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Immunotherapy: two checkpoint inhibitors generate responses against castration-resistant metastatic prostate cancer

Some patients with metastatic prostate cancer respond to a combination of immune checkpoint inhibitors after hormonal therapy and chemotherapy have failed, according to early results from a clinical trial led by investigators at The University of Texas MD Anderson Cancer Center presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco.

The results of combining the CTLA-4 blocking drug Ipilimumab ( Yervoy ) with the PD-1 inhibitor Nivolumab ( Opdivo ) provide an encouraging step for a cancer that's been highly resistant to immune checkpoint therapies.

Among castration-resistant patients who had progressed after second-generation hormonal therapy ( cohort 1 ), 25% ( 8 of 32 ) had their tumors shrink from the immunotherapy combination at a median follow-up of 11.9 months.
Among those who progressed after chemotherapy and hormonal therapy ( cohort 2 ) 10% ( 3 of 30 ) had a response at median follow-up of 13.5 months.

This was the first combination trial of two immune checkpoint therapies in prostate cancer. These results support the idea that immune checkpoint blockade can play an important role in the treatment of these patients and provide the foundation to test this strategy in a larger clinical trial.

There were four complete responders, two in each cohort, among the 62 patients who could be evaluated for tumor growth.

Side effects from the combination were consistent with those experienced in previous combination trials for other cancers, with 42% of patients in cohort 1 and 53% in cohort 2 experiencing grade 3 to 5 adverse events.
Among cohort 1, 33% had to discontinue participation due to adverse events, with 35.6% having to withdraw from cohort 2.
The most common adverse events were diarrhea, fatigue, skin rash, nausea and hypothyroidism.
Four patients died from treatment-related adverse events, two in each cohort.

Disease progression was the most common reason to leave the trial, with 51.1% of cohort 1 and 44.4% of cohort 2 discontinuing for that reason.

The researchers also analyzed a number of biomarkers and found that higher tumor mutational burden was associated with response.

In previous clinical trials, neither drug succeeded as single therapy against prostate cancer, a so-called cold malignancy because it does not attract the attention of the immune system.
Few T cells, the adaptive immune system's targeted warriors, infiltrate prostate tumors.

In a phase I trial, no patients responded to Nivolumab alone because the PD-1 inhibitor requires an immune response to be under way in order to attack tumors.

The multi-center combination clinical trial was organized after research published in Nature Medicine by Padmanee Sharma and Jim Allison, provided scientific underpinning for the combination in prostate cancer.

Analyzing tumor samples before and after treatment in a clinical trial of Ipilimumab and the anti-hormonal drug Leuprolide, researchers found that Ipilimumab caused an immune response to the cancer reflected by major T cell penetration of tumors.

They also found that PD-L1, a ligand that turns on the PD-1 checkpoint on T cells, was heavily expressed by the tumor and surrounding tissue in response, shutting down the T cell attack.
Researchers hypothesized that combination treatment would induce an immune response with Ipilimumab and then protect that response from deactivation by PD-1 with Nivolumab. ( Xagena )

Source: University of Texas MD Anderson Cancer Center, 2019