Looking at Immunotherapies for Patients with Metastatic Prostate Cancer

A subset of patients with metastatic prostate cancer experienced prolonged survival as a result of treatment with the immunotherapy Yervoy (ipilimumab), according to study findings published in Science Translational Medicine.

Researchers in the phase 2 trial found that certain patients with metastatic castration-resistant prostate cancer, which typically has a limited response to immunotherapy, could benefit from treatment with Yervoy. The investigation also uncovered biomarkers in the tumors that could help doctors identify patients most likely to respond to the medication. The participants who fared best were those whose tumors, before treatment, had a higher density of active T cells, also known as immune cells.

Yervoy is among a class of drugs known as checkpoint inhibitors, which interfere with the activity of proteins that otherwise keep the immune system in check. Yervoy targets the protein CTLA-4. These kinds of drugs free up the immune system to better recognize and kill cancer cells and tend to work best in tumors that have numerous mutations, such as melanoma and lung cancer. Prostate tumors have fairly low mutation levels, the authors pointed out, but immunotherapy also can be more effective in some tumors that express the protein PD-L1 or contain T cells.

The researchers, all from The University of Texas MD Anderson Cancer Center in Houston, knew that previous clinical trials had found some responses to immuno- therapy among patients with prostate cancer, so they focused on whether checkpoint inhibition could stimulate effective immune responses in tumors with low mutation levels. Their trial included 30 patients with metastatic castration-resistant prostate cancer; 29 were treated with Yervoy between January 2015 and May 2018, and one did not receive treatment.

After a median follow-up of 45.5 months, the researchers separated the patients into two groups based on length of life and time until disease grew or spread while receiving Yervoy. In the group that showed favorable results, six of nine patients were alive at the time of analysis, with survival ranging from 33 to 54 months. All 10 patients in the group with unfavorable results died of their disease, with survival ranging from 0.6 to 10.3 months from the start of treatment.

Across all participants, the median time until disease progression was three months and median overall survival was 24.3 months.

The researchers found a couple of reasons for the better outcomes. The men in the favorable group had a high level of cancer-killing CD8 T cells in their tumors and greater expression of the protein interferon gamma, another key to immunity. Furthermore, their T cells recognized and responded to the antigens produced by tumor cells, whereas T cells from patients in the unfavorable group did not appear to have those capabilities.

Eight patients (28%) experienced serious side effects from receiving Yervoy, with dermatitis and diarrhea among the most common.

“We were encouraged to see that prostate cancers with a low mutational burden do in fact express neoantigens that elicit T-cell responses that lead to favorable clinical outcomes,” co-lead corresponding author Dr. Padmanee Sharma said in a press release. “Our findings indicate

that anti-CTLA-4 immune checkpoint therapy warrants additional studies in order to develop treatment strategies that may improve survival of patients with metastatic prostate cancer.”

One immunotherapy is already approved for patients with prostate cancer, but it works differently from Yervoy. Provenge (sipuleucel-T) is made from a patient’s own harvested immune cells, which are exposed in a lab to a cancer-fighting protein and then infused back into the patient. Provenge is indicated to treat minimally symptomatic lower-burden metastatic prostate cancer and is not widely used.