Prognostic Value of Germline DNA Repair Gene Mutations in De Novo Metastatic and Castration‐Sensitive Prostate Cancer

5035 Background: ARV7+ mCRPC is an aggressive phenotype with a median PFS of 3-4 mo and OS of 7-9 mo. We hypothesized that ARV7+ tumors would be enriched for DNA repair mutations, rendering them more responsive to combined immune checkpoint blockade. Methods: We enrolled 15 mCRPC pts with ARV7+ CTCs (using a CLIA-certified assay) into a single arm phase 2 study. Pts received Nivo 3 mg/kg plus Ipi 1 mg/kg every 3 wk x 4 doses, then maintenance Nivo 3 mg/kg every 2 wk. Targeted sequencing for DNA repair defects was performed on pretreatment tumor biopsies (n=11) or cell-free DNA (n=4). Primary endpoint: PSA50response rate. Secondary endpoints: objective response rate (ORR) in pts with measurable disease, durable PFS (lack of progression ≥24 wk), PSA‐PFS, radiographic (r)PFS, overall survival (OS), and frequency/intensity of AEs. Results: 15 ARV7+ men were enrolled, with median f/u 8.4 (range 1.9–10.5) mo. Median age was 65, 47% had ECOG ≥1, median PSA was 115 ng/mL, 67% had visceral/nodal mets, all had bone mets, and 60% had ≥4 prior regimens for mCRPC. Mean ARV7/AR ratio was 23% (range 3–75%). 6/15 men (40%) had pathogenic DNA repair gene mutations ( BRCA2, ATM, MSH6, FANCM, FANCA, POLH). Overall, the PSA50rate was 1/15 (7%), ORR was 2/8 (25%), durable PFS rate was 3/15 (20%), PSA-PFS was 3.0 (95%CI 2.1–4.9) mo, rPFS was 3.9 (95%CI 2.8–5.5) mo, and OS was 9.5 (95%CI 7.2–NA) mo. Outcomes appeared better in DNA repair deficient (DRD+) tumors vs. DNA repair proficient (DRD–) tumors (TABLE). 15 grade 3-4 treatment-related AEs occurred in 7/15 (46%) men (including 2 hepatitis, 2 colitis, 1 pneumonitis); there were no treatment-related deaths. Conclusions: In this first study targeting ARV7+ mCRPC, treatment with Ipi/Nivo had acceptable safety and encouraging efficacy, particularly in men with DRD+ tumors. DNA repair mutations may be enriched in ARV7+ prostate cancer. Clinical trial information: NCT02601014. [Table: see text]

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Re: Germline DNA-Repair Gene Mutations and Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer Receiving First-Line Abiraterone and Enzalutamide

The Journal of Urology ◽

10.1016/j.juro.2018.08.026 ◽

2018 ◽

Vol 200 (5) ◽

pp. 945-945

Author(s):

Samir S. Taneja

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Gene Mutations ◽

Castration Resistant Prostate Cancer ◽

First Line ◽

Repair Gene ◽

Castration Resistant ◽

Dna Repair Gene

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Commentary on: “Inherited DNA-repair gene mutations in men with metastatic prostate cancer.” Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, Garofalo A, Gulati R, Carreira S, Eeles R, Elemento O, Rubin MA, Robinson D, Lonigro R, Hussain M, Chinnaiyan A, Vinson J, Filipenko J, Garraway L, Taplin ME, AlDubayan S, Han GC, Beightol M, Morrissey C, Nghiem B, Cheng HH, Montgomery B, Walsh T, Casadei S, Berger M, Zhang L, Zehir A, Vijai J, Scher HI, Sawyers C, Schultz N, Kantoff PW, Solit D, Robson M, Van Allen EM, Offit K, de Bono J, Nelson PS. N Engl J Med. 2016 Aug 4;375(5):443–53.

Urologic Oncology Seminars and Original Investigations ◽

10.1016/j.urolonc.2017.07.006 ◽

2017 ◽

Vol 35 (9) ◽

pp. 575-576 ◽

Cited By ~ 1

Author(s):

Byron H. Lee

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Metastatic Prostate Cancer ◽

Gene Mutations ◽

Repair Gene ◽

Dna Repair Gene

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Commentary on “Inherited DNA-repair gene mutations in men with metastatic prostate cancer”. Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, Garofalo A, Gulati R, Carreira S, Eeles R, Elemento O, Rubin MA, Robinson D, Lonigro R, Hussain M, Chinnaiyan A, Vinson J, Filipenko J, Garraway L, Taplin ME, AlDubayan S, Han GC, Beightol M, Morrissey C, Nghiem B, Cheng HH, Montgomery B, Walsh T, Casadei S, Berger M, Zhang L, Zehir A, Vijai J, Scher HI, Sawyers C, Schultz N, Kantoff PW, Solit D, Robson M, Van Allen EM, Offit K, de Bono J, Nelson PS. N Engl J Med. 2016;375(5):443–53.

Urologic Oncology Seminars and Original Investigations ◽

10.1016/j.urolonc.2017.05.012 ◽

2017 ◽

Vol 35 (8) ◽

pp. 536-537

Author(s):

Stephen J. Freedland ◽

William J. Aronson

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Metastatic Prostate Cancer ◽

Gene Mutations ◽

Repair Gene ◽

Dna Repair Gene

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Frequency of DNA repair gene mutations in localized and metastatic prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.10 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 10-10 ◽

Cited By ~ 2

Author(s):

Marc Dall'Era ◽

Allison Glass ◽

Primo Lara ◽

Ryan Hartmaier ◽

Ralph deVere White ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Gene Mutations ◽

Prostate Tumors ◽

Repair Gene ◽

Dna Repair Gene ◽

Platinum Based Chemotherapy ◽

Visceral Metastases ◽

Prostate Cancers ◽

Repair Genes

10 Background: DNA repair gene mutations are important molecular alterations in prostate cancer pathogenesis. Germline mutations in DNA repair genes, particularly BRCA2, were recently recognized as associated with metastatic prostate cancer and may also be particularly sensitive to platinum based chemotherapy and PARP inhibitor therapy. We sought to characterize alterations in DNA repair pathway genes in both primary and metastatic prostate tumors. Methods: We studied the distribution of DNA repair gene mutations in 936 prostate cancers harvested from localized and metastatic tumors. Tumor DNA underwent hybrid capture for all coding exons of 395 cancer-related genes plus select introns from 19 or 31 genes frequently rearranged in cancer and sequenced to a median exon coverage depth of >500x using Illumina sequencing and were analyzed for base substitutions/insertions, copy number alterations and rearrangements. We utilized two described lists of genes involved in DNA repair : our own in-house list of 74 (UCD) and a list of 20 DNA repair genes associated with cancer predisposition syndromes utilized in a recent publication by Pritchard et al. We further stratified the frequency of mutations by tissue site (prostate versus metastases). Results: We identified 228/936 unique samples with at least one likely functional mutation in a DNA repair gene (24.4%). Mutations were identified in 20.1% of prostate tumors (13% UCD, 18.4% Pritchard et al.) and in 18.8% of bone metastases. The highest rates of DNA repair mutations were found in visceral metastases including brain, pelvis and liver, higher than either prostate tissue or bone sites (p=<0.01). The most commonly (≥1% of samples) mutated genes in the DNA repair pathways are: BRCA2 (11.43%), ATM (5.77%), MSH6 (2.46%), MSH2 (2.14%), ATR (1.60%), MLH1 (1.28%), and BRCA1(1.18%). Conclusions: DNA repair gene mutations are more common in metastatic than localized prostate tumors. Visceral metastases appear enriched for these mutations compared with localized tumors or bone metastases. Genomic profiling may identify prostate cancers potentially sensitive to platinum-based chemotherapy or PARP inhibition.

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