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Expert Tracks the Activity of PARP Inhibitors in Ovarian Cancer

Caroline Seymour
Published: Wednesday, Jul 11, 2018

Dr NAME – no MD

Gottfried E. Konecny, MD

Three international studies have shown the value of PARP inhibition after achieving a complete or partial response to chemotherapy for patients with ovarian cancer, with the greatest benefit in those who harbor germline or somatic BRCA mutations, said Gottfried E. Konecny, MD.

The ARIEL3, NOVA, and SOLO2 trials demonstrated improvements in progression-free survival (PFS) in patients with germline or somatic BRCA mutations who were treated with rucaparib (Rubraca), niraparib (Zejula), and olaparib (Lynparza), respectively. The activity of PARP inhibitors was less evident in patients with BRCA-like signatures and those demonstrating only platinum sensitivity, but these data have helped inform which patients can derive the most benefit from the therapy, he added.

“Knowing that there are subsets of patients who derive great benefit should direct our treatment decisions,” said Konecny.

In an interview during the 2018 OncLive® State of the Science Summit™ on Ovarian Cancer, Konecny, an associate professor of medicine, University of California, Los Angeles, discussed developments in the understanding of response to PARP inhibition in ovarian cancer.

OncLive: What are the updates in PARP inhibition in ovarian cancer?

Konecny: We now understand that about 50% percent of all patients with ovarian cancer harbor a deficiency in DNA damage repair. This makes them susceptible to DNA-damaging agents, such as platinum agents or PARP inhibitors. We now have 3 PARP inhibitors approved for the treatment of patients with ovarian cancer. The first experience we had with these inhibitors was in patients with recurrent disease, specifically with germline BRCA and later somatic mutations.

To summarize key lessons that are true across all 3 PARP inhibitors, the activity extends beyond patients who have a BRCA germline or somatic mutation. The activity of PARP inhibitors tracks with platinum sensitivity, as both are associated with DNA damage-repair deficiencies. We know that the better the response to the platinum agent, the better the response to the PARP inhibitor. We also know that the earlier you treat a patient, the better the response is. Responses are higher with 1 prior line of therapy, somewhat lower with 2 prior lines, and even lower with 3 or more prior lines of therapy.

This is true across all PARP inhibitors, as shown in the ARIEL2 study for patients with BRCA-positive advanced ovarian cancer and in the QUADRA study. These [QUADRA] data were presented at the 2018 ASCO Annual Meeting. This has been shown in earlier studies with olaparib. We also know that it is not important whether you have a germline or a somatic mutation. Both predict sensitivity to the PARP inhibitor.

We have also begun to understand treatment resistance. If a patient has been exposed to many lines of chemotherapy, the chances of responding to PARP inhibitors are approximately 30% to 40% and in some cases, 50%. That means a lot of patients fail this treatment.

This could be a result of genetic adaptions to the therapy, which are summarized under reversion mutations. These are genetic changes that happen during treatment or during the preceding platinum treatment that restore a normal or partially normal BRCA protein. These new mutations restore the DNA repair deficiency and weaken the efficacy of these PARP inhibitors. This tells us that moving forward, appropriate patient selection will be important.

There are other mechanisms that are being discussed for treatment failure. We are gaining preclinical insights through escape mechanisms; these are quite complex. We’re trying to circumvent [these mechanisms] by developing trials that will look at combination therapies with PARP inhibitors. These include antiangiogenic agents and the class of immuno-oncology drugs that include drugs such as MEK inhibitors or DNA-damaging agents that may augment or synergize with PARP inhibition. These include ATM and WEE1 inhibitors.

In the end, we have to overcome primary resistance or synergize with PARP inhibitors to overcome these initial weaknesses in treating heavily pretreated patients.

Knowing that PARP inhibitors correlate with platinum sensitivity, they have been also studied in the maintenance setting. Maintenance is particularly important in ovarian cancer because the disease has a very typical pattern of frequent recurrence. A patient’s progression-free intervals between treatments tend to get shorter. A typical platinum-sensitive patient may do well for 2 years but then suffer a recurrence. It’s often the case that the subsequent recurrence will occur within a shorter time frame. Extending PFS has become an important objective.

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