Nav: Home

Lethal prostate cancer treatment may benefit from combination immunotherapy

June 25, 2018

Researchers at the Johns Hopkins Kimmel Cancer Center and the Bloomberg~Kimmel Institute for Cancer Immunotherapy (BKI) released a study investigating the use of combination checkpoint immunotherapy in the treatment of a lethal form of advanced prostate cancer. The study suggested a genetic subset of prostate cancer may benefit from this form of immunotherapy.

The study targeted AR-V7+ prostate cancer with a combination of two checkpoint blockers, ipilimumab and nivolumab, in 15 patients with this aggressive variant, first discovered at Johns Hopkins in 2014.

This is the first clinical trial to target this specific form of prostate cancer, which can kill patients in only six to nine months and has inadequate treatment options. It is the first reported study of combination immunotherapy using both ipilimumab and nivolumab in prostate cancer.

The study was published by Oncotarget on June 19, 2018.

"This is the first prostate cancer study to be supported by the Bloomberg~Kimmel Institute for Cancer Immunotherapy since the institute was launched and provides the first evidence that immunotherapy can indeed benefit some patients with prostate cancer, a cancer type previously thought to be completely immunotherapy resistant," said Drew Pardoll, M.D., Ph.D., director of the BKI.

Patients on the trial received treatment by IV infusion consisting of 3 milligrams per kilogram of nivolumab plus 1 milligram per kilogram of ipilimumab every three weeks for four doses, followed by a maintenance regimen of 3 milligrams per kilogram of nivolumab alone every two weeks thereafter. The patients were enrolled between December 2016 and October 2017.

The data showed two out of the 15 men (13 percent) experienced a decrease in the level of prostate-specific antigen (PSA) of at least 50 percent. More encouragingly, one-quarter of patients achieved an objective response, meaning that their tumors shrank partially or completely with combination immunotherapy. These responses were typically lasted at least nine months. At least two of the patients remain alive for more than 18 months, which is much longer than expected for men with AR-V7+ prostate cancer.

Six of 15 patients (40 percent) had a genetic subtype of prostate cancer that harbored somatic and/or germline mutations in one DNA-repair genes involved in the BRCA pathway, first shown to predispose women to breast and ovarian cancer. In these six men, gene mutations of BRCA2, ATM, and ERCC4 were individually detected in those patients.

"Remarkably, all of the benefit from ipilimumab plus nivolumab appeared to occur in patients who had one of these gene mutations, particularly in two men with BRCA2 mutations," said Emmanuel Antonarakis, M.B.B.Ch., senior author of the study.

"This finding is important, because BRCA2 is not a gene that was previously thought to sensitize patients to immune checkpoint inhibitors and, if true, will have profound implications for other diseases, such as breast and ovarian cancers where these genes are frequently mutated," said Antonarakis. "In the setting of prostate cancer, about 20-25 percent of patients have mutations in BRCA2 and related genes, which are involved in a DNA-repair process called homologous recombination. This study suggests that these gene mutations may be even more common in men with the AR-V7+ type of prostate cancer."

While prostate cancer is generally regarded as a low-mutation-burden tumor and immune-checkpoint blockade has resulted in only rare clinical regressions when used as a monotherapy, the data suggested AR-V7+ prostate cancers may be associated with a greater number of DNA-repair gene mutations and a higher mutation load and could be further exploited by using combination immunotherapy.

"If these findings are confirmed, this could offer some hope to these patients with AR-V7+ disease who have few, if any, good treatment options," said Antonarakis.

The study showed the combination of nivolumab plus ipilimumab demonstrated acceptable safety and tolerability in men with AR-V7+ advanced prostate cancer. Based on the encouraging preliminary findings, Antonarakis said he will expand his study to involve a greater number of patients. The expanded study is open to enrollment and actively seeking new patients.
-end-
The Bloomberg~Kimmel Institute for Cancer Immunotherapy was founded in 2016 with a series of philanthropic investments totaling $125 million from benefactors Michael R. Bloomberg, Sidney Kimmel and more than a dozen other supporters. It is a groundbreaking collaboration between clinical and scientific specialties, supporting cancer immunotherapy research across many cancer types.

COI: Emmanuel Antonarakis is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Medivation, ESSA, AstraZeneca, Clovis and Merck; has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol Myers-Squibb, AstraZeneca, Clovis and Merck; and is the co-inventor of a biomarker technology that has been licensed to Qiagen. Victor Velculescu is a founder of Personal Genome Diagnostics (PGDx), is a member of its scientific advisory board and board of directors, and owns PGDx stock. He is also on the Scientific Advisory Board for Ignyta.

This research was sponsored by Bristol-Myers Squibb (Princeton, New Jersey), which also provided both study drugs free of cost. This research was also partially supported by National Institutes of Health grants P30 CA006973 and R01 CA185297, Department of Defense grants W81XWH-13-PCRP-CCA and W81XWH-15-2-0050, and the Bloomberg~Kimmel Institute for Cancer Immunotherapy. Genomic studies were partially supported by National Institutes of Health grant R01 CA121113 and the Commonwealth Foundation.

Johns Hopkins Medicine

Related Prostate Cancer Articles:

First prostate cancer therapy to target genes delays cancer progression
For the first time, prostate cancer has been treated based on the genetic makeup of the cancer, resulting in delayed disease progression, delayed time to pain progression, and potentially extending lives in patients with advanced, metastatic prostate cancer, reports a large phase 3 trial.
Men taking medications for enlarged prostate face delays in prostate cancer diagnosis
University of California San Diego School of Medicine researchers report that men treated with medications for benign prostatic hyperplasia (enlarged prostate) experienced a two-year delay in diagnosis of their prostate cancer and were twice as likely to have advanced disease upon diagnosis.
CNIO researchers confirm links between aggressive prostate cancer and hereditary breast cancer
The study has potential implications for families with members suffering from these types of tumours who are at an increased risk of developing cancer.
Distinguishing fatal prostate cancer from 'manageable' cancer now possible
Scientists at the University of York have found a way of distinguishing between fatal prostate cancer and manageable cancer, which could reduce unnecessary surgeries and radiotherapy.
Researchers find prostate cancer drug byproduct can fuel cancer cells
A genetic anomaly in certain men with prostate cancer may impact their response to common drugs used to treat the disease, according to new research at Cleveland Clinic.
More Prostate Cancer News and Prostate Cancer Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Rethinking Anger
Anger is universal and complex: it can be quiet, festering, justified, vengeful, and destructive. This hour, TED speakers explore the many sides of anger, why we need it, and who's allowed to feel it. Guests include psychologists Ryan Martin and Russell Kolts, writer Soraya Chemaly, former talk radio host Lisa Fritsch, and business professor Dan Moshavi.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...