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PARPi in Ovarian Cancer
How I Am Using PARP Inhibitors in the Care of Patients With Ovarian Cancer

Released: May 02, 2019

Expiration: April 30, 2020

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During the past few years, the discovery that PARP inhibitors have activity in BRCA-mutated cancers has been translated into therapeutic strategies for ovarian cancer. Currently, 3 PARP inhibitors are FDA approved as single agents in ovarian cancer: olaparib, rucaparib, and niraparib. The advent of PARP inhibitors is dramatically changing the treatment landscape of ovarian cancer. In this commentary, I take a brief look at the data and clinical relevance of these new agents.

Current Indications and Ongoing Trials
Three phase III trials have demonstrated benefit for PARP inhibitors vs placebo as maintenance therapy for patients with recurrent, platinum-sensitive ovarian cancer: SOLO‑2 (olaparib), NOVA (niraparib), and ARIEL3 (rucaparib). All 3 drugs have now been FDA approved for that indication regardless of BRCA mutation status, although patients with BRCA mutations have seen more robust benefit from PARP inhibitors.

In addition to their use as maintenance therapy, single‑agent PARP inhibitors have been investigated in women with ovarian cancer who are even more heavily pretreated and have underlying BRCA mutations. Olaparib was originally approved by the FDA in patients with recurrent ovarian cancer and germline BRCA mutations who received at least 3 prior lines of treatment. Likewise, rucaparib originally received FDA approval for patients with recurrent ovarian cancer and germline and/or somatic BRCA mutations who received 2 or more prior lines of therapy.

In December 2018, the FDA expanded the indication of olaparib to include maintenance treatment for newly diagnosed patients with advanced BRCA-positive ovarian cancer after first-line chemotherapy. The new approval was based on results from the phase III SOLO‑1 study, which demonstrated that olaparib resulted in a 70% reduction in the risk of progression or death vs placebo. Currently, niraparib and rucaparib are being studied as first-line maintenance therapy for newly diagnosed ovarian cancer in the ongoing phase III PRIMA and ATHENA trials, respectively. It's an incredibly exciting time as we wait for these trials to mature and report out.

PARP Inhibitors in Clinical Practice

Considerations for BRCA Testing in Clinical Practice
Every patient who is diagnosed with ovarian cancer should undergo germline panel testing for BRCA mutations and should be seriously considered for tumor somatic testing as well. In our clinic, after a patient is diagnosed, we try to have her see a genetic counselor as soon as possible. In parallel, we conduct tumor somatic testing for BRCA1/2 mutations. The germline testing is important for cascade testing so the family can decide whether to get tested if the patient has a mutation. Knowing germline and somatic BRCA testing results is important for the use of a PARP inhibitor in newly diagnosed patients based on the SOLO-1 data.

At this time, diagnostic tests for homologous recombination deficiency (HRD) are being developed for PARP inhibitors as well. For example, the myChoice test was submitted to the FDA for approval in early 2019. At last year’s American Society of Clinical Oncology Annual Meeting, data presented from the phase II QUADRA study showed that niraparib had durable activity in a heavily pretreated patient population with recurrent HRD-positive ovarian cancer. In the future, these tests may expand the clinical utility of PARP inhibitors beyond patients with ovarian cancer and BRCA1/2 mutations alone.

Choosing the Right PARP Inhibitor for the Right Patient
Of importance, the 3 PARP inhibitors approved for the treatment of ovarian cancer all appear to have very similar efficacy. Broadly speaking, response rates, PFS, and other outcomes are comparable among PARP inhibitors, as seen in both maintenance studies and single-agent trials. So, clinicians must choose the optimal agent based on other factors, such as toxicity profiles; each of these PARP inhibitors has specific toxicity mitigation strategies. Of note, olaparib and niraparib cross the blood–brain barrier, whereas rucaparib does not. If a patient has a brain metastasis or carcinomatous meningitis, for example, she will likely benefit more from olaparib or niraparib.

Cost is a substantial consideration for PARP inhibitors: each drug costs approximately $14,000 per month. If insurance will not cover a particular PARP inhibitor, clinicians should determine if a patient assistance program is available from the manufacturer. The dosing schedule is another factor in determining which PARP inhibitor to use. Olaparib and rucaparib are given twice daily, whereas niraparib is taken just once a day and may be more appropriate for patients less likely to adhere to twice-daily dosing. In addition, each drug is metabolized differently. Olaparib is metabolized by CYP3A4, and rucaparib is metabolized by CYP2D6, whereas niraparib is metabolized by carboxylesterases. In clinical practice, if a patient is receiving another drug that is metabolized by the same enzyme, this might alter my recommendation for a specific PARP inhibitor.

Treatment Strategies for Using PARP Inhibitors
In clinical practice, clinicians must choose the optimal time to integrate PARP inhibitors into the treatment of individual patients with ovarian cancer. Should they be used as maintenance after first- or second-line therapy, or saved until later in the treatment course?

Every physician will have a slightly different take on the optimal use of PARP inhibitors. Clearly, PARP inhibition makes sense for women who are carriers of BRCA mutations or develop somatic BRCA mutations, have not been exposed to a PARP inhibitor, and have platinum‑sensitive recurrence. In this clinical scenario, I give platinum‑based chemotherapy followed by PARP inhibitor maintenance after their maximum response.

Of importance, there are no solid randomized data that support retreatment with PARP inhibitors. Typically, after a patient receives platinum-based therapy for recurrence, she will then receive a PARP inhibitor until her disease progresses. If she develops resistance to a PARP inhibitor, another PARP inhibitor may not benefit her. However, if a patient chooses to stop a PARP inhibitor due to toxicity and later develops recurrent platinum-sensitive disease, I might consider retreatment with a different PARP inhibitor.

Your Thoughts
What are your thoughts or questions on the use of PARP inhibitors for patients with ovarian cancer? Let me know in the comments box below.