A combination of two approved immunotherapies — Opdivo (nivolumab) and Yervoy (ipilimumab) — appears to delay cancer progression and lengthen survival in a subset of patients with an aggressive form of castration-resistant prostate cancer, results from an ongoing pilot trial led by Johns Hopkins School of Medicine show.
The study, “Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer,” was published in the journal Oncotarget.
It targeted patients with AR-V7-positive prostate cancer — tumors that produce a variant of the androgen receptor that is resistant to current hormone therapies. These patients generally have a median overall survival of seven to nine months.
This type of prostate cancer was first discovered by a Johns Hopkins-led team of researchers in 2014.
The pilot trial (NCT02601014), led by a scientist involved in that earlier work, examined if a combination of two immune checkpoint inhibitors — Yervoy and Opdivo — could be of some benefit to patients with this type of cancer.
Based on positive preliminary findings, the trial has been expanded and is actively recruiting patients at its Maryland site.
Fifteen people were enrolled and treated with an intravenous infusion of Yervoy and Opdivo every three weeks for a total of 12 weeks (four doses), followed by a maintenance regimen of Opdivo every two weeks for up to 36 weeks.
Among eight patients with measurable tumors, one-quarter of them — or two people — had partly or completely reduced tumors, the study reports.
But only patients whose tumors had mutations in genes involved in DNA repair, including mutations at the BRCA2, ATM or ERCC4 genes, benefitted from this treatment approach.
“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 Emmanuel Antonarakis, the study’s senior author, in a news release.
Response measures were generally better in DNA repair-deficient patients with one of the noted mutations, both in terms of survival without a raise in PSA levels — a blood marker of prostate cancer — or survival without tumor growth on CT scans.
Two patients who achieved a higher than 50% reduction in PSA levels had mutations in the BRCA2 gene.
Another two, with mutations in ATM and BRCA2, are alive more than 18 months post-treatment, considerably longer than is usually seen in men with AR-V7-positive cancer.
This study “provides the first evidence that immunotherapy can indeed benefit some patients with prostate cancer, a cancer type previously thought to be completely immunotherapy resistant,” Drew Pardoll, MD, director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy at John Hopkins, said in the release
“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,” Antonarakis added.
The combination treatment did not lead to unexpected adverse events and was generally well-tolerated.
This combination immunotherapy is already FDA-approved, and has shown promising results for the treatment of multiple advanced cancers.
“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,” Antonarakis said.