- Email: [email protected]
A phase III randomized, placebo-controlled, double-blind study of niraparib plus abiraterone acetate and prednisone versus abiraterone acetate and prednisone in patients with metastatic prostate cancer (NCT03748641)
abstracts 896TiP
ProBio: An outcome-adaptive, multi-arm, open-label, multiple assignment randomised controlled biomarker-driven trial in patients with metastatic castration-resistant prostate cancer
J. Lindberg, B. De Laere, A. Crippa, M. Eklund, H. Gro¨nberg Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
897TiP
A phase III randomized, placebo-controlled, double-blind study of niraparib plus abiraterone acetate and prednisone versus abiraterone acetate and prednisone in patients with metastatic prostate cancer (NCT03748641)
K.N. Chi1, D. Rathkopf2, G. Attard3, M.R. Smith4, E. Efstathiou5, D. Olmos6, E.J. Small7, J.Y. Lee8, P. Sieber9, C. Dunshee10, D. Ricci11, J.S. Simon12, X. Zhao13, N. Kothari14, S. Cheng15, S.K. Sandhu16 1 Medical Oncology, BC Cancer Agency - Vancouver, Vancouver, BC, Canada, 2Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA, 3Research Department of Oncology, UCL Cancer Institute/Paul O’Gorman Building, London, UK, 4 Hematology Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 5Genitourinary Medical Oncology, The M. D. Anderson Cancer Center, Houston, TX, USA, 6Oncology, CNIO-IBIMA, Hospitales Universitarios Virgen de la Victoria y Regional de Malaga, Malaga, Spain, 7Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA, 8Department of Urology, St. Mary’s Hospital of Catholic University, Seoul, Republic of Korea, 9Urology, Lancaster Urology, Lancaster, PA, USA, 10Urology, Urological Associates of Southern Arizona, Tucson, AZ, USA, 11Oncology Translational Research, Janssen Research and Development, Spring House, PA, USA, 12Oncology Diagnostics, Janssen R&D/Johnson & Johnson Pharmaceutical R&D, Raritan, NJ, USA, 13Clinical Biostatistics, Janssen R&D, Fremont, CA, USA, 14WC Clinical Oncology, Janssen R&D, Los Angeles, CA, USA, 15WC Clinical Oncology, Janssen R&D/Johnson & Johnson Pharmaceutical R&D, Raritan, NJ, USA, 16Division of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia Background: Preclinical data suggest synergistic antitumor activity when a PARP inhibitor (PARPi) is combined with an androgen pathway inhibitor. The addition of a PARPi to abiraterone acetate and prednisone (AAP) shows improved radiographic progression-free survival (rPFS) versus AAP alone in patients with mCRPC regardless of the presence of DNA repair gene defects (DRD).1 Interim results from a phase 1 study2 support safety and tolerability of a combination of niraparib 200 mg plus AAP in patients with mCRPC. The objective of this Phase 3 study is to compare the efficacy and safety of niraparib plus AAP versus AAP with placebo as first-line therapy for mCRPC. Trial design: The multicenter global MAGNITUDE study will open in 300 sites and 28 countries and will enroll patients with mCRPC untreated with other than ongoing androgen deprivation therapy [ADT] and 4 months of exposure to AAP. Cohort 1 (n ¼ 400) will comprise patients whose tumors have DRD, as determined by either a blood or tissue assay. Cohort 2 (n ¼ 600) will enroll patients whose tumors are not DRD þve. Enrollment began in February 2019. The primary objective of the study is to compare radiographic progression-free survival (rPFS) for patients treated with
v354 | Genitourinary Tumours, Prostate
niraparib and AAP versus AAP and placebo as first-line therapy for mCRPC. To test superiority of combination vs AAP, sample sizes were estimated to provide 92% power to detect HR 0.67 in the two cohorts at a 2-tailed level of significance of 0.05. Major secondary objectives are to assess the effect of the combination treatment on overall survival, time to chronic opioid use, time to pain progression and time to cytotoxic chemotherapy. Safety and pharmacokinetic profiles will be evaluated. Clinical trial identification: NCT03748641. Editorial acknowledgement: Ann C Sherwood, PhD with funding from Janssen Pharmaceuticals. Legal entity responsible for the study: Janssen Pharmaceuticals. Funding: Janssen Pharmaceuticals. Disclosure: K.N. Chi: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: ESSA; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Amgen; Research grant / Funding (institution): Tokai; Research grant / Funding (institution): Lilly/ImClone; Research grant / Funding (institution): Bristol-Meyers Squibb; Research grant / Funding (institution): Merck. D. Rathkopf: Research grant / Funding (institution): Tracon Pharma; Research grant / Funding (institution): Genentech Roche; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Taiho Pharmaceuticals; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Ferring; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Janssen Oncology. G. Attard: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Veridex; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche Ventana; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Millennium; Advisory / Consultancy, Travel / Accommodation / Expenses: Abbott; Advisory / Consultancy, Travel / Accommodation / Expenses: Essa; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Sanofi Aventis. M.R. Smith: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (institution), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Gilead; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer. E. Efstathiou: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Oric Pharma; Advisory / Consultancy: Bayer; Advisory / Consultancy: Tolmar; Research grant / Funding (self): Astellas; Research grant / Funding (self): Pfizer. D. Olmos: Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution): Janssen Oncology; Advisory / Consultancy: Clovis; Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (self), Research grant / Funding (institution): Genentech. E.J. Small: Advisory / Consultancy, Shareholder / Stockholder / Stock options: Fortis Therpeutics; Shareholder / Stockholder / Stock options: Harpoon Therapeutics; Honoraria (self), Advisory / Consultancy: Janssen; Advisory / Consultancy: Beigene. P. Sieber: Speaker Bureau / Expert testimony, Research grant / Funding (self): Astellas; Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (self): Dendreon; Research grant / Funding (self): Janssen; Research grant / Funding (self): Allergan; Research grant / Funding (self): Effector; Research grant / Funding (self): Myovant; Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): Hinova; Research grant / Funding (self): Merck. C. Dunshee: Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Ferring; Advisory / Consultancy: Sanofi Genzyme; Research grant / Funding (institution): Astellas Medivation; Research grant / Funding (institution): Janssen Oncology; Research grant / Funding (institution): Dendreon; Research grant / Funding (institution): Eleven Biotherapeutics; Research grant / Funding (institution): Myovant Sciences; Research grant / Funding (institution): Siemens; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Exact Sciences; Research grant / Funding (institution): TesoRx Pharmaceuticals. D. Ricci: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. J.S. Simon: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. X. Zhao: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. N. Kothari: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. S. Cheng: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. S.K. Sandhu: Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self): Merck Sharp & Dohme; Honoraria (self): Roche/Genentech; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Travel / Accommodation / Expenses: Janssen; Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Tolmar. All other authors have declared no conflicts of interest.
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz248.054/5578299/ by guest on 07 October 2019
Background: Despite multiple retrospective studies have demonstrated the clinical validity of molecularly-guided therapy selection in metastatic castrate-resistant prostate cancer (mCRPC), none have validated the actual clinical utility in the context of a randomised controlled trial. We hypothesise that treatment decisions based on plasmaderived cell-free DNA (cfDNA) profiling will increase progression-free survival (primary endpoint), which would result in prolonged overall survival and improved quality-of-life (secondary endpoints). Trial design: The Prostate Biomarker (ProBio) trial is a recently-initiated adaptive, multi-arm, open-label, multiple assignment randomized controlled biomarker driven phase 3 trial in men with mCRPC. Men (n ¼ 750) will be randomized to receive either standard of care or an experimental treatment with abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, or carboplatin based on molecular biomarker signatures, as inferred from our liquid biopsy profiling. Therefor a prostate-specific1.48 Mb biomarker panel was designed and validated, which is capable of detecting 1) mutations in 78 genes, 2) genomic structural rearrangements in 11 prostate cancer-associated genes, 3) genome-wide copy number alterations, 4) 63 microsatellites to infer microsatellite instability, 4) tumour mutational burden and 5) estimate the circulating tumour DNA (ctDNA) fraction. The initial pre-defined biomarker signatures are defined as tumour properties or mutations in certain genes/pathways identified in the scientific literature as potentially important in prostate cancer treatment response encompassing the androgen receptor (AR), TP53, DNA-repair deficiency (DRD) and the TMPRSS2-ERG fusion. The statistical design of ProBio is novel, since the randomisation probabilities for a given experimental systemic therapy are subjective to change as the trial evolves and learns from prior experience. Secondly, ProBio implements a re-randomization of non-responding patients. Clinical trial identification: 2018-002350-78 (16/07/2018), NCT03903835 (29/03/ 2019). Legal entity responsible for the study: ProBio Investigators. Funding: The Swedish Research Council, The Erling-Persson Family Foundation, The Swedish Cancer Foundation. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
