of-pocket expenses or indirect costs associated with time lost from work for the patient or caregivers, must be considered, as these drugs are expensive. At the recommended dose for maintenance therapy, the approximate cost of PARP inhibitors is $16,000 to $19,000 per month in the United States.¹³ An incremental cost-effectiveness ratio of $258,864 per progression-free life-year-saved has been estimated for 1 year of olaparib maintenance in patients with platinum-sensitive disease and pathogenic germline BRCA mutations.¹⁴ Taken together, it becomes difficult from a policy perspective to determine that this class of drugs is cost effective. 

The addition of PARP inhibitors to our armamentarium for treating ovarian cancer is undoubtably beneficial to women with this disease. Effectiveness, toxicity, safety, and cost all must be balanced for an individual patient to determine the right PARP inhibitor for the right patient at the right time. 

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