TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer

Abstract

Purpose: Prostate cancer (PCa) becomes resistant to androgen ablation through adaptive upregulation of the androgen receptor in response to the low-testosterone microenvironment. Bipolar androgen therapy (BAT), defined as rapid cycling between high and low serum testosterone, disrupts this adaptive regulation in castration-resistant PCa (CRPC).

Methods: The TRANSFORMER (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance) study is a randomized study comparing monthly BAT (n = 94) with enzalutamide (n = 101). The primary end point was clinical or radiographic progression-free survival (PFS); crossover was permitted at progression. Secondary end points included overall survival (OS), prostate-specific antigen (PSA) and objective response rates, PFS from randomization through crossover (PFS2), safety, and quality of life (QoL).

Results: The PFS was 5.7 months for both arms (hazard ratio [HR], 1.14; 95% CI, 0.83 to 1.55; P = .42). For BAT, 50% decline in PSA (PSA50) was 28.2% of patients versus 25.3% for enzalutamide. At crossover, PSA50 response occurred in 77.8% of patients crossing to enzalutamide and 23.4% to BAT. The PSA-PFS for enzalutamide increased from 3.8 months after abiraterone to 10.9 months after BAT. The PFS2 for BAT→enzalutamide was 28.2 versus 19.6 months for enzalutamide→BAT (HR, 0.44; 95% CI, 0.22 to 0.88; P = .02). OS was 32.9 months for BAT versus 29.0 months for enzalutamide (HR, 0.95; 95% CI, 0.66 to 1.39; P = .80). OS was 37.1 months for patients crossing from BAT to enzalutamide versus 30.2 months for the opposite sequence (HR, 0.68; 95% CI, 0.36 to 1.28; P = .225). BAT adverse events were primarily grade 1-2. Patient-reported QoL consistently favored BAT.

Conclusion: This randomized trial establishes meaningful clinical activity and safety of BAT and supports additional study to determine its optimal clinical integration. BAT can sensitize CRPC to subsequent antiandrogen therapy. Further study is required to confirm whether sequential therapy with BAT and enzalutamide can improve survival in men with CRPC.

Trial registration: ClinicalTrials.gov NCT02286921.