ProBio: An outcome-adaptive, multi-arm, open-label, multiple assignment randomised controlled biomarker-driven trial in patients with metastatic castration-resistant prostate cancer
J. Lindberg, B. De Laere, A. Crippa, M. Eklund, H. Gro¨nberg Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
897TiP
A phase III randomized, placebo-controlled, double-blind study of niraparib plus abiraterone acetate and prednisone versus abiraterone acetate and prednisone in patients with metastatic prostate cancer (NCT03748641)
K.N. Chi1, D. Rathkopf2, G. Attard3, M.R. Smith4, E. Efstathiou5, D. Olmos6, E.J. Small7, J.Y. Lee8, P. Sieber9, C. Dunshee10, D. Ricci11, J.S. Simon12, X. Zhao13, N. Kothari14, S. Cheng15, S.K. Sandhu16 1 Medical Oncology, BC Cancer Agency - Vancouver, Vancouver, BC, Canada, 2Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA, 3Research Department of Oncology, UCL Cancer Institute/Paul O’Gorman Building, London, UK, 4 Hematology Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 5Genitourinary Medical Oncology, The M. D. Anderson Cancer Center, Houston, TX, USA, 6Oncology, CNIO-IBIMA, Hospitales Universitarios Virgen de la Victoria y Regional de Malaga, Malaga, Spain, 7Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA, 8Department of Urology, St. Mary’s Hospital of Catholic University, Seoul, Republic of Korea, 9Urology, Lancaster Urology, Lancaster, PA, USA, 10Urology, Urological Associates of Southern Arizona, Tucson, AZ, USA, 11Oncology Translational Research, Janssen Research and Development, Spring House, PA, USA, 12Oncology Diagnostics, Janssen R&D/Johnson & Johnson Pharmaceutical R&D, Raritan, NJ, USA, 13Clinical Biostatistics, Janssen R&D, Fremont, CA, USA, 14WC Clinical Oncology, Janssen R&D, Los Angeles, CA, USA, 15WC Clinical Oncology, Janssen R&D/Johnson & Johnson Pharmaceutical R&D, Raritan, NJ, USA, 16Division of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia Background: Preclinical data suggest synergistic antitumor activity when a PARP inhibitor (PARPi) is combined with an androgen pathway inhibitor. The addition of a PARPi to abiraterone acetate and prednisone (AAP) shows improved radiographic progression-free survival (rPFS) versus AAP alone in patients with mCRPC regardless of the presence of DNA repair gene defects (DRD).1 Interim results from a phase 1 study2 support safety and tolerability of a combination of niraparib 200 mg plus AAP in patients with mCRPC. The objective of this Phase 3 study is to compare the efficacy and safety of niraparib plus AAP versus AAP with placebo as first-line therapy for mCRPC. Trial design: The multicenter global MAGNITUDE study will open in 300 sites and 28 countries and will enroll patients with mCRPC untreated with other than ongoing androgen deprivation therapy [ADT] and 4 months of exposure to AAP. Cohort 1 (n ¼ 400) will comprise patients whose tumors have DRD, as determined by either a blood or tissue assay. Cohort 2 (n ¼ 600) will enroll patients whose tumors are not DRD þve. Enrollment began in February 2019. The primary objective of the study is to compare radiographic progression-free survival (rPFS) for patients treated with
v354 | Genitourinary Tumours, Prostate
niraparib and AAP versus AAP and placebo as first-line therapy for mCRPC. To test superiority of combination vs AAP, sample sizes were estimated to provide 92% power to detect HR 0.67 in the two cohorts at a 2-tailed level of significance of 0.05. Major secondary objectives are to assess the effect of the combination treatment on overall survival, time to chronic opioid use, time to pain progression and time to cytotoxic chemotherapy. Safety and pharmacokinetic profiles will be evaluated. Clinical trial identification: NCT03748641. Editorial acknowledgement: Ann C Sherwood, PhD with funding from Janssen Pharmaceuticals. Legal entity responsible for the study: Janssen Pharmaceuticals. Funding: Janssen Pharmaceuticals. Disclosure: K.N. Chi: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: ESSA; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Amgen; Research grant / Funding (institution): Tokai; Research grant / Funding (institution): Lilly/ImClone; Research grant / Funding (institution): Bristol-Meyers Squibb; Research grant / Funding (institution): Merck. D. Rathkopf: Research grant / Funding (institution): Tracon Pharma; Research grant / Funding (institution): Genentech Roche; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Taiho Pharmaceuticals; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Ferring; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Janssen Oncology. G. Attard: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Veridex; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche Ventana; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Millennium; Advisory / Consultancy, Travel / Accommodation / Expenses: Abbott; Advisory / Consultancy, Travel / Accommodation / Expenses: