Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012

Abstract

Purpose To determine whether cotargeting poly (ADP-ribose) polymerase-1 plus androgen receptor is superior to androgen receptor inhibition in metastatic castration-resistant prostate cancer (mCRPC) and whether ETS fusions predict response. Patients and Methods Patients underwent metastatic site biopsy and were stratified by ETS status and randomly assigned to abiraterone plus prednisone without (arm A) or with veliparib (arm B). Primary objectives were: confirmed prostate-specific antigen (PSA) response rate (RR) and whether ETS fusions predicted response. Secondary objectives were: safety, measurable disease RR (mRR), progression-free survival (PFS), and molecular biomarker analysis. A total of 148 patients were randomly assigned to detect a 20% PSA RR improvement. Results A total of 148 patients with mCRPC were randomly assigned: arm A, n = 72; arm B, n = 76. There were no differences in PSA RR (63.9% v 72.4%; P = .27), mRR (45.0% v 52.2%; P = .51), or median PFS (10.1 v 11 months; P = .99). ETS fusions did not predict response. Exploratory analysis of tumor sequencing (80 patients) revealed: 41 patients (51%) were ETS positive, 20 (25%) had DNA-damage repair defect (DRD), 41 (51%) had AR amplification or copy gain, 34 (43%) had PTEN mutation, 33 (41%) had TP53 mutation, 39 (49%) had PIK3CA pathway activation, and 12 (15%) had WNT pathway alteration. Patients with DRD had significantly higher PSA RR (90% v 56.7%; P = .007) and mRR (87.5% v 38.6%; P = .001), PSA decline ≥ 90% (75% v 25%; P = .001), and longer median PFS (14.5 v 8.1 months; P = .025) versus those with wild-type tumors. Median PFS was longer in patients with normal PTEN (13.5 v 6.7 months; P = .02), TP53 (13.5 v 7.7 months; P = .01), and PIK3CA (13.8 v 8.3 months; P = .03) versus those with mutation or activation. In multivariable analysis adjusting for clinical covariates, DRD association with PFS remained significant. Conclusion Veliparib and ETS status did not affect response. Exploratory analysis identified a novel DRD association with mCRPC outcomes.

Trial registration: ClinicalTrials.gov NCT01576172.

Figures

Fig 1.

CONSORT diagram. (*) Safety evaluable. (†) Defined as having received two cycles of therapy or removed because of toxicity; five patients who received

Fig 2.

Landscape of molecular alterations, DNA-repair status, and survival in this cohort of patients with metastatic castration-resistant prostate cancer (mCRPC). (A) Next-generation sequencing of tumor tissues identified alterations in different genes for each patient (n = 80) as depicted in the matrix, called by each allele. Three groups of patients were determined based on DNA-damage repair defect (DRD) status, represented at the top by black (biallelic DRD), gray (monoallelic DRD), or white boxes (wild-type [WT] DRD). Above this, maximum percent decreases in prostate-specific antigen (PSA) levels throughout treatment are graphed for each patient, and those with confirmed PSA responses are noted with dark blue bars. Progression-free survival (PFS; months), treatment (abiraterone [A/ABI], veliparib [V/VEL]), and ETS fusion status are also indicated at the top of the matrix for each patient. (B) Matrix of DRD status associated with PTEN alterations. Patients along the top in black correspond to patients in this study, and patients in green represent cases from an additional mCRPC cohort. (C) PFS curves are shown for patients with WT/monoallelic or biallelic DRD status. LOH, loss of heterozygosity.

Fig 3.

Survival by DNA-repair status and treatment arm. Progression-free survival (PFS) curves are shown by treatment arm for patients with wild-type (WT)/monoallelic or biallelic DNA-damage repair defect (DRD), as determined by next-generation sequencing of tumors shown in Figure 2 of the main manuscript: (A) abiraterone/prednisone; (B) abiraterone/prednisone plus veliparib.

Fig A1.

Progression-free survival (PFS) in patients with metastatic castration-resistant prostate cancer treated with abiraterone (A) or abiraterone plus veliparib (A + V) and stratified by ETS gene fusion status. (A) PFS curves are shown for all 148 response-evaluable patients treated with abiraterone/prednisone alone (n = 72) or in combination with veliparib (n = 76). (B) PFS curves are shown for each treatment arm stratified by ETS gene fusion status (determined by immunohistochemistry or in situ hybridization).

Fig A2.

Depth of prostate-specific antigen (PSA) decline by DNA-damage repair defect (DRD) status. WT, wild type.