Response rates to immunotherapy treatment for prostate cancer patients improves markedly when specific molecular features of the tumour are selected for, compared to trials in unselected patients, shows a new clinical trial led by researchers and clinicians from UCL and UCLH.
Immunotherapy, which works by boosting the immune system’s ability to detect and destroy cancer cells, has transformed care in many forms of cancer in recent years. But despite being the most common cancer in men, prostate cancer has remained largely unresponsive to this form of treatment.
Results for the multicentre NEPTUNES trial, published in the Journal of Clinical Oncology, show that patients whose cancer has specific genetic features or high immune cell count may benefit far more than previously thought from a combination of two immunotherapy drugs, nivolumab and ipilimumab.
The trial included 74 patients with metastatic castration-resistant prostate cancer (mCRPC), which means that the cancer has spread to other parts of the body and has become resistant to hormone therapy. The patients all had alterations in DNA repair genes (which keep our DNA intact by repairing damage) and a high presence of immune cells around the tumour that formed a certain ‘immunogenic signature’, which was used to select participants for immunotherapy treatment.
Around one third of patients (32%) in the trial responded to immunotherapy, which meant the tumour got smaller, as measured on scans and/or blood tests. This is a substantial improvement to previous immunotherapy trials in prostate cancer, where only about 10% of patients responded.
Dr Mark Linch, senior author of the study from UCL Cancer Institute and a consultant oncologist at UCLH, said: “Previous immunotherapy trials for prostate cancer, which gave the drugs to all participants without selecting for any gene or cellular traits, have been disappointing and really put the brakes on research in this area for a while.
“But our findings suggest that immunotherapy could be a powerful option for a subset of prostate cancer patients with a certain immunogenic signature, which is around a quarter of patients with this type of cancer in the UK.
“At the moment, these patients would only be expected to live for one to two years based on currently available treatment options. Immunotherapy offers a more effective and personalised treatment, and though larger trials are needed before it can be introduced into the clinic, the fact that we have patients who are alive and well over five years later is a very encouraging sign.”
The response to the immunotherapy was even higher for those with certain genetic markers. Patients with mismatch repair deficiency (inability to repair DNA errors) had the highest response rate at 70%, followed by those with loss of function in the BRCA2 gene (50%) and those with a high proportion of immune cells around the tumour (43%). Three patients had all three of these markers and all three responded to treatment.
The trial also tested two dosing strategies. A higher ipilimumab and low nivolumab dose had a better response rate (40%) but more toxicity, while low iipilimumab dose and higher nivolumab dose was better tolerated but had a lower response rate (25%).
The research builds on previous work to better understand prostate cancer on a more personalised level.
Dr Gianmarco Leone, first author of the study from UCL Cancer Institute, said: “In previous work we and others characterised prostate cancer and found generally low numbers of immune cells. This is likely to be because of physical and chemical exclusion of the immune cells by the tumour and lack of mutations for the immune cells to target. However, we did find that some patients had much higher mutation rates than others, and some had lots of immune cells around the tumour. This led us to hypothesise that patients who fit this profile would respond better to immunotherapy, and I’m excited to say that this is exactly what the current trial has shown.
“In terms of the effectiveness of immunotherapy, to have patients with long-lasting responses to treatment who are still disease-free years later is a great achievement. I hope our results will reignite interest in immunotherapy for prostate cancer.”
The researchers say the next step would be a larger trial to fine-tune the treatment approach, with a view to getting regulatory approval for it to be used to treat advanced metastatic prostate cancer in patients most likely to benefit.
This study was supported by Bristol Myers Squibb, the Rosetrees Trust, the John Black Charitable Foundation and Cancer Research UK.
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