Novel Targeted Agents Emerging in Ovarian Cancer

Diana P. English, MD

Among the recent success in the ovarian cancer landscape with PARP inhibitors, many novel agents have also emerged and are paving paths in various settings of the disease.

Antibody-drug conjugates (ADCs) are being evaluated in ovarian cancer. Mirvetuximab soravtansine is currently being investigated in the phase III FORWARD I trial (NCT02631876). In this study, mirvetuximab soravtansine is being compared with investigator’s choice of chemotherapy in patient’s with platinum-resistant disease, explained Diana P. English, MD, a gynecologic oncologist at Stanford Hospital and Clinics.

English also noted that p53 mutation is a target of interest in ovarian cancer. Although drugs are still in trials for the treatment of patients with ovarian cancer who harbor p53 mutations, she emphasized the importance of tumor profiling in this disease. These panels give results that are now actionable, and may help patients who have specific alterations.

OncLive: Could you please provide an overview of your presentation?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Ovarian Cancer, English discussed the promise for ADCs in the landscape of ovarian cancer treatment and targeting p53 mutations in patients with ovarian cancer.English: I spoke about novel treatment options in ovarian cancer, namely ADCs, and a bit about p53 reactivation drug therapy. The most promising thing would be the ADCs that are already in phase III trials.

Namely the ADC, mirvetuximab soravtansine, which targets the folate receptor-alpha (FRα). This ADC has the antibody specific to the FRα. It is linked to a cytotoxic agent, which is the antimicrotubular agent DM4. The specificity of the antibody for the FRα, allows us to target tumor cells that tend to have a high expression of FRα.

About 80% of ovarian cancers overexpress FRα, and about 60% of ovarian cancers express it at high levels. [Overexpression is] anywhere from 50% to 75% of tumor cells with intense staining on immunohistochemistry. In the population of patients who are platinum resistant and not heavily pretreated—less than 3 prior lines—this drug has shown some very meaningful and promising results, with objective response rates around 39%.

Are there any other ADCs in development?

It is now being looked at in a phase III clinical trial, called FORWARD I, and being compared with physician’s choice in platinum-resistant ovarian cancer. The physician’s choice options include the typical single agents that we use in platinum-resistant ovarian cancer such as doxorubicin, topotecan, and paclitaxel. The typical single agents used in this setting have response rates in the range of 10% to 20%. This ADC does seem to hold promise.There are other ADCs targeting other antigens or proteins that are overexpressed in ovarian cancer. One [target] is mesothelin, which is expressed on the majority of ovarian cancers. There is an ADC called anetumab ravtansine that is targeting the mesothelin protein. This ADC is conjugated to the antimicrotubular agent DM4. It did show some promise in ovarian cancer, but there were more meaningful results in mesothelioma. There is a phase II trial looking at this ADC in combination with bevacizumab (Avastin) versus bevacizumab plus paclitaxel in platinum-resistant disease.

What is the interplay between the reactivation of p53 and cancer cell proliferation?

What are the drugs that are used currently to target p53?

Where would you like to see research focus moving forward?

The appeal of ADCs is the potential for them to be very specific to a particular target protein, or antigen overexpressed in ovarian cancer and spare normal tissue. Hopefully, we will have better outcomes and less adverse events.p53 is a very common tumor suppressor gene that is studied and is mutated in many cancers. It is often mutated in ovarian cancers. The potential there is that this protein is often mutated and leads to dysregulation of the cell cycle and the prolonged survival of cells in cancer, now we are able to reactivate and return this mutant p53 back to a wild-type that can interact with DNA and lead to apoptosis. We may have a drug therapy in the near future that may be used for several tumors, including ovarian cancer. There are 2 drugs that seem to be the most promising; one is PRIMA-1 and the other is APR-246. There is a clinical trial looking at APR-246 and is studying this drug in the phase Ib/II setting and combining this drug with platinum-based therapy. The results are still pending.Moving forward, I would be most interested in the use of mirvetuximab soravtansine. This does seem to be the most promising, and platinum-resistant patients currently have very few options. We do have what seems to be a standard of care in bevacizumab plus chemotherapy. There were also recent data looking at PARP inhibitors in combination with pembrolizumab (Keytruda) or other immunotherapy for platinum-resistant disease. The results that we are seeing for mirvetuximab soravtansine, at least from the phase I study, looked to be very promising. If this drug is going to offer fairly good responses, less toxicity and better quality of life for platinum-resistant patients, then I would say that drug is probably one of the most promising agents.

I often see patients who have tumor profiling done, and we were getting results that, until recently, were not actionable. For example, the p53 mutation was previously not considered druggable. We definitely should continue to look at these drugs that reactivate p53, because if we do find one that is able to give us good response rates with limited toxicity, then it will bring hope to so many patients that have this mutation.

We have also learned so much and have made a lot of headway in the use of maintenance therapy, in particular with the use of PARP inhibitors. This will likely change significantly the future of patients with ovarian cancer.