Gynecologic Malignancies Management Makes Significant Strides With ADCs, PARP Inhibitors, and Checkpoint Blockade

Alexander Babatunde Olawaiye, MD

Progress in gynecologic malignancies is undeniable with 4 potential treatment strategies for frontline maintenance therapy alone in advanced ovarian cancer and 2 newly approved first-in-class treatment therapies in metastatic cervical cancer, explained Alexander Babatunde Olawaiye, MD, who added that as the armamentarium expands, so too should personalized treatment decisions.

“Many agents are available to us as frontline maintenance therapy. It’s time for us to pay attention to the data and strategize what we’re going to use in who,” Olawaiye said in an interview with OncLive^® following an Institutional Perspectives in Cancer webinar on Women’s Health/Ovarian Cancer.

“Many times, treatment has consequences. We are using the treatment to help the patient and push back on the cancer, but there is a cost, and I don’t mean monetary cost, although that can be part of it, but the cost to the patient for being treated, Therefore, it’s important to look at the data, to look at the patient, and to look at the treatment scenario and choose optimal strategies for the patient at the most minimum cost in [financial and treatment] toxicity.”

In the interview, Olawaiye, chair of the event, director, Gynecologic Oncology Research Program, assistant professor, Gynecologic Oncology, the University of Pittsburgh and Magee-Womens Hospital, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, discussed frontline and second-line maintenance in ovarian cancer, the role of surgery in platinum-sensitive disease, and updates in cervical and endometrial cancers.

OncLive^®: Your presentation focused on frontline maintenance therapy in advanced ovarian cancer. How quickly did the treatment landscape change since the pivotal PARP inhibitor trials came out?

Olawaiye: Maintenance therapy has been explored for a long period, but it wasn’t until around 2015 to 2017 that we hit any breakthrough, except for bevacizumab [Avastin], which was approved as frontline maintenance therapy in 2012. Since that time, we have gained at least 3 agents in the frontline setting. Bevacizumab is [an] important [agent], but the gain in progression-free survival [PFS] for patients who are treated with that agent as maintenance therapy is modest at approximately 3.5 months.

Then the PARP inhibitors came to the market, first with olaparib [Lynparza] as a single agent in patients with germline and somatic BRCA1/2 mutations. The agent was approved in this specific population based on data from the SOLO-1 trial [NCT01844986], which was very impressive. Very quickly after that we had niraparib [Zejula] from the PRIMA study [NCT02655016], which was administered to all-comers and then received FDA approval in all-comers. The PFS was impressive, with an HR in the 0.3 to 0.4 range. Then the combination of olaparib and bevacizumab, which was tested in the PAOLA-1 trial [NCT02477644], showed impressive PFS in patients with homologous recombination–deficient [HRD] cancers. If you wind the clock back before 2012, we had nothing, and since 2012, we now have at least 4 treatment strategies for frontline maintenance therapy in ovarian cancer.

What are some of the notable similarities and differences of the pivotal trials?

One of the things that is important to remember is that the patients who were included in the [pivotal PARP inhibitor] trials, although by and large are similar, have some distinct characteristics. For instance, in the PRIMA study, patients had to have residual lesions at the beginning of their treatment, meaning that when they began chemotherapy, they had residual cancer that was measurable on imaging, and then that was tracked to see that they were responding. [Then qualifying patients] enrolled on the study and received niraparib as maintenance therapy.

All the studies included patients who had up-front surgery [or] neoadjuvant chemotherapy, so the surgical approach of the treating physician at the beginning of therapy did not preclude patients from being able to benefit from these important [treatment] strategies.

What is known about the potential benefit of PARP inhibitors in earlier stages of disease?

For patients with stage I and II ovarian cancer, who may have high-grade serous or endometrioid ovarian cancer and a germline or tissue BRCA1/2 mutation, or HRD tumors, we do not have data as to whether maintenance therapy is beneficial. We do know that these patients tend to do very well because stage is very important to prognosis, but: Can we extend the length of their PFS? Can we make a meaningful impact on the outcome of early ovarian cancer by using maintenance therapy? That’s a very important question we haven’t asked.

Your colleague, Jamie Lesnock, MD, of UPMC Hillman Cancer Center and UPMC Magee-Womens Hospital, spoke about second-line maintenance in ovarian cancer. How does platinum sensitivity help guide treatment recommendations in this setting?

Dr Lesnock talked about the PARP inhibitors that are being used as second-line and beyond maintenance therapy. In this treatment scenario, almost all the PARP inhibitors on the market are approved in this area. Olaparib, rucaparib [Rubraca], and niraparib are all approved in this indication, and we have used bevacizumab in second-line treatment and as maintenance therapy for a long time and it’s approved for this indication as well. Dr Lesnock discussed all the data that led to the approvals of these agents.

What is important in the second-line and beyond treatment scenario is that, apart from the germline or somatic mutation and HRD status of the cancer that we know usually separates those who are expected to benefit from those who are not, we have another important surrogate [for response], which is platinum sensitivity. That is one of the areas that Dr Lesnock emphasized. If the patient’s cancer is platinum sensitive, the potential for benefit [with PARP inhibitors] is very high. Therefore, the patient should be encouraged to include a PARP inhibitor in their treatment strategy. Usually what happens is once you’ve treated the patient with what is usually 4 cycles of platinum-based chemotherapy, if the disease has been responding, you don’t have to go beyond 4 cycles. Instead, you can transition to one of the PARP inhibitors that is approved in that treatment scenario and then use that to complete the treatment and then continue it as maintenance therapy.

