Shaping a New Future With Novel Therapeutics in Gynecologic Cancers

Combinations with PARP inhibitors featuring immunotherapy and chemotherapy, rechallenging treatment with PARP, and targeting folate receptor–alpha (FRα) are all active areas of research with the potential to improve cure rates in ovarian cancer, according to Ritu Salani, MD, MBA.

“We've seen a [revolution] of care with PARP inhibitors and strategies using PARP inhibitors,” said Salani. “More recently, we're seeing [novel] therapies; we're still using combinations with immunotherapy. We're seeing some other new targets, such as folate receptors, and other strategies that may provide care for patients.”

Beyond ovarian cancer, both the cervical and endometrial cancer paradigms have seen a boost in outcomes due to immunotherapeutic developments, but research hasn’t halted there either, she added.

In an interview with OncLive^®during the 2020 Institutional Perspectives in Cancer webinar on ovarian cancer, Salani, a gynecologic oncologist at the University of California, Los Angeles, further discussed updates to PARP inhibition and FRα-targeting agents in ovarian cancer, the role of bevacizumab (Avastin) across all lines of ovarian cancer therapy, and immunotherapy highlights in cervical and endometrial cancer.

OncLive^®: Do combination regimens with immunotherapy and PARP inhibitors appear promising in this space?

Salani: We have a maintenance strategy study that's looking at PARP inhibitors versus immunotherapy versus the combination of PARP inhibitors and immunotherapy. That's going to mature in the near future and might, hopefully, shed some light on the true role of immunotherapy in patients with ovarian cancer. There are also studies looking at immunotherapy in combination with chemotherapy. We haven't seen excellent or even favorable response rates in this setting, but there are some ongoing studies looking at these combinations in different populations of patients with ovarian cancer.

There have been some small, phase 1 studies that have looked at this combination in solid tumors. [ATHENA] is one of those studies that's going to help elucidate and shed light on the actual role of the combination [of immunotherapy and PARP inhibitors in ovarian cancer].

What other immunotherapeutic approaches hold potential in ovarian cancer?

There are some exciting avenues of immunotherapy, such as looking at T-cell receptors and T-cell therapy, but we're using that mostly for cervical cancer. I have not seen that strategy used yet in ovarian cancer, but I'm sure it's a matter of time before other approaches for immunotherapy besides checkpoint inhibitors start coming to the forefront.

What developments are you interested in that target FRα?

The most common one that we're using in clinical trials is mirvetuximab soravtansine. Some studies are [investigating the agent, such as] FORWARD I and MIRASOL, which is one of the more common studies that's really focusing on patients with the presence of the biomarker. You have to have [to express] FRα to be enrolled in the study, but they're selecting this population because these are the patients who have demonstrated in earlier clinical studies who benefit most from this agent. It's really exciting.

One of the other things that have been explored is mirvetuximab soravtansine in combination with chemotherapy and also with bevacizumab. We're seeing some real avenues for potential change there.

How could retreatment with PARP inhibitors be used for patients who experience relapse?

That's going to be 1 of the challenges—understanding the role of PARP after PARP, especially since more patients with ovarian cancer are becoming candidates for PARP inhibitors. There are studies looking at that question.

For instance, there's the DUETTE study, which is ongoing, looking at PARP after PARP. One of the interesting things about this study is it's looking at PARP in combination with an ATR inhibitor. [This] may be the way to overcome PARP resistance—by combining [PARP] with another agent. Some of these patients also may age out of the use of PARP as a maintenance therapy. They may not have actually been truly resistant, therefore, rechallenging them with PARP makes sense.

Is there an optimal place to utilize bevacizumab?

That's kind of the holy grail: finding the optimal use of bevacizumab. One of the interesting things about the drug is that it doesn't have resistance. It has been successful in first-line, second-line, and multiple rechallenges for patients as long as patients can tolerate the therapy. It's been a drug that's shown activity across the board, even in rechallenge purposes. However, if we can determine where to utilize it with the maximum efficiency and the least [amount of] toxicity, [that would] be ideal.

What is the biggest unmet need or challenge that you would like to see addressed moving forward?

One of the biggest needs for patients with ovarian cancer is finding a higher cure rate, so that these patients don't have to deal with chronic therapies or recurrent disease. PARP inhibitors have made a dent in that, so that's an exciting and new change. 

Patients with platinum-resistant and -refractory disease are the most challenging. These patients really suffer, even with [the available] therapies because these are long-term therapies; they’re dealing with toxicities, not just disease symptoms. We need to find therapies that actually address this and not only [achieve] responses, but also good durable responses and remission.

Moving onto other gynecologic cancers, what are the most interesting research efforts in cervical cancer?

In cervical cancer, which is a particular passion of mine [in terms of research], there have been a lot of exciting changes. Immunotherapy has been [like] PARP inhibitors for cervical cancer; we're seeing a lot of advances there. The response rate hasn't been outstanding, but this has been observed in heavily pretreated women. As we move these therapies into earlier stages of disease, we'll start seeing more durable and pronounced responses in patients.

We're also looking at combinations of immunotherapies, whether it's a CTLA-4 inhibitor and a PD-1/PD-L1 inhibitor, or immunotherapy in combination with chemotherapy. There are some exciting avenues here. 

We're also looking at combinations of immunotherapy with bevacizumab or other antiangiogenic agents. There's a lot of growth focusing on immunotherapy; not just checkpoint inhibitors, but also tumor-infiltrating lymphocytes and T-cell receptor therapy, where it's tailored to that patient's disease. We're targeting the biology of the disease. This is the true definition of personalized medicine.

Endometrial cancer has also demonstrated responses to immunotherapy. Can you touch upon some of the remaining questions with it?

The biggest updates in endometrial cancer fall under the immunotherapy umbrella. We [need to] understand more about mismatch repair deficiencies, Lynch syndrome, and using immunotherapy for these patients. Now, there are also combination [therapies gaining traction]. We've seen that the combination of a PD-1 inhibitor with lenvatinib (Lenvima) has also been beneficial in patients who don't have that mismatch repair deficiency and has shown nice response rates. [However, the regimen] is toxic, so we have to find the balance of maintaining or balancing toxicity with responses. 

Some other exciting areas are the use of hormonal therapy in combination with mTOR inhibitors. We're using trastuzumab (Herceptin) for specific serous subtypes with HER2/neu mutations. We're starting to tailor therapies to the biology of the disease, as well.

What is the role of molecular testing in cervical and endometrial cancer?

[Molecular testing] may help us understand what mutations there are and what may [count as] a targetable mutation.

For patients with endometrial cancer, we typically do immunohistochemistry staining on the tumor. That might alert us to which patients need germline testing for Lynch syndrome. Molecular testing may not help identify a germline mutation, but it may help identify a target for the tumor.