Updates to Ovarian Cancer Guidelines Emphasize Importance of Germline, Somatic Testing

David O'Malley, MD

David O'Malley, MD

Several bevacizumab (Avastin) combinations and the use of 3 FDA-approved PARP inhibitors have been introduced in the National Comprehensive Cancer Network (NCCN) guidelines for the treatment of patients with ovarian cancer. Based on these updates, the use of germline and somatic testing has become increasingly important in making treatment decisions for these patients.

Over time, germline testing has become routine in the treatment of these patients; however, the latest updates in regard to PARP inhibitors and bevacizumab as treatment and maintenance therapy options in ovarian cancer have demonstrated the importance of conducting somatic testing in these patients as well, particularly after recurrence.

“Somatic testing, at the very least, should include BRCA, microsatellite instability (MSI), and other HRD genes,” said David O’Malley, MD. “Even though the occurrence of MSI is quite low in serous cancers of the ovary — it’s actually more common in clear cell and endometroid – but, in that 1% or more chance that it is positive, we have a significant treatment, PD-1 inhibitors that can be used in these patients.”

In an interview withTargeted Oncology,O’Malley, a professor in the Department of Obstetrics and Gynecology, The Ohio State University Comprehensive Cancer Center, discussed the updates with bevacizumab and PARP inhibitors as a treatment and maintenance therapy option for patients with ovarian cancer and recurrent disease. He also discussed considerations for selecting the right agent for the right patient.

TARGETED ONCOLOGY:Could you discuss the role of bevacizumab in the updated NCCN guidelines for ovarian cancer?

O’Malley:Bevacizumab changes in the NCCN guidelines mainly focus around the upfront setting. The recent FDA approval of bevacizumab in the first-line setting, which includes treatment and maintenance 1 year after therapy, is the most important change. In addition, bevacizumab is also indicated for platinum-sensitive treatment and maintenance, as well as treatment combined with other cytotoxic therapies. They included pegylated liposomal doxorubicin, paclitaxel, and topotecan (Hycamtin). The other addition within the NCCN guidelines this year is [bevacizumab] combined with cyclophosphamide (Cytoxan), which would be an oral formulation of cyclophosphamide.

TARGETED ONCOLOGY:What data support these updates?

O’Malley:The data that support these new updates centers around randomized phase III trials, GOG 218, as well as ICON7 for the upfront, GOG 213 for the platinum-sensitive, and the AURELIA trial for the platinum-resistant. A cyclophosphamide and bevacizumab [combination] was actually based on 2 randomized phase II trials, but due to the findings within those, they were added to the guidelines this year.

TARGETED ONCOLOGY:What role do PARP inhibitors play in the recurrent ovarian cancer landscape?

O’Malley:PARP inhibitors in the recurrent ovarian cancer landscape have [roles as] both maintenance as well as treatment. Let’s start with the treatment. The treatment of olaparib (Lynparza) is indicated for germline mutations with 3 or more prior lines of therapy. Rucaparib (Rubraca) is indicated for somatic or tumorBRCAmutations or germline, in 2 or more prior lines of therapy. Those are the treatment indications.

The maintenance are all 3 drugs currently available: olaparib, rucaparib, and niraparib (Zejula). Those are for platinum-sensitive maintenance, meaning people who have achieved a partial or complete response after platinum-based doublet therapy and are then maintained with 1 of those 3 drugs. Currently, all 3 drugs are indicated for patient all-comers, meaning both germline and wild-type BRCA.

TARGETED ONCOLOGY:What are the criteria for selecting patients that would be good candidates for PARP inhibitors?

O’Malley:There are currently no guidelines specifically about who to select, except if they have had a partial or complete response. However, we do believe that the impressive nature of the findings with our maintenance therapy in platinum-sensitive disease in the very high percentage of patients will ultimately become resistant in that setting, we would really favor all patients having maintenance therapy at this point. That maintenance therapy will include bevacizumab or 1 of the 3 PARP inhibitors on the market.

TARGETED ONCOLOGY:How do you decide which agent would be appropriate for each patient?

O’Malley:How to select the right agent for the right patient is really one of the questions we are trying to answer currently. With our current understanding, it seems pretty clear that patients with germline or somatic BRCA should have a PARP for maintenance if they have not already had one. If they have already had one and progressed, that is a bit unclear and would most likely not be recommended. However, if they have had a PARP previously and have not progressed, for example they had it for 2 years as part of research protocol, those patients would be very appropriate to go back to a PARP inhibitor, particularly if they had a somatic or germline [mutation].

The other molecular markers that we are looking at are homologous recombination deficiency (HRD), and those can be the specific genes that work within that pathway versus some of the commercially available assignments. There’s 2 commercially assigned that are either loss of heterozygosity or HRD-positivity. Those appear to be a subgroup that would benefit. However, bevacizumab has also had very good results when we are looking at the maintenance therapy. We are trying to identify which agents and when we should use those. That continues to be an area of research that we are focused on.

TARGETED ONCOLOGY:Could you also discuss the NCCN guidelines for PARP inhibitors as a maintenance therapy in ovarian cancer?

O’Malley:PARP maintenance in ovarian cancer is for patients who have a partial or complete response to platinum-based doublet therapy. Those current indications are to continue the PARP inhibitor indefinitely in the platinum-sensitive [setting]. In those patients, as long as they are achieving clinical benefit and not having significant toxicities, [the guidelines recommend] to continue that therapy until that time.

TARGETED ONCOLOGY:Would you say [we are] getting better at identifying what patient should receive which agent?

O’Malley:We are getting better, but we still have a long way to go. Between the BRCA testing, other HRD genes and mutations, as well as, for example, methylation of the BRCA, RAD51, RAD51C and RAD51D, we are identifying more and more patients that clearly should have PARP as part of their maintenance program. We will continue to identify those patients, for example, of loss of heterozygosity or the HRD-positive patients that will help us separate those who we should be treating with PARP inhibitors versus anti-vascular therapy.

In addition, with some of the ongoing phase III trials, we may find that combination therapy, particularly in those that are wild-type, will be our best path forward.

TARGETED ONCOLOGY:What is the take-home message from these updates?

O’Malley:One of the most important aspects within these new guidelines is the emphasis on germline and somatic testing. The NCCN guidelines continued over time to remind us to use germline testing in patients diagnosed with ovarian cancer. One of the biggest changes in the guidelines this year is that anybody that has recurrence, if they haven’t already been tested, to make sure that we have somatic testing. Somatic testing, at the very least, should include BRCA, MSI, and other HRD genes. Even though the occurrence of MSI is quite low in serous cancers of the ovary — it’s actually more common in clear cell and endometroid – but, in that 1% or more chance, that it is positive, we have a significant treatment, PD-1 inhibitors that can be used in these patients.