Ipilimumab plus nivolumab and DNA-rep... - Advanced Prostate...

Advanced Prostate Cancer

20,782 members25,887 posts

Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer.

pjoshea13 profile image
0 Replies

New Johns Hopkins study below.

"AR-V7-expressing metastatic prostate cancer is an aggressive phenotype with poor progression-free survival (PFS) and overall survival (OS). Preliminary evidence suggests that AR-V7-positive tumors may be enriched for DNA-repair defects, perhaps rendering them more sensitive to immune-checkpoint blockade. We enrolled 15 metastatic prostate cancer patients with AR-V7-expressing circulating tumor cells into a prospective phase-2 trial. Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses, then maintenance nivolumab 3 mg/kg every 2 weeks."

"Ipilimumab plus nivolumab demonstrated encouraging efficacy in AR-V7-positive prostate cancers with DRD {DNA-repair deficiency} mutations, but not in the overall study population."

"Outcomes appeared generally better in DRD+ vs. DRD- tumors with respect to PSA responses (33% vs. 0% ...), ORR {objective response rates} (40% vs. 0% ...)"

-Patrick

ncbi.nlm.nih.gov/pubmed/299...

Oncotarget. 2018 Jun 19;9(47):28561-28571. doi: 10.18632/oncotarget.25564. eCollection 2018 Jun 19.

Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer.

Boudadi K1, Suzman DL2, Anagnostou V1, Fu W1, Luber B1, Wang H1, Niknafs N1, White JR1, Silberstein JL3, Sullivan R1, Dowling D1, Harb R1, Nirschl TR1, Veeneman BA4,5, Tomlins SA4,6, Wang Y7, Jendrisak A7, Graf RP7, Dittamore R7, Carducci MA1, Eisenberger MA1, Haffner MC8, Meeker AK8, Eshleman JR8, Luo J3, Velculescu VE1, Drake CG9, Antonarakis ES1,3.

Author information

1

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

2

Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.

3

Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

4

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.

5

Present address: Pfizer Inc., Pearl River, NY, USA.

6

Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.

7

Epic Sciences Inc., San Diego, CA, USA.

8

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

9

Department of Hematology/Oncology, Columbia University Medical Center, New York, NY, USA.

Abstract

AR-V7-expressing metastatic prostate cancer is an aggressive phenotype with poor progression-free survival (PFS) and overall survival (OS). Preliminary evidence suggests that AR-V7-positive tumors may be enriched for DNA-repair defects, perhaps rendering them more sensitive to immune-checkpoint blockade. We enrolled 15 metastatic prostate cancer patients with AR-V7-expressing circulating tumor cells into a prospective phase-2 trial. Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses, then maintenance nivolumab 3 mg/kg every 2 weeks. Targeted next-generation sequencing was performed to determine DNA-repair deficiency (DRD) status. Outcomes included PSA response rates, objective response rates (ORR), PSA progression-free survival (PSA-PFS), clinical/radiographic PFS and OS. Median age of participants was 65, median PSA was 115 ng/mL, 67% had visceral metastases, and 60% had ≥4 prior systemic therapies. Six of 15 men (40%) had DRD mutations (three in BRCA2, two in ATM, one in ERCC4; none had microsatellite instability). Overall, the PSA response rate was 2/15 (13%), ORR was 2/8 (25%) in those with measurable disease, median PSA-PFS was 3.0 (95%CI 2.1-NR) months, PFS was 3.7 (95%CI 2.8-7.5) months, and OS was 8.2 (95%CI 5.5-10.4) months. Outcomes appeared generally better in DRD+ vs. DRD- tumors with respect to PSA responses (33% vs. 0%; P=0.14, nonsignificant), ORR (40% vs. 0%; P=0.46, nonsignificant), PSA-PFS (HR 0.19; P<0.01, significant), PFS (HR 0.31; P=0.01, significant), and OS (HR 0.41; P=0.11, nonsignificant). There were no new safety concerns. Ipilimumab plus nivolumab demonstrated encouraging efficacy in AR-V7-positive prostate cancers with DRD mutations, but not in the overall study population.

KEYWORDS:

AR-V7; DNA repair; ipilimumab; nivolumab; prostate cancer

PMID: 29983880 PMCID: PMC6033362 DOI: 10.18632/oncotarget.25564

Written by
pjoshea13 profile image
pjoshea13
To view profiles and participate in discussions please or .
Read more about...

You may also like...

FDA Approves Darolutamide Plus Docetaxel for Metastatic Hormone-Sensitive Prostate Cancer

t-for-darolutamide-plus-docetaxel-in-metastatic-hormone-sensitive-prostate-cancer More info:...

Supplements for metastatic prostate cancer

safe to take after initial treatment for metastatic prostate cancer. I see many different posts...

Brca1 and metastatic prostate cancer

for options for my dad . 73 yr old with metastatic prostate cancer . He has brca1 gene . Zytiga and...

metastatic prostate cancer

my dad has castrate resistant metastatic pc in bones- currently his psa is going up but his scans...

Metastatic prostate cancer

I’m new to this site. I have stage 4 metastatic prostate cancer and have been through every...