Plasma Androgen Receptor Copy Number Status at Emergence of Metastatic Castration-Resistant Prostate Cancer: A Pooled Multicohort Analysis

Abstract

Purpose: Increases in androgen receptor (AR) copy number (CN) can be detected in plasma DNA when patients develop metastatic castration-resistant prostate cancer. We aim to evaluate the association between AR CN as a continuous variable and clinical outcome.

Patients and methods: PCR2023 was an international, multi-institution, open-label, phase II study of abiraterone acetate plus prednisolone (AAP) or abiraterone acetate plus dexamethasone that included plasma AR assessment as a predefined exploratory secondary end point. Plasma AR CN data (ClinicalTrials.gov identifier: NCT01867710) from this study (n = 133) were pooled with data from the following three other cohorts: cohort A, which was treated with either AAP or enzalutamide (n = 73); the PREMIERE trial (ClinicalTrials.gov identifier: NCT02288936) of biomarkers for enzalutamide (n = 94); and a phase II trial from British Columbia (ClinicalTrials.gov identifier: NCT02125357) that randomly assigned men to either AAP or enzalutamide (n = 201). The primary outcome measures for the biomarker analysis were overall survival and progression-free survival.

Results: Using multivariable fractional polynomials analysis using Cox regression models, a nonlinear relationship between plasma AR CN and outcome was identified for overall survival, where initially for small incremental gains in CN there was a large added hazard ratio that plateaued at higher CN. The CN cut point associated with the highest local hazard ratio was 1.92. A similar nonlinear association was observed with progression-free survival. In an exploratory analysis of PCR2023, the time from start of long-term androgen-deprivation therapy to start of AAP or abiraterone acetate plus dexamethasone was significantly shorter in patients with plasma AR CN of 1.92 or greater than patients with plasma AR CN of less than 1.92 (43 v 130 weeks, respectively; P = .005). This was confirmed in cohort A (P = .003), the PREMIERE cohort (P = .03), and the British Colombia cohort (P = .003).

Conclusion: Patients with metastatic castration-resistant prostate cancer can be dichotomized by a plasma AR CN cut point of 1.92. Plasma AR CN value of 1.92 or greater identifies aggressive disease that is poorly responsive to AR targeting and is associated with a prior short response to primary androgen-deprivation therapy.

Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Anna WingateResearch Funding: Janssen (Inst) Travel, Accommodations, Expenses: JanssenVincenza ConteducaConsulting or Advisory Role: Bayer, Astellas Pharma, Janssen-Cilag, Sanofi Travel, Accommodations, Expenses: Bayer, Astellas Pharma, Janssen-Cilag, SanofiDaniel KhalafConsulting or Advisory Role: BayerFabio CalabròConsulting or Advisory Role: PfizerSusan FeyerabendConsulting or Advisory Role: Janssen-CilagEnrique GrandeHonoraria: Pfizer, Bristol-Myers Squibb, Ipsen, Roche, Eisai, Eusa Pharma, MSD, Genzyme, Adacap, Novartis, Pierre Fabre, Lexicon, Celgene, Janssen-Cilag, Astellas Pharma Consulting or Advisory Role: MSD, Pfizer, Ipsen Research Funding: MTEM/Threshold (Inst), Roche, Pfizer (Inst), AstraZeneca (Inst), Ipsen (Inst) Travel, Accommodations, Expenses: Bristol-Myers Squibb, Genentech, Pfizer, Janssen-CilagAlfredo BerrutiConsulting or Advisory Role: Janssen-Cilag, Astellas Pharma Speakers' Bureau: Janssen-Cilag Research Funding: Astellas Pharma (Inst), Janssen-Cilag (Inst) Travel, Accommodations, Expenses: Janssen-Cilag, SanofiCora N. SternbergHonoraria: Pfizer, Astellas Pharma, Sanofi, Ipsen, AstraZeneca. Janssen Consulting or Advisory Role: Bristol-Myers Squibb, Novartis, Bayer, Eisai, MSD, Clovis Oncology, Pfizer, Roche, Ipsen, Incyte, AstraZeneca, Sanofi, Merck, Medscape, UroToday Research Funding: Janssen (Inst), Genentech (Inst), Bayer (Inst), Sanofi (Inst), Medivation (Inst), Exelixis (Inst), Genzyme (Inst), Aragon Pharmaceuticals (Inst), Array BioPharma (Inst), Aveo (Inst), AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Boehringer Ingelheim (Inst), Clovis Oncology (Inst), Eisai (Inst), Genentech (Inst), GlaxoSmithKline (Inst), Eli Lilly (Inst), Incyte (Inst), Merck (Inst), Millennium (Inst), Myovant Sciences (Inst), Nektar (Inst), Pfizer (Inst), Clovis Atlas (Inst)Rob JonesHonoraria: Astellas Pharma, Janssen, AstraZeneca, MSD Oncology, Bristol-Myers Squibb, Pfizer, Novartis, Ipsen, Seattle Genetics, Sanofi, Bayer, Genentech, Eusa Pharma, Pharmacyclics Consulting or Advisory Role: Clovis Oncology Research Funding: Roche (Inst), Astellas Pharma (Inst), AstraZeneca (Inst), Pfizer (Inst), Novartis (Inst), Exelixis (Inst), Clovis Oncology (Inst) Travel, Accommodations, Expenses: Ipsen, Bayer, Janssen, Astellas Pharma, MSD OncologyFlorence LefresneEmployment: Johnson & Johnson Stock and Other Ownership Interests: Johnson & Johnson Honoraria: Johnson & Johnson Research Funding: Johnson & Johnson Travel, Accommodations, Expenses: Johnson & JohnsonMarjolein LahayeEmployment: Janssen-Cilag Leadership: Janssen-Cilag Stock and Other Ownership Interests: Janssen-Cilag Honoraria: Janssen-Cilag Consulting or Advisory Role: Janssen-CilagShibu ThomasEmployment: Janssen Research & Development Leadership: Janssen Research & Development Stock and Other Ownership Interests: Janssen Research & Development Research Funding: Janssen Oncology Patents, Royalties, Other Intellectual Property: Four patents (Inst) Travel, Accommodations, Expenses: Janssen Research & DevelopmentDong ShenEmployment: Janssen Research & Development Stock and Other Ownership Interests: Janssen Research & DevelopmentDeborah RicciEmployment: Janssen Stock and Other Ownership Interests: Janssen Patents, Royalties, Other Intellectual Property: Janssen (Inst) Travel, Accommodations, Expenses: JanssenMichael GormleyEmployment: Janssen Research & Development Stock and Other Ownership Interests: Johnson & Johnson Patents, Royalties, Other Intellectual Property: I have several patents pending where I am listed as the inventor of things that have been developed in the course of my work at Janssen Research and Development (Inst) Travel, Accommodations, Expenses: Janssen Research & DevelopmentAxel S. MerseburgerHonoraria: Janssen-Cilag, Astellas Pharma, Ipsen, Roche, Bristol-Myers Squibb, Eisai, Takeda, Pfizer, Novartis Consulting or Advisory Role: MSD Oncology, Bristol-Myers Squibb, Janssen-Cilag, Astellas Pharma, Ipsen Speakers' Bureau: Ipsen Research Funding: Novartis (Inst), AstraZeneca (Inst), Janssen-Cilag (Inst), Bristol-Myers Squibb (Inst), Clovis Oncology (Inst) Travel, Accommodations, Expenses: Janssen-Cilag, Astellas Pharma, IpsenBertrand TombalHonoraria: Amgen, Astellas Pharma, Bayer, Ferring, Sanofi, Janssen, Pfizer, Myovant Sciences Consulting or Advisory Role: Astellas Pharma, Bayer, Ferring, Janssen, Takeda, Steba Biotech, Sanofi Speakers' Bureau: Amgen, Janssen Research Funding: Ferring (Inst) Travel, Accommodations, Expenses: Amgen, Astellas Pharma, Bayer, Ferring, Janssen, SanofiKim N. ChiHonoraria: Sanofi, Janssen, Astellas Pharma, Bayer Consulting or Advisory Role: Essa, Astellas Pharma, Janssen, Sanofi, Amgen, Bayer, AstraZeneca, Roche Research Funding: Janssen (Inst), Astellas Pharma (Inst), Bayer (Inst), Sanofi (Inst), Tokai Pharmaceuticals (Inst), Eli Lilly/ImClone (Inst), Bristol-Myers Squibb (Inst), Merck (Inst), Roche (Inst)Ugo De GiorgiConsulting or Advisory Role: Pfizer, Janssen, Astellas Pharma, Sanofi, Bristol-Myers Squibb, Bayer, Ipsen, Merck Research Funding: Sanofi (Inst), AstraZeneca (Inst), Roche (Inst) Travel, Accommodations, Expenses: Bristol-Myers Squibb, Ipsen, Janssen, PfizerEnrique Gonzalez-BillalabeitiaTravel, Accommodations, Expenses: Bristol-Myers Squibb, Pfizer, Bristol-Myers Squibb, Janssen-Cilag, Astellas Pharma, Sanofi, Roche, PfizerAlexander W. WyattConsulting or Advisory Role: Genzyme Speakers' Bureau: Janssen Research Funding: JanssenGerhardt AttardHonoraria: Janssen, Astellas Pharma, Janssen (I) Consulting or Advisory Role: Janssen-Cilag, Veridex, Ventana Medical Systems, Astellas Pharma, Medivation, Novartis, Millennium, Abbott Laboratories, ESSA, Bayer, Pfizer Speakers' Bureau: Janssen, Astellas Pharma, Takeda, Sanofi, Ventana Medical Systems Research Funding: Janssen (Inst), Arno Therapeutics (Inst), Innocrin Pharma (Inst) Patents, Royalties, Other Intellectual Property: I am on the Institute of Cancer Research Rewards to Inventors list of abiraterone acetate Travel, Accommodations, Expenses: Janssen, Astellas Pharma, Medivation, Ventana Medical Systems, Abbott Laboratories, Bayer, ESSA, Janssen (I), Astellas Pharma (I), Pfizer Other Relationship: Institute of Cancer Research No other potential conflicts of interest were reported.

