Treatment Approaches Evolving in Recurrent Ovarian Cancer

Dennis R. Scribner Jr, MD

Recurrence marks a significant shift in the treatment of patients with ovarian cancer, in which it changes from a focus on cure to a focus on effective management, says Dennis R. Scribner Jr, MD. While PARP inhibitors have demonstrated impressive efficacy and tolerability and have helped streamline the process, there are many facets of effective care.

“I try and put it in this perspective: We can’t cure chronic issues like asthma, hypertension, or diabetes, but people live long and [full] lives with those medical issues; they can still maintain a very good quality of life [QoL],” says Scribner.

Molecular profiling will help identify patients who will reap the most benefit from available therapies. Although PARP inhibitors and chemotherapy have been shown to be vital to the management of the disease, Scribner insists that patient preferences should also be considered when choosing treatment.

“The science behind all of those variables is very important, but we sometimes lack an understanding of what patients have to go through in terms of their performance status, family and/ or personal issues, travel time to get to the doctor, and determining whether to take pills or come in to get chemotherapy.”

OncLive: How would you define the current state of ovarian cancer?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Ovarian Cancer, Scribner, clinical associate professor, University of Arizona School of Medicine, Arizona Oncology, discussed the elements and evolution of treatment for patients with recurrent ovarian cancer.Scribner: Our focus has been on developing clinical trials that will help women extend their lives and reduce adverse events (AEs). It’s difficult once patients recur, but we have several different therapeutic options that allow us to manage these patients for many years.

Everybody would agree that it’s complicated because it’s not just about the best drugs. In the recurrent setting, you have to take into account patients’ previous toxicities, the time from their last therapy, histology, molecular markers, molecular makeup, whether they are BRCA1/2-positive, and whether or not they have homologous recombination deficiency (HRD). You also have to look at the number of prior therapies they have received.

It’s a complicated but important conversation to have with patients so that they understand their options. They’re always going to ask, “What you would do?” You have to think about it as a management scheme so that if plan A doesn’t work, you have plans B and C in place.

What is the role of chemotherapy?

We now have oral PARP inhibitors for patients in the recurrent setting who are on third- and fourth-line therapies. Now, we’re looking at them as maintenance therapy. There are a lot of checkpoint inhibitors [being explored]. It’s amazing that we now have drugs that allow our immune system to recognize cancer cells when, in the past, they were hidden by these receptors. Now, we can block them. I’m hopeful that this will take us to the next category of drugs that we can use to help these women.There is always going to be a role for chemotherapy. It becomes more convoluted when the response rates from chemotherapy are equal to or less than some of the PARP inhibitors, for example. Platinum-sensitive patients show astronomically high response rates to platinum-based drugs, in the 6- to 12-month or even 12-month-or-greater range.

We are never going to get away from chemotherapy. I’m hopeful that as we learn more about the molecular makeup and identify different variables within the tumors, we can better choose the best chemotherapy for each patient. The reason 2 patients with the same stage and histology can have very different responses to the same chemotherapy regimen has to do with molecular aspects of the disease, which we are just beginning to understand.

Can you speak to the explosion of PARP inhibitors in this field?

Molecular profiling allows us to identify particular markers and predict which drugs a patient will respond better to; it’s a much better way of tailoring individual treatment. The days of everyone getting a certain chemotherapy at a certain stage are no longer. You should be looking at the histology and molecular profile [of each patient] so that we can get better results.PARP inhibitors came onto the scene several years ago after they were examined in phase II trials in the recurrent setting. Study 19 showed response rates of 35% with olaparib (Lynparza). We were giving etoposide pills a long time ago as a treatment for patients who were too sick to get chemotherapy. Now, oral cancer therapeutics have emerged as efficacious. The original phase II trials showed response rates that were equal to or sometimes better than chemotherapy in recurrent patients.

We are now in the process of finding out where in the treatment schema these PARP inhibitors belong. Waiting until the fourth-line setting is probably not the best time. Can we give them in the third-line setting? Can we give them after first recurrence and as a maintenance therapy? The ENGOT-OV16/NOVA trial showed a huge improvement in progression-free survival (PFS) of 22 months versus 8 months in patients with HRD.

What is the impact of PFS, number of lines of therapy, and molecular signature on a patient’s course of treatment?

We are also trying to identify which patients are the best candidates for them. HRD testing is still clunky, so we’re still trying to figure out what the best test to use is. There’s no doubt that we have a good handle on testing for BRCA1/2 positivity. Patients [who harbor HRD in their tumors] are going to see a great benefit with PARP inhibitors.The most important thing is the patient. There are many variables that affect a patient’s QoL [beyond their cancer]. QoL and survivorship is incredibly important. Patients need to understand the AEs of these therapeutic agents and the end result. I often don’t have to explicitly say that the cancer is likely to take their life; they understand the prognosis.

We don’t just practice in a laboratory, we practice in the real world. Those real-world variables, in addition to their histology, stage, setting, line of therapy, and molecular signals, have to be taken into account so we can give our patients the best treatment. Do we use PARP inhibitors, do we add angiogenesis inhibitors, or do we go to research? Are we at a point where we can look at chemotherapy plus checkpoint inhibitors? All of those things are super-important scientifically, but you have to add in the humanistic approach to understand that the patients are people.

What about combinations with immunotherapy and PARP inhibitors? Are there any being explored?

Is there anything else you would like to emphasize?

Everybody has a different tolerance when it comes to therapy. Just as if we were managing hypertension, diabetes, or asthma, we have to focus in on making sure that patients have the highest QoL. Though we don’t cure those diseases, we can certainly ensure a high QoL for a very long time. That’s how I see it in the recurrent setting.My partner, Dr Bradley J. Monk, is an excellent researcher who is part of the inner workings of many research trials. Our group is very lucky to have someone like him to fill us in within that area. As I put patients on PARP inhibitor trials, I’ve noticed AEs that you wouldn’t think would surface, such as transient liver enzyme elevations, pneumonitis, and skin changes. For the most part, the patients who I‘ve had on these experimental checkpoint inhibitors have done very well. You want these patients, especially young women with this disease, to be on these aggressive and experimental therapies because it gives them an extra chance to be cured. We do cure about one-fourth of our patients with advanced-stage ovarian cancer, which is really phenomenal.I want to make sure people get genetic testing; that’s among the most important aspects of all of this. Ovarian cancer is a silent and common cancer. It’s important that women with a strong family history of breast cancer, specifically firstdegree and second-degree relatives with early-age diagnosis, get tested—even though we don’t have a good screening test for ovarian cancer like we do for breast, cervical, and colon cancers. Lynch syndrome carries a 16% to 18% risk of ovarian cancer.

Women and clinicians need to start thinking on a genetic level. Primary care providers have to start thinking on that genetic level so that we can identify women who are at risk of developing this cancer earlier. The average age of diagnosis is 62 or 63; that is well past menopause. If we have the ability to reduce people’s risk of developing these cancers by prophylactically, surgically removing those organs, we can save many patients’ lives.