Conflict of interest statement

Samuel R. DenmeadeStock and Other Ownership Interests: Sophiris BioConsulting or Advisory Role: Sophiris BioTravel, Accommodations, Expenses: Sophiris Bio Neeraj AgarwalConsulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Foundation One Inc, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI PharmaResearch Funding: Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Takeda, Novartis, Pfizer, BN ImmunoTherapeutics, Exelixis, TRACON Pharma, Rexahn Pharmaceuticals, Amgen, AstraZeneca, Active Biotech, Bavarian Nordic, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Newlink Genetics, Prometheus, Sanofi David C. SmithResearch Funding: Agensys, Incyte, Lilly, Novartis, Seattle Genetics, Bristol-Myers Squibb/Medarex, Genentech, Astellas Pharma, Bayer, ESSA, Roche, MedImmune Michael T. SchweizerConsulting or Advisory Role: ResverlogixResearch Funding: Janssen, AstraZeneca, Roche, Pfizer, Zenith Epigenetics, Madison Vaccines, Inc., Immunomedics, Bristol-Myers Squibb, Merck, Tmunity Therapeutics, Inc. Mark N. SteinConsulting or Advisory Role: Merck Sharp & Dohme, Exelixis, Exelixis, XencorResearch Funding: Oncoceutics, Merck Sharp & Dohme, Janssen Oncology, Medivation/Astellas, Advaxis, Suzhou Kintor Pharmaceuticals, Harpoon, Bristol-Myers Squibb, Genocea Biosciences, Lilly, Nektar, Seattle Genetics, Xencor, Tmunity Therapeutics, Inc., Exelixis Vasileios AssikisConsulting or Advisory Role: BayerSpeakers' Bureau: AstraZeneca Przemyslaw W. TwardowskiHonoraria: Astellas Medivation, Bayer, Janssen, Genentech/Roche, Sanofi/AventisConsulting or Advisory Role: Sanofi/Aventis, JanssenSpeakers' Bureau: Astellas Pharma, Bayer, Janssen, Genentech, Sanofi Thomas W. FlaigLeadership: Aurora OncologyStock and Other Ownership Interests: Aurora OncologyConsulting or Advisory Role: Seattle Genetics, Janssen OncologyResearch Funding: Novartis, Bavarian Nordic, Dendreon, GTx, Janssen Oncology, Medivation, Sanofi, Pfizer, Bristol-Myers Squibb, Roche/Genentech, Exelixis, Aragon Pharmaceuticals, Sotio, Tokai Pharmaceuticals, Astrazeneca/MedImmune, Lilly, Astellas Pharma, Agensys, Seattle Genetics, La Roche-Posay, MerckPatents, Royalties, Other Intellectual Property: The University of Colorado has filed 2 patents related in which I am an inventor. These are related to early-stage bladder cancer treatment and detection. Neither is commercialized or licensed at this time. Russell Z. SzmulewitzHonoraria: Astellas PharmaConsulting or Advisory Role: AstraZeneca, AbbVie, Exelixis, Merck, Amgen, Janssen Oncology, Sanofi, Astellas Pharma, PfizerResearch Funding: AbbVie, Astellas Pharma, Incyte, Macrogenics, Janssen OncologyPatents, Royalties, Other Intellectual Property: Patent licensed by The University of Chicago of which I am a co-inventor to Corcept Therapeutics for combination AR/GR inhibition in prostate cancerTravel, Accommodations, Expenses: Corcept Therapeutics Jeffrey M. HolzbeierleinConsulting or Advisory Role: BasileaResearch Funding: MDxHealth(OPTIONAL) Uncompensated Relationships: Astellas Medivation Ralph J. HaukeStock and Other Ownership Interests: AethlonResearch Funding: US Oncology, Bristol-Myers Squibb, Merck, Amgen, Novartis, Exelixis Guru SonpavdeHonoraria: UpToDateConsulting or Advisory Role: Genentech, Merck, Eisai, AstraZenecam, Janssen, Bristol-Myers Squibb, Exelixis, EMD Serono, Astellas Pharma, Bicycle Therapeutics, Pfizer, Seattle GeneticsSpeakers' Bureau: Physicans' Education Resource, Onclive, Research to Practice, MedscapeResearch Funding: Janssen, Sanofi, AstraZenecaTravel, Accommodations, Expenses: Bristol-Myers SquibbOther Relationship: AstraZeneca, Bristol-Myers Squibb, Astellas Pharma, Bavarian Nordic, Debiopharm GroupQED Therapeutics, Elsevier Jorge A. GarciaHonoraria: UpToDate, MerckJanssen, Amgen, Bayer, MJH AssociatesConsulting or Advisory Role: Sanofi, Bayer, Eisai, Clovis Oncology, Targeted OncologySpeakers' Bureau: Bayer, Sanofi, MerckSanofi/AventisResearch Funding: Pfizer, Orion Pharma GmbH, Janssen Oncology, Genentech/Roche, Lilly, MerckTravel, Accommodations, Expenses: Bayer, Sanofi, Eisai, Medivation/Astellas, Merck, Clovis Oncology, Janssen Arif HussainConsulting or Advisory Role: AstraZeneca, Bayer, Exelixis, Janssen OncologyResearch Funding: Sotio, Merck, Bayer, Clovis Oncology, Pfizer, Constellation Pharmaceuticals, Nektar, Roche/Genentech, Infinity Pharmaceuticals Oliver SartorStock and Other Ownership Interests: Lilly, GlaxoSmithKline, AbbVie, Cardinal Health, United Health Group, PSMA Therapeutics, Clarity Pharmaceuticals, Noria Therapeutics, Clovis OncologyConsulting or Advisory Role: Bayer, Sanofi, AstraZeneca, Dendreon, Constellation Pharmaceuticals, Advanced Accelerator Applications, Pfizer, Bristol-Myers Squibb, Bavarian Nordic, EMD Serono, Astellas Pharma, Progenics, Blue Earth Diagnostics, Myovant Sciences, Myriad Genetics, Novartis, Clarity Pharmaceuticals, Fusion Pharmaceuticals, Isotopen Technologien, Janssen, Noxopharm, Clovis Oncology, Noria Therapeutics, Point Biopharma, TeneoBio, Telix Pharmaceuticals, TheragnosticsResearch Funding: Sanofi, Endocyte, Merck, InVitae, Constellation Pharmaceuticals, Advanced Accelerator Applications, AstraZeneca, Dendreon, Sotio, Janssen, ProgenicsExpert Testimony: SanofiTravel, Accommodations, Expenses: Bayer, Johnson & Johnson, Sanofi, AstraZeneca, Progenics Shifeng MaoConsulting or Advisory Role: Sanofi, Cardinal HealthSpeakers' Bureau: Bristol-Myers Squibb Michael A. CarducciConsulting or Advisory Role: Roche/Genentech, Pfizer, Foundation Medicine, ExelixisResearch Funding: Bristol-Myers Squibb, Pfizer, AstraZeneca, EMD Serono, Arcus Biosciences Mark C. MarkowskiHonoraria: Clovis Oncology, Exelixis Mario A. EisenbergerLeadership: VeruStock and Other Ownership Interests: VeruHonoraria: Merck Sharp & Dohme, Bristol-Myers Squibb, Seattle Genetics Emmanuel S. AntonarakisHonoraria: Sanofi, Dendreon, Medivation, Janssen Biotech, ESSA, Astellas Pharma, Merck, AstraZeneca, Clovis OncologyConsulting or Advisory Role: Sanofi, Dendreon, Janssen Biotech, ESSA, Merck, AstraZeneca, Clovis Oncology, Lilly, BayerResearch Funding: Janssen Biotech, Johnson & Johnson, Sanofi, Dendreon, Aragon Pharmaceuticals, Exelixis, Millennium, Genentech, Novartis, Astellas Pharma, Tokai Pharmaceuticals, Merck, AstraZeneca, Clovis Oncology, Constellation PharmaceuticalsTravel, Accommodations, Expenses: Sanofi, Dendreon, MedivationNo other potential conflicts of interest were reported.

Figures

FIG 1.

TRANSFORMER CONSORT diagram. BAT, bipolar androgen therapy.

FIG 2.

Kaplan-Meier estimates of (A) PFS and (B) OS, (C) waterfall plot of PSA response to initial therapy, (D) subgroup analysis of OS. BAT, bipolar androgen therapy; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; INF, infinity; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen.

FIG 3.

Kaplan-Meier estimates of OS in the crossover population. (A) Comparison of OS in the subset of patients receiving BAT→enzalutamide versus enzalutamide→BAT, after eliminating those who came off study without crossing over. (B) Comparison of OS in the subset of patients receiving BAT→enzalutamide (after eliminating patients who did not cross over) versus enzalutamide-only patients who did not cross over to receive BAT. BAT, bipolar androgen therapy; HR, hazard ratio; NA, not accessible; OS, overall survival.

FIG 4.

(A) Waterfall plot of PSA response to crossover therapy, (B) Kaplan-Meier estimates of PFS2, (C) subgroup analysis of PFS2. BAT, bipolar androgen therapy; ECOG, Eastern Cooperative Oncology Group; PFS, progression-free survival; PSA, prostate-specific antigen.