© 2019 by American Society of Clinical Oncology.

Figures

FIG 1.

Clinical cohorts, markers of tumor volume, and association with plasma androgen receptor (AR) status. (A) Flow diagram of the patient selection for biomarker evaluation in PCR2023. (B) AR copy number (CN) distribution across the four clinical cohorts (PCR2023, cohort A, PREMIERE, and British Colombia crossover study) included in the pooled analysis (N = 501). Multivariable fractional polynomials analysis was performed using Cox regression models on data pooled from four cohorts including age and CN and stratified by trial. (C) Distributions of AR CN versus maximum log-likelihood statistics. Maximum log-likelihood statistics were used as a correlative measure to identify the optimal cut point of AR CN in association with overall survival outcome. (D) Visual inspection showed that the cut point region overlaps with the turning point of decreasing local hazard ratio (HR) identified via the maximum log-likelihood statistics approach.

FIG 2.

Plasma androgen receptor (AR) copy number (CN) and outcome. (A) Association between estimated plasma AR CN status and four circulating clinical indices of tumor volume markers. Groups were split into plasma AR CN normal or plasma AR CN gain. Cell-free DNA (cfDNA) yield, prostate-specific antigen (PSA), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) levels are reported; ALP and LDH levels are reported relative to upper limit of normal (ULN) The association between outcome and patients dichotomized by a plasma AR CN of 1.92 or greater in PCR2023 is included as an example, showing (C) overall survival and (D) progression-free survival for patients with normal AR CN and AR CN gain.

FIG 3.

Time from start of androgen-deprivation therapy (ADT) to start of abiraterone acetate or enzalutamide divided by androgen receptor (AR) copy number (CN) of 1.92 or greater (AR CN gain) or AR CN of less than 1.92 (AR CN normal). AR CN normal is demonstrated by the blue violin plots, whereas AR CN gain is demonstrated by the light red violin plots. Box plots within the violin plots indicate the median and the upper and lower quartiles, with whiskers extending from the shortest to longest time on ADT. The x-axis (weeks) is scaled as log2.