Understanding the Role of PARP Inhibitors

An Interview with Don S Dizon MD FACP, FASCO, Director of Women's Cancers at the Lifespan Cancer Institute.

What is the burden of ovarian cancer? Can you give an overview of this patient population? 
Ovarian cancer is diagnosed in about 20,000 women annually in the United States; it makes it the second most common female genital tract cancer, but at 14,000 deaths each year, it is also the most fatal. It is not a typical diagnosis in young or child-bearing aged women; the median age is in the 60s. Unfortunately, symptoms are not usually present until the cancer has migrated out of the ovary; as a result, most women are diagnosed only when the disease is advanced (involving the abdomen or the omentum). Incidence is highest in white and Hispanic women; lowest in black and Asian/Pacific Islanders. 

Is genetic testing a requirement among these patients? What role does this play in treatment selection?
Genetic testing is strongly recommended in all women diagnosed with ovarian cancer, especially if it is of a high-grade cancer type or a serous histology. Testing for genetics is important for a few reasons: (1) it can be prognostic if a mutation (particularly in BRCA genes) is identified as these patients tend to have good and durable responses to standard treatment; (2) it can predict who would benefit from Poly(ADP)-Ribose Phosphorylase (PARP) inhibitors if needed to treat recurrence; and (3) if found, we can test the family to see if others might carry the same mutation- which can open up ways to prevent cancer in affected relatives, both male and female. 

How do PARP inhibitors work? What makes them unique for the treatment of Ovarian cancer?
Women with mutations involving DNA repair pathways have only so many ways that they repair DNA, which involves PARP. By blocking it with an inhibitor, cells with damaged DNA cannot repair and are driven to cell death, or apoptosis. 

When should PARP inhibitors be used?
There are two ways we can use PARP inhibitors: the first is for women who have recurred and have responded to treatment using a platinum agent (ie, carboplatin) once more. These women typically will have recurred after 6 months and are referred to as having platinum-sensitive recurrent disease. Once a response is obtained, their doctors might stop the chemotherapy in favor of PARP inhibitors as a maintenance treatment (ie, to maintain the response without using chemotherapy). For this indication, it appears PARP inhibitors have an impact (ie, can prolong the time without disease progression) in all women in this category. Hence, a known mutation in BRCA (inherited or in the tumor- a somatic mutation) is not required.

In addition, PARP inhibitors can be used in women with a known mutation in BRCA who require treatment for a tumor response. In this circumstance, use of PARP inhibitors is restricted to those with a known mutation.

What are some challenges associated with use of PARP inhibitors?
Even though these are oral drugs, they can be toxic: nausea and vomiting, fatigue, and lowered blood counts are common to all of the FDA-approved drugs. 

What are the financial implications of PAPR inhibitor use? Are these drugs cost-effective?
This is a difficult issue as these drugs are very expensive. We are just now asking questions about value for the patient and for our health systems. So, instead of cost, we need to look at the balance between effectiveness, toxicity and safety, and cost. Only then can we begin to figure out how to “value” these new drugs. I am a strong believer though that the patient must be included in these conversations. 

Is there anything else you’d like to add?
These drugs add to our armamentarium for treating ovarian cancer. They aren’t a cure, but they are leading us towards a longer life, particularly for women with recurrent disease. They are a huge step forward, but they aren’t without their risks- both for physical and financial toxicity. We will do well by being thoughtful with our patients.

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