Essa; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Sanofi Aventis. M.R. Smith: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (institution), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Gilead; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer. E. Efstathiou: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Oric Pharma; Advisory / Consultancy: Bayer; Advisory / Consultancy: Tolmar; Research grant / Funding (self): Astellas; Research grant / Funding (self): Pfizer. D. Olmos: Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution): Janssen Oncology; Advisory / Consultancy: Clovis; Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (self), Research grant / Funding (institution): Genentech. E.J. Small: Advisory / Consultancy, Shareholder / Stockholder / Stock options: Fortis Therpeutics; Shareholder / Stockholder / Stock options: Harpoon Therapeutics; Honoraria (self), Advisory / Consultancy: Janssen; Advisory / Consultancy: Beigene. P. Sieber: Speaker Bureau / Expert testimony, Research grant / Funding (self): Astellas; Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (self): Dendreon; Research grant / Funding (self): Janssen; Research grant / Funding (self): Allergan; Research grant / Funding (self): Effector; Research grant / Funding (self): Myovant; Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): Hinova; Research grant / Funding (self): Merck. C. Dunshee: Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Ferring; Advisory / Consultancy: Sanofi Genzyme; Research grant / Funding (institution): Astellas Medivation; Research grant / Funding (institution): Janssen Oncology; Research grant / Funding (institution): Dendreon; Research grant / Funding (institution): Eleven Biotherapeutics; Research grant / Funding (institution): Myovant Sciences; Research grant / Funding (institution): Siemens; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Exact Sciences; Research grant / Funding (institution): TesoRx Pharmaceuticals. D. Ricci: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. J.S. Simon: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. X. Zhao: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. N. Kothari: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. S. Cheng: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. S.K. Sandhu: Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self): Merck Sharp & Dohme; Honoraria (self): Roche/Genentech; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Travel / Accommodation / Expenses: Janssen; Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Tolmar. All other authors have declared no conflicts of interest.
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz248.054/5578299/ by guest on 07 October 2019
Background: Despite multiple retrospective studies have demonstrated the clinical validity of molecularly-guided therapy selection in metastatic castrate-resistant prostate cancer (mCRPC), none have validated the actual clinical utility in the context of a randomised controlled trial. We hypothesise that treatment decisions based on plasmaderived cell-free DNA (cfDNA) profiling will increase progression-free survival (primary endpoint), which would result in prolonged overall survival and improved quality-of-life (secondary endpoints). Trial design: The Prostate Biomarker (ProBio) trial is a recently-initiated adaptive, multi-arm, open-label, multiple assignment randomized controlled biomarker driven phase 3 trial in men with mCRPC. Men (n ¼ 750) will be randomized to receive either standard of care or an experimental treatment with abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, or carboplatin based on molecular biomarker signatures, as inferred from our liquid biopsy profiling. Therefor a prostate-specific1.48 Mb biomarker panel was designed and validated, which is capable of detecting 1) mutations in 78 genes, 2) genomic structural rearrangements in 11 prostate cancer-associated genes, 3) genome-wide copy number alterations, 4) 63 microsatellites to infer microsatellite instability, 4) tumour mutational burden and 5) estimate the circulating tumour DNA (ctDNA) fraction. The initial pre-defined biomarker signatures are defined as tumour properties or mutations in certain genes/pathways identified in the scientific literature as potentially important in prostate cancer treatment response encompassing the androgen receptor (AR), TP53, DNA-repair deficiency (DRD) and the TMPRSS2-ERG fusion. The statistical design of ProBio is novel, since the randomisation probabilities for a given experimental systemic therapy are subjective to change as the trial evolves and learns from prior experience. Secondly, ProBio implements a re-randomization of non-responding patients. Clinical trial identification: 2018-002350-78 (16/07/2018), NCT03903835 (29/03/ 2019). Legal entity responsible for the study: ProBio Investigators. Funding: The Swedish Research Council, The Erling-Persson Family Foundation, The Swedish Cancer Foundation. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology