Background

Enzalutamide (ENZ) + leuprolide acetate (L) and ENZ alone delayed metastasis-free survival (MFS) vs placebo (P) + L in high-risk BCR nmHSPC in the phase 3 EMBARK (NCT02319837) trial. Pt-reported outcomes (PROs) provide a pt perspective on disease/treatment (Tx) experience not captured by clinical assessment.

Methods

nmHSPC pts with high-risk BCR (prostate-specific antigen [PSA] doubling time ≤9 months, screening PSA ≥2 ng/mL above nadir post radiotherapy or ≥1 ng/mL post radical prostatectomy) were randomized (1:1:1) to ENZ + L, ENZ alone, and P + L. PROs were assessed at baseline (BL) and every 12 weeks until development of metastasis or death. The main objectives were to assess Tx effects in time to first and confirmed (at next visit) clinically meaningful deterioration (TTFD/TTFCD) as measured with the Brief Pain Inventory Short Form (BPI-SF) worst pain and Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score using predefined thresholds. Other objectives were: Tx effects in TTFD and TTFCD measured by the European Organisation for Research and Tx of Cancer QoL Questionnaire-Prostate 25 (QLQ-PR25) and European QoL 5-Dimensions 5-Levels (EQ-5D-5L) visual analogue scale (VAS). Comparisons were made for ENZ + L vs P + L and ENZ alone vs P + L. Intent-to-treat population was analysed.

Results

At BL, 327–332 pts per group completed the PRO questionnaire; completion rates were 85–95%. No significant differences in TTFD or TTFCD were seen among Tx groups vs P + L in FACT-P total score, BPI-SF worst pain, or EQ-5D-5L VAS. In QLQ-PR25, TTFCD for sexual activity was significantly longer with ENZ alone vs P + L; TTFCD for hormone Tx-related symptoms was significantly shorter with ENZ + L vs P + L (Table). Table: 1766MO

Conclusions

ENZ + L or ENZ alone improved MFS without negatively impacting global HRQoL or clinical pain progression, vs P + L in nmHSPC pts. Sexual activity may be better preserved with ENZ alone vs P + L.

Clinical trial identification

NCT02319837.

Editorial acknowledgement

Medical writing and editorial assistance were provided by Vibha Dhamija (MSc), Olga Klibanov (PharmD), and Rucha Kurtkoti (MS) from IQVIA, funded by the study sponsors.

Legal entity responsible for the study

Astellas Pharma Inc. and Pfizer Inc.

Funding

This study was funded by Astellas Pharma Inc. and Pfizer Inc., the co-developers of enzalutamide.

