Combination immunotherapy benefits subset of patients with advanced prostate cancer

September 10, 2020

HOUSTON -- Results from a Phase II trial led by researchers at The University of Texas MD Anderson Cancer Center suggest that a combination of ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) can generate durable responses in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC), an "immune-cold" cancer that does not typically respond well to immunotherapy.

In a cohort of patients without previous chemotherapy treatment, the overall response rate (ORR) was 25% and median overall survival (OS) was 19 months. In a post-chemotherapy cohort, the ORR was 10% and media OS was 15.2 months. Four patients (two in each cohort) achieved a complete response.

The results of the CheckMate 650 trial, published today in Cancer Cell, are the first report of combination immune checkpoint inhibitors in mCRPC. Early results from this study were presented at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium. Based on the findings, alternate dosing regimens are now being evaluated in an expanded clinical trial to reduce treatment-related toxicities.

"Historically, prostate cancer has been very resistant to checkpoint inhibitors because it is immunologically cold with few tumor-infiltrating T cells," said principal investigator Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology. "These results suggest that a combination approach to increase T cell infiltration and then block inhibitory pathways may be a useful strategy for treating these patients. Going forward, we plan to optimize the schedule and dosing to improve the safety profile."

Designing a combination strategy

In previous research published in Nature Medicine, Sharma and colleagues discovered that prostate cancers deploy multiple mechanisms to dampen the anti-tumor immune response. Although anti-CTLA-4 therapy could recruit T cells, the tumor-infiltrating T cells elicited compensatory inhibitory pathways, including immune-suppressing proteins PD-L1 and VISTA.

This would explain why previous clinical trials evaluating single-agent checkpoint inhibitors have not been effective in treating patients with mCRPC, said Sharma, who co-directs MD Anderson's immunotherapy platform, part of the institution's Moon Shots Program®.

The researchers hypothesized that combining anti-CTLA-4 (ipilimumab) with anti-PD-1 (nivolumab) may be effective in bringing T cells into the tumor and overcoming the resulting immunosuppressive response.

The multi-institution, open-label study enrolled 90 men with mCRPC, who received the combination therapy every three weeks. Patients were enrolled in two cohorts: one with and one without prior chemotherapy. Participants were 77.8% Caucasian, 10% Black/African-American and 12.2% other.

In addition to response rates, the combination therapy achieved disease control in 46.9% and 13.3% of patients, with a median progression-free survival of 5.5 and 3.8 months in the pre- and post-chemotherapy cohorts, respectively.

Despite the positive responses, grade 3 and 4 treatment-related adverse events occurred in 42.2% of pre-chemotherapy patients and 53.3% of post-chemotherapy patients. The most common of these events was diarrhea, pneumonitis, colitis and increased lipase. Treatment-related adverse events led to discontinuation of therapy in a total of 31 patients. There were four treatment-related deaths, two in each cohort.

"There were patients who had clear benefit as a result of treatment, but there also were patients who had serious adverse events, which led us to amend the protocol to evaluate alternate schedules and doses and improve the safety of this approach," said Sharma.

Based on these data, the trial has been expanded to include more than 400 patients, with different dosing and schedules to identify strategies that can improve efficacy and minimize toxicities.

Exploring biomarkers associated with response

The researcher team also conducted analyses to identify potential biomarkers associated with clinical outcomes in these patients.

While this study represents a small number of patients, their findings suggest that the combination may be more effective in patients with a relatively high tumor mutational burden (TMB). This is in agreement with previous work that suggests certain patients with mCRPC may respond to checkpoint blockade despite having low TMB relative to other cancers, such as melanoma and lung cancer.

"The current study represents the first step in trying to identify mCRPC patients who would benefit from combination therapy with ipilimumab plus nivolumab based on chemotherapy exposure as well as preliminary biomarker analyses," said co-author Sumit Subudhi, M.D., Ph.D., assistant professor of Genitourinary Medical Oncology. "The data generated to date are encouraging, but we clearly have more work to do in the expansion cohort as we try to administer effective combination strategies with fewer toxicities."
-end-
This study was supported by Bristol-Meyers Squibb and ONO Pharmaceutical Company, Limited. Sharma is a member of the Parker Institute for Cancer Immunotherapy (PICI) and co-director of PICI at MD Anderson. A full list of authors and their disclosures can be found with the paper here.

About MD Anderson

The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. The institution's sole mission is to end cancer for patients and their families around the world. MD Anderson is one of only 51 comprehensive cancer centers designated by the National Cancer Institute (NCI). MD Anderson is ranked No.1 for cancer care in U.S. News & World Report's "Best Hospitals" survey. It has ranked as one of the nation's top two hospitals for cancer care since the survey began in 1990, and has ranked first 16 times in the last 19 years. MD Anderson receives a cancer center support grant from the NCI of the National Institutes of Health (P30 CA016672).

University of Texas M. D. Anderson Cancer Center

Related Prostate Cancer Articles from Brightsurf:

Low risk of cancer spread on active surveillance for early prostate cancer
Men undergoing active surveillance for prostate cancer have very low rates - one percent or less - of cancer spread (metastases) or death from prostate cancer, according to a recent study published in the Journal of Urology®, an Official Journal of the American Urological Association (AUA).

ESMO 2020: Breast cancer drug set to transform prostate cancer treatment
A drug used to treat breast and ovarian cancer can extend the lives of some men with prostate cancer and should become a new standard treatment for the disease, concludes a major trial which is set to change clinical practice.

Major trial shows breast cancer drug can hit prostate cancer Achilles heel
A drug already licensed for the treatment of breast and ovarian cancers is more effective than targeted hormone therapy at keeping cancer in check in some men with advanced prostate cancer, a major clinical trial reports.

The Lancet: Prostate cancer study finds molecular imaging could transform management of patients with aggressive cancer
Results from a randomised controlled trial involving 300 prostate cancer patients find that a molecular imaging technique is more accurate than conventional medical imaging and recommends the scans be introduced into routine clinical practice.

Common genetic defect in prostate cancer inspires path to new anti-cancer drugs
Researchers found that, in prostate cancer, a mutation leading to the loss of one allele of a tumor suppressor gene known as PPP2R2A is enough to worsen a tumor caused by other mutations.

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.

Read More: Prostate Cancer News and Prostate Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.