Markman Peels Back the Curtain on the Effects of Growing Uncertainties in Gynecologic Oncology

Maurie Markman, MD

Ensuring that each patient is treated with the right therapy at the right time is becoming muddled by the lack of representative clinical trial data and the insufficient use of genetic sequencing in oncology, according to Maurie Markman, MD, who added that larger discussions are needed to prevent the continued avalanche of information overload.

“If you don’t do the testing, how do you know if PARP inhibitors might be relevant? It’s not that doctors are not interested in having the information, they are simply overwhelmed, and we need to figure out how to get this information to the doctors so they can optimally care for patients [with ovarian cancer],” Markman said.

In this special with OncLive®, Markman, who is president of medicine & science at City of Hope Atlanta, Chicago, and Phoenix, discussed the questions that have resulted from advances with systemic therapy in gynecologic oncology and those that need to be answered in order to build a better framework for decision support in the community setting.

Present Management of Ovarian Cancer From the Systemic Perspective

Markman: We turn our attention to the current state of affairs and what the future [may look like] in terms of the questions in the management of ovarian cancer from the systemic perspective. Time would not allow me to cover all the controversies, all the unknowns, all the uncertainties, all the questions. They’re massive and growing by the week with new reports. For ovarian cancer, remarkably, the core chemotherapy remains the same as it was 20, even 30 years ago, with carboplatin and paclitaxel which demonstrates just how good these drugs are––but that’s where the certainty ends. [Outstanding] questions are not answered by trials. They may be answered by opinions, but not by trials, and certainly not by the FDA or any other edict.

What is the role of bevacizumab [Avastin]? It [has] a massive role, and I’ll come back to that. How many––4, 5-plus––phase 3 randomized trials looking at bevacizumab in ovarian cancer have shown an effect on outcome––progression-free survival––which is the only relevant outcome that you can look at? Not that you can’t show an improvement in overall survival [OS], but because with all the secondary, third-line, fourth-line therapies that are available, it’s going to be very hard in the future to show an effect on OS. My point being, what about the role of bevacizumab? What about the role of intraperitoneal therapy? Now, some of you may think that that question has been resolved. Let me assure you, it has not. And I would refer you to commentaries that I’ve done with OncLive, [but it’s] a completely unresolved question because of the problems with the trials and questions about bevacizumab.

What about the role of neoadjuvant chemotherapy? When should it be used? When should it not be used? When should we use surgery? What about the role of PARP inhibitors in the management of the illness? [it’s] very complex, [because there are] multiple PARP inhibitors. How long should they be given? What are the potential adverse effects? What about the combination strategies? Those are just questions in the frontline setting. In the second-line setting, this question of 6 months, 12 months, platinum-sensitive resistant: does it make any sense anymore? And the answer of course is it doesn’t, because with maintenance therapy, and particularly if you’re using an agent like an anti-PARP, which acts very much like a platinum agent in some ways, would you go back to a platinum if a patient recurred? Maybe, yes, maybe no. Where are the data to tell you and help you? We don’t know.

Again, [where does] bevacizumab [fit in]? Bevacizumab is a drug that has been completely and adequately explored in ovarian cancer. You might talk about individual trials, but the facts are that bevacizumab seems to potentiate the effects of perhaps all drugs we give, not because it necessarily synergizes, but it might improve blood flow to the area, improve the ability for the drug to get there. How do we explore this? When do we use bevacizumab? When do we not use bevacizumab? [These] questions [are] completely unanswered. What about the optimal sequence of therapy in ovarian cancer, which is increasingly becoming more of a chronic illness. It’s less of a question today of which drugs you’ll give in the setting of recurrent disease [and more of] what sequence you will give them. And finally, there’s massive questions about the role, routine role, in my opinion, of next-generation sequencing [NGS] in the 1% to 2% of patients with ovarian cancer with a variety of abnormalities where there’s now FDA-approved agents. Should that be obtained on every patient? My opinion is yes.

And if you have an abnormality, how do you sequence [treatment with] that [in mind]? We know, and studies have been done, [showing] that maybe only half of the patients who might or should have had NGS, have that done. [In terms of] seeing if a patient has a BRCA mutation, maybe half of the patients get that [testing].