Turning to cervical and endometrial cancer, your colleague, Madeline Courtney-Brooks, MD, MP, of UPMC Hillman Cancer Center and UPMC Magee-Womens Hospital, highlighted treatment updates in cervical and endometrial cancer with antibody-drug conjugates (ADCs) and checkpoint inhibitors. What was emphasized about the use of the agents in the paradigm?

Dr Brook’s presentation mainly focused on the new ADC, tisatumab vedotin-tftv [Tivdak], which is a combination of an antibody called tisatumab that is tagged to monomethyl auristatin E. This agent was evaluated in patients with progressive disease following 2 lines of treatment for recurrent or metastatic cervical cancer. The investigators reported a response rate of approximately 28% in this group, which is not something we have seen before. Therefore, we are excited about this new addition to our treatment armamentarium and the opportunities to offer something to patients who we previously didn’t have much to offer to.

She also emphasized that the treatment comes with a peculiar adverse effect, which is the keratoconjunctivitis and the need to make sure that at the beginning of therapy that there is a concerted effort to [connect] the patient with an ophthalmologist who is familiar with this agent who can help limit the effect of the treatment on the eyes.

The first go-to combination for recurrent or metastatic cervical cancer, based on data from the GOG 240 trial [NCT00803062], is cisplatin with paclitaxel and bevacizumab or the non-platinum doublet of paclitaxel with topotecan and then bevacizumab. The KEYNOTE-826 [NCT03635567] study used cisplatin/paclitaxel with or without bevacizumab and then randomized patients to pembrolizumab [Keytruda] or not.

The patients who received pembrolizumab did much better and had an overall survival advantage. That [regimen] has been approved by the FDA and is therefore the standard for recurrent/metastatic cervical cancer management. In the trial, bevacizumab was optional, but I believe more than 80% of the patients got bevacizumab, so it’s reasonable to consider it as an integral part of our standard. That’s an exciting new finding.

Finally, your colleague Paniti Sukumvanich, MD, of UPMC Hillman Cancer Center and UPMC Magee-Womens Hospital, provided insight into the role of surgery in platinum-sensitive, recurrent ovarian cancer. What were some of the key points that were made about the decision to pursue surgery in this setting?

Dr Sukumvanich looked at the role of surgery for recurrent, platinum-sensitive ovarian cancer. If the cancer is platinum resistant, we usually consider that a contraindication to surgery. Studies have been published, some of them led by investigators in the United States, such as GOG 213 [NCT00565851], which was led by Robert Coleman, MD, of US Oncology Research, and then others, led by European investigators, the most important of which is DESKTOP III [NCT01166737].

Dr Sukumvanich’s talk focused on GOG 213 and the DESKTOP trials. He emphasized that surgery has a role in recurrent, platinum-sensitive ovarian cancer, and that surgery can lead to benefit for patients. The problem is that it can be difficult to select for surgery. Selectivity is key. The way patients were selected for the aforementioned trials may be the reason why DESKTOP III showed benefit [with surgery], whereas the GOG 213 surgical arm did not show benefit [with surgery].

The treating physician should understand that if you decide to [pursue surgery] rather than just use systemic therapy, that the surgery should achieve no visible residual disease. If that happens, there is benefit for the patient, and the benefit can be very significant. The problem is if you choose to go to surgery, and the surgery is not optimal, there is a negative impact on the outcome of that patient’s cancer treatment. I cannot overemphasize how critical that is. If you’re not going to be able to clean out [the patient’s abdomen], do not go to surgery because you’re not only not helping the patient, but you can also be harming the patient.

Although immunotherapy has found a role in cervical and endometrial cancer, it has yet to demonstrate benefit in ovarian cancer. Where do you see research headed with this modality in this setting?

By biological or molecular evaluation, ovarian cancer should be amenable to immunomodulation. Unfortunately, a lot of the big trials that we have done have not shown a positive impact of immunomodulation in ovarian cancer. This includes trials where single-agent checkpoint inhibitors were used and trials where checkpoint inhibitors were combined with chemotherapeutic agents and VEGF inhibitors, such as JAVELIN Ovarian 100 [NCT02718417], JAVELIN Ovarian 200 [NCT02580058], and IMagyn050 [NCT03038100]. All these trials showed disappointing results even though many of the earlier small studies showed positive impact.

Despite that, we still believe that ovarian cancer is amenable to immunomodulation. It is now a question of: Who amongst patients with ovarian cancer will benefit, and for those patients: How should we use immunomodulation? Is it by combining it with PARP inhibitors? Is it by combining checkpoint inhibitors, such as anti–CTLA-4, anti–PD-1/PD-L1, and anti–B7 agents?

We await the results of some of the trials that have been done that are combining these strategies that include immunomodulation. That is an area of very intense research that we are hoping will lead to something positive for patients with ovarian cancer.