Expert Tracks the Activity of PARP Inhibitors in Ovarian Cancer

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.

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

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.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.

Three international studies have addressed the value of adding a PARP inhibitor after achieving a complete or partial response to chemotherapy. PARP inhibitors are approved for all patients who have platinum-sensitive disease. However, these studies did a diligent job in retrospectively analyzing those patients in terms of their BRCA status.

[The analysis] accounted for BRCA-ness, which is now analyzed by assessing homologous recombination deficiency (HRD), BRCA wild-type, and patients who have a normal double-strand repair who are not HRD deficient but still platinum sensitive. BRCA-ness is essentially a genomic scarring that results from the inability to repair DNA double strand breaks. BRCA wild-type includes patients with both germline or somatic mutations.

It is clear across all studies that the greatest benefit is seen in those who have germline or somatic BRCA mutations. There was a doubling in PFS in patients who were BRCA-positive or had HRD. There was a clinically smaller improvement in patients who were biomarker negative.

Knowing that there are subsets of patients who derive great benefit should direct our treatment decisions. You have to consider the potential toxicities of treatment or the potential cost of treatment, now that we know there are subsets of patients who derive clinically less meaningful improvements.

Inhibiting PARP as a targeted therapy in cells that have DNA repair-deficient mechanisms is a very important [concept]. You need to have a reliable test or an assay to select patients who may respond to PARP inhibition if these drugs are moved outside the space of extreme platinum sensitivity.

Genomic scarring is a very stable feature. Once a tumor develops genomic scarring, it has an increased fraction of DNA that is affected by gains or losses. Genomic scarring is something that stays throughout the further progression [of disease]. Even if a patient suffers a reversion mutation or any mechanism that could restore the normal BRCA protein, precluding them from responding to a PARP inhibitor, they would still have this genomic scarring.

Can you elaborate on the 3 international studies you mentioned?

It may be a mix of test assays, including sequencing, expression studies, and assessing copy number changes that, as a conglomerate, will give us a much more reliable assay to specify which patients will respond to PARP inhibitors.The first study is the ARIEL3 study, which assessed the value of adding rucaparib to treatment in patients with recurrent, platinum-sensitive disease. The standard dose was 600 mg twice daily. Many patients required dose reductions during this trial. Despite dose reductions, the data are statistically significant and clinically meaningful.

The NOVA study compared niraparib to placebo in a 2:1 fashion in patients who had a partial or complete response [to a platinum-based agent] and normalization of CA-125. Likewise, over 60% of these patients had to dose reduce from 300 mg to 200 mg. Retrospective studies showed [the dose reduction] did not minimize the treatment effect. Patients who received 200 mg daily experienced the same benefit as those who received 300 mg daily.

Study 19 was conducted years ago and assessed the use of olaparib as maintenance therapy. Patients who had a good response to preceding chemotherapy received the capsule form of 400 mg twice daily. This is supplemented by the SOLO2 study, which looked at the improvement in PFS with olaparib. Patients who had shown a partial or complete response after platinumbased chemotherapy received 300 mg twice daily in tablet form.

Are there data supporting combination therapies?

Could PARP inhibitors have an impact in other gynecologic cancers?

All studies showed nearly 4- to 5-fold improvements in PFS in patients who had a germline or somatic mutation. There was a more than doubling in PFS in patients who had a BRCA-like signature and approximately a 3- to 4-month improvement in patients who were exquisitely platinum sensitive and biomarker negative.There are. At the 2018 ASCO Annual Meeting there was a combination study of a PI3K inhibitor plus olaparib. There are ongoing studies that are combining angiogenesis inhibitors. There were 2 recent presentations at the 2018 SGO Annual Meeting, which compared the use of niraparib in combination with immunotherapy and olaparib with an angiogenesis inhibitor.The phenomenon of DNA repair deficiency, specifically as it pertains to double-strand break repair is not limited to ovarian cancer. We now know that among 32 different cancer types, that is most prevalent in ovarian cancer.

Endometrial cancer, particularly high-grade serous carcinoma, has a sizable number of patients who have HRD and could likewise benefit from PARP inhibitors. This is being pursued in prostate cancer. It’s very clear that gastrointestinal malignancies, certain subsets in lung cancer, and other diseases have a [similar] pattern.

At some point, HRD will become a signature that is a predictive marker for response to platinum agents or PARP inhibitors, as microsatellite instability or tumor mutational burden is a signature in immunotherapy