Enter Immunotherapy in Endometrial Cancer

We’re now going to briefly talk about immunotherapy and how that has transformed the management of endometrial cancer. I emphasized in a previous [article] that the way we treated [patients with] endometrial cancer from a systemic perspective was basically how we treat [patients with] ovarian cancer. Nothing could be further from the truth today. The backbone from a systemic perspective remains carboplatin and paclitaxel, still very active drugs, but the role of immunotherapy has now become incredibly prominent in a very positive way. However, there are multiple questions.

Which drugs do you use? Does it make a difference? Perhaps yes, perhaps no. Where are the comparative studies? How long do you give the immunotherapy? What is the specific role of a variety of proposed biomarkers for immunotherapy? Is it relevant today to know if a patient has mismatch repair deficiency, or should all patients, for example, in the metastatic, recurrent setting get an immunotherapeutic agent? What is the role of the biomarker, PD-L1? And increasingly, because of very provocative data where PARP inhibitors been used, what is the role, not of necessarily of knowing whether a patient has a BRCA mutation—because the percentage of patients is probably relatively low in this setting, although I don’t know if we know for sure—but what about homologous repair deficiency, or other types of biomarkers that might indicate a PARP inhibitor is relevant? Do we get these tests? Should we get these tests? Should we make decisions based on this? And of course, we have some awesome, provocative data not standard of care yet about the potential relevance of the use of therapies that are determined by whether a patient has P53 [wild-type] or mutated status. Where is that going to be in our paradigm? What about in the second-line setting? If a patient develops recurrence, do we repeat the therapies we gave before? [Where does that leave] immunotherapeutic agents? What about chemotherapy agents?

This is a different population from the population of women with ovarian cancer. There are limited number of patients. Therefore, it’s harder to do trials. As we know, historically, this is a population that’s often older than [those with] ovarian cancer, a population that has comorbidities, diabetes, high blood pressure, obesity, and heart disease. So, for the studies that are done, the trials that are done where the patient population does not even remotely represent the real-world population, how do we translate those results into optimal care of patients that we are taking care of in the community? Again, we critically need decision support. We need pragmatic trials that are going to answer these questions, not just getting new drugs approved.

Systemic Therapy in Cervical Cancer

It’s always difficult for me to talk about systemic therapy of advanced [or] metastatic cervix cancer when I am aware, and everyone should be aware, that this is a disease we should be on the verge of eliminating, [potentially through] screening to detect it early, which we’re now failing at. Of course, the worst situation of all, is the question of human papillomavirus vaccination, which should have been routine a long time ago, [with] clear evidence [indicating] that between 95% and 98% of cervix cancer would be gone. That’s [a discussion] for another day. It’s very hard to discuss the enormous difficulties, the pain and suffering, the loss of life for an illness that should not be, but we’ve had major advances in the management of cervix cancer. [There’s] no question about [it from] a systemic [therapy] level.

As I mentioned earlier, we had cisplatin. Cisplatin has an impact, and with chemoradiation there’s no question in early, localized disease, [or] regional advanced disease that we can favorably affect survival, and we had no systemic therapy beyond that. Bevacizumab has had a positive impact. Immunotherapy, of course, has had an enormous impact, and we now even have second-line immunotherapeutic agents. However, this is a very complex population. It’s a population that’s younger, generally, but often very fragile, not only because of co-morbidities. They may have socioeconomic status leading to nutritional issues. There’s the morbidity associated with the disease itself and its surgical treatments, although that is certainly lessening. How do you pay for these drugs that are coming out?

At the level of decision support for doctors, what is the role of a variety of biomarkers? What is the role of specific immunotherapy? Should they be given together? What is the specific role of bevacizumab? What is the role of retreating with a platinum agent or other cytotoxic agents to potentiate the effects of the immunotherapy? Who is going to conduct the trial that’s going to help in the community setting, the real-world patient with the comorbidities that would never have allowed them to go on a clinical trial that allowed the drug to be [approved] in the first place. [Doctors need to] know when and when not to make that decision. These are critical questions. Are we going to pay for all of this? These are issues that need to be addressed. They need to be addressed to help the individual patients and to help doctors make the right decisions for their patients. This is a very difficult topic, but we need to deal with it and discuss it.