1908 - Androgen Receptor (AR) Aberrations in Patients (Pts) With Metastatic Castration-Sensitive Prostate Cancer (mCSPC) Treated With Apalutamide (APA) Plus Androgen Deprivation Therapy (ADT) in TITAN

Background

TITAN evaluated APA vs placebo (PBO), + ADT, in pts with mCSPC. APA improved overall survival (OS [HR, 0.67; 95% CI, 0.51-0.89; p = 0.0053]) vs PBO. We evaluated AR aberrations at baseline (BL) and end of treatment (EOT) and assessed associations of EOT AR aberrations with outcomes in TITAN.

Methods

From 265 pt samples (APA, n = 116; PBO, n = 149) available for evaluation, a subset was analyzed for circulating tumor (ct)DNA and AR aberrations (ARv7, AR amplification, AR ligand binding domain mutations) from cell-free (cf)DNA and cfRNA using next-generation sequencing and PCR, respectively. Associations with OS and duration on first subsequent therapy were assessed.

Results

BL characteristics of pts were balanced between biomarker-positive groups. Among aberrations at BL, AR amplification was associated with longer duration of prior ADT (4.2 mo vs 1.6 mo, pts with vs without AR amplification; p = 0.034). ctDNA % and frequency of AR aberrations increased from BL to EOT. At EOT, ctDNA % was similar in APA and PBO groups (60% and 66%), and AR aberrations were less frequent with APA vs PBO (Table). Regardless of treatment group, OS was significantly shorter with detection of any AR aberration at EOT (OS: 2.7 [1.1-6.6], p = 0.0278, APA; 6.1 [1.9-20.3], p = 0.0007, PBO). Detection of any AR aberration at EOT was significantly associated with duration on first subsequent therapy (2.0 [1.0-4.0], p = 0.0386).Table:

883P Frequency of AR aberrations at BL and EOT

Only pts with ARv7, AR amplification, and AR mutation measured are reported. ^bFrom Fisher’s exact test for comparison vs PBO, p = 0.04.

Conclusions

In TITAN, AR amplification at BL was associated with even brief ADT exposure. AR aberrations were fewer at EOT with APA vs PBO. Pts with AR aberrations at EOT had worse outcomes vs pts without. Taken together, these findings suggest that early APA + ADT provides long-term benefits vs ADT alone without increased acquisition of AR aberrations. The detailed biological mechanisms underlying these findings need to be further studied.

Clinical trial identification

NCT02489318.

Editorial acknowledgement

Larissa Belova, PhD, of Parexel.

Legal entity responsible for the study

Janssen Research & Development.

Funding

Janssen Research & Development.

Disclosure

K.N. Chi: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Amgen; Advisory / Consultancy: Essa; Advisory / Consultancy, Research grant / Funding (institution): Lilly/ImClone; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Tokai Pharmaceuticals; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Amgen; Advisory / Consultancy: Essa; Advisory / Consultancy, Research grant / Funding (institution): Lilly/ImClone; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Tokai Pharmaceuticals. S. Thomas: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. N. Agarwal: Advisory / Consultancy: Argos Therapeutics; AstraZeneca; Bayer; Bristol-Myers Squibb; Clovis Oncology; Eisai; EMD Serono; Exelixis; Foundation One Inc; Genentech/Roche; Lilly; Medivation/Astellas; Merck; Nektar; Novartis; Pfizer; Research grant / Funding (institution): Active Biotech; Amgen; AstraZeneca; Bavarian Nordic; Bayer; BN ImmunoTherapeutics; Bristol-Myers Squibb; Calithera Biosciences; Celldex; Eisai; Exelixis; Genentech; GlaxoSmithKline; Immunomedics; Janssen; Medivation; Merck; Newlink Geneti. F. Feng: Leadership role, Shareholder / Stockholder / Stock options: PFS Genomics; Advisory / Consultancy: Dendreon; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Janssen Oncology; Advisory / Consultancy: Ferring Pharmaceuticals; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Bayer HealthCare Pharmaceuticals; Advisory / Consultancy: Blue Earth Diagnostics; Advisory / Consultancy: Celgene; Advisory / Consultancy: Medivation/Astellas Pharma; Research grant / Funding (institution): Zenith Epigenetics; Licensing / Royalties, I helped develop a molecular signature to predict radiation resistance in breast cancer, and this signature was patented by the University of Michigan, my employer; it is in the process of being licensed to PFS Genomics, a company that I helped found: Patents, Royalties, Other Intellectual Property. G. Attard: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas Pharma; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Medivation; Advisory / Consultancy, Travel / Accommodation / Expenses: Abbott Laboratories; Advisory / Consultancy: ESSA; Advisory / Consultancy: Janssen-Cilag; Advisory / Consultancy: Millennium; Advisory / Consultancy: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ventana Medical Systems; Advisory / Consultancy: Veridex; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Takeda; Research grant / Funding (institution): Arno Therapeutics; Licensing / Royalties: The Institute of Cancer Research Rewards to Inventors list of abiraterone acetate; Non-remunerated activity/ies, Other relationship: Institute of Cancer Research. A.W. Wyatt: Advisory / Consultancy: Genzyme; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Janssen. M. Gormley: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. D.S. Ricci: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. A. Lopez-Gitlitz: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. K. Deprince: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. J. Larsen: Full / Part-time employment: Janssen; Shareholder / Stockholder / Stock options: Johnson & Johnson. W. Chen: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. B. Miladinovic: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. V. Naini: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. S. Chowdhury: Honoraria (self), Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy: Janssen-Cilag; Honoraria (self): Novartis; Research grant / Funding (institution): Sanofi/Aventis.