Disclosure

S.J. Freedland: Financial Interests, Personal, Speaker, Consultant, Advisor, Paid for study and received compensation for consulting: Astellas Pharma; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Bayer, Pfizer, Janssen, Merck, Sanofi, Myovant; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Sanofi; Other, Personal, Steering Committee Member: Astellas Pharma, Pfizer, Janssen. U.F.F. De Giorgi: Financial Interests, Personal, Advisory Board: Pfizer, BMS, MSD, PharmaMar, Astellas, Bayer, Ipsen, Novartis, Eisai, Janssen; Financial Interests, Personal, Invited Speaker: Roche, BMS, Clovis Oncology, AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca, Sanofi, Roche. A. Rannikko: Financial Interests, Personal, Speaker, Consultant, Advisor: Janssen, Orion; Financial Interests, Personal, Membership or affiliation: Ida Montin Foundation, Orion Research Foundation; Financial Interests, Institutional, Research Grant: HUS Helsinki University Hospital, Cancer Foundation Finland, Academy of Finland, Jane and Aatos ErikkoFoundation, Finland. C. Pieczonka: Other, Institutional, Funding: Pfizer; Financial Interests, Personal, Speaker, Consultant, Advisor: Cellvax, Myovant, Dendreon, Bayer, Janssen, Pfizer, Blue Earth, Eli Lilly, Daiichi Sankyo, Merck, AstraZeneca, Sun; Other, Personal, Advisory Board: Myovant, Bayer, Janssen, Astellas, Pfizer, Sun, Merck, AstraZeneca, Dendreon; Other, Personal and Institutional, Writing Engagement: Pfizer, Astellas. R. Tutrone: Other, Institutional, Funding: Astellas, Pfizer, Merck, Biotechne, Lilly, Point Biopharma, Bayer, Novartis; Financial Interests, Personal, Speaker, Consultant, Advisor: Nymox Corp, Biotechne; Other, Personal and Institutional, Speaker’s Bureau: Myovant, Astellas, Pfizer; Financial Interests, Personal, Stocks/Shares: Nymox, Novartis. B. Venugopal: Other, Personal and Institutional, Writing Engagement: Pfizer; Other, Institutional, Sponsor/Funding: Exelixis, Ipsen, Pfizer, Merck, Tavanta; Financial Interests, Personal, Speaker, Consultant, Advisor: Eisai; Other, Personal, Financially compensated role: BMS, Eisai, EUSA pharma, Ipsen, Merck; Other, Personal, Advisory Board: Eisai. H. Woo: Other, Personal and Institutional, Stocks/Shares, Data analytics company. Remuneration by way of share options: Prospection Pty Ltd; Other, Personal, Speaker, Consultant, Advisor, Presentation honoraria: Bayer, Astellas, Cipla, Janssen; Other, Personal, Other, Proctoring honoraria: Boston Scientific Corporation; Other, Personal, Advisory Board, Honoraria: Astellas; Other, Personal, Non remunerated activity, Board Director - unpaid: Royal Australasian College of Surgeons, Urological Society of Australia and New Zealand, Australian and New Zealand Urogential and Prostate Cancer Trials Group, Australasian Urological Foundation. M. Ramirez Backhaus: Other, Personal, Speaker, Consultant, Advisor, Consulting fees; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; payment for expert testimony; support for attending meeting and travel: Janssen; Other, Personal, Speaker, Consultant, Advisor, Consulting fees; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bayer; Other, Personal, Speaker, Consultant, Advisor, Consulting fees; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; support for attending meeting, travel: Astellas. S. Supiot: Other, Institutional, Funding: Astellas; Other, Institutional, Research Grant: AstraZeneca, Janssen, Novartis AAA, Bayer, Reflexion Medical, Boston Scientifics; Financial Interests, Personal, Speaker, Consultant, Advisor: Astellas, AstraZeneca, Janssen, Ipsen, Takeda, Ferring, Novartis AAA, Bayer, MSD; Other, Personal, Financially compensated role: Astellas, AstraZeneca, Janssen, Ipsen, Takeda, Ferring, Novartis AAA, Bayer, MSD; Other, Personal, Advisory Board: Astellas, Janssen, Ipsen, Novartis AAA, Bayer; Other, Personal, Other, Support for attending meetings and/or travel: Reflexion Medical, Boston Scientifics, Astellas, AstraZeneca, Janssen, Ipsen, Takeda, Ferring, Novartis AAA, Bayer, MSD, Reflexion Medical, Boston Scientifics. A. Lantz: Other, Institutional, Research Grant: Prostate Cancer Foundation Sweden, AhrénsFoundation, Åke WibergsFoundation. A. Ganguli: Other, Personal and Institutional, Full or part-time Employment: Astellas; Other, Personal, Stocks/Shares: AbbVie. J. Ivanova: Other, Personal, Stocks/Shares: Pfizer; Other, Personal and Institutional, Full or part-time Employment: Pfizer. P. Kral: Other, Personal and Institutional, Speaker, Consultant, Advisor: Astellas. F. Saad: Financial Interests, Personal, Advisory Board: Astellas, Bayer, BMS, Janssen, Sanofi, Pfizer, Myovant, Novartis, AstraZeneca, Merck, Myovant; Financial Interests, Institutional, Local PI: Novartis, Astellas, Bayer, Janssen, Sanofi, BMS, Amgen, Pfizer, Merck; Financial Interests, Institutional, Coordinating PI: AstraZeneca. N.D. Shore: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BMS, Boston Scientific, Clovis Oncology, Cold Genesys, Dendreon, Exact Imaging, Exact Sciences, FerGene, Genesis Care Us, Invitae, Janssen, MDxhealth, Merck, Myovant, Myriad, Nymox, Pacific Edge, Pfizer, Propella, PreView, Sanofi Genzyme, Speciality Networks, Sesen Bio, Tolmar, Urogen, Clarity, Lantheus, Lilly, Photocure, Telix, Photocure, Vaxiion, Asieris, Alessa Therapeutics, Akido, Arquer, Fize medical, GConcology, Genentech, Guardant, Ferring, Foundation Medicine, Immunitybio, Incyte, Minomic, NGM, Nonagen, Novartis, PlatformQ, Profound, Promaxo, Protara, Vessi; Financial Interests, Personal, Member of Board of Directors: Photocure. All other authors have declared no conflicts of interest.

Background

Effective prognostication will allow better targeting of treatment (Rx) combinations for advanced PCa. A MMAI prognostic test (ArteraAI Prostate) was recently developed in localized PCa. We aimed to validate ArteraAI in advanced PCausing final data from 3 STAMPEDE trials (NCT00268476).

Methods

The MMAI model used digitized whole scan images from new H&E core prostate biopsies (PB), local Gleason score (GS), tumor stage (T), age and pre-ADT serum PSA. Fine-Gray/Cox regression adjusted for Rx allocation and cumulative incidence analyses were performed to evaluate associations with endpoints, as defined in STAMPEDE, for both continuous score (per standard deviation increase) and categorical (quartile,Q). PCa-specific mortality (PCSM) was the endpoint of primary interest. Death not from PCa was treated as a competing risk. HR, 95% CI, and p<0.001 (denoted by *) are reported.

Results

Of 3879 patients recruited Oct 2005 – Jan 2014 to ADT +/- radiotherapy (RT) alone or + Doc +/-zoledronic acid or + AAP, 3725 consented to tissue analysis, 2079 had H&E with sufficient tumor of which 1964 had all of GS, T, pre-ADT PSA (918 M0, 1046 M1, median follow-up: 7.8 years, yr). ArteraAI was strongly associated with PCSM (HR 1.67, 1.5-1.84*), overall survival (1.51,1.4-1.63*), failure-free survival (1.48, 1.38-1.59*), and metastatic progression-free survival (1.59, 1.46-1.73*). ArteraAI Q4 v Q1-3 showed similar results for all endpoints, including PCSM (2.27, 1.95-2.65*). Of component clinical variables, p* for PCSM were PSA Q4 v Q1-3 (1.8, 1.54-2.11), Gleason 8-10 v <=7 (1.64, 1.36-1.98), and T4 v T1-2 (1.77, 1.36-2.32). ArteraAI Q4 v Q1-3 had more PCSM events at 5 yr: 16% (11-21) v 6% (4-8) in M0, 58% (52-64) v 40% (36-43) in M1 and notably for M0 treated with ADT +/- RT+ AAP: 18% (9-28) v 2% (0-4%).

Conclusions

ArteraAI successfully validated in STAMPEDE with stronger prognostic associations than individual clinical variables. The MMAI model identified poor prognostic features in PB from high-risk M0 and M1 PCa.

Clinical trial identification

NCT00268476.

Legal entity responsible for the study

University College London (UCL) - Professor Gerhardt Attard.

Funding

Prostate Cancer UK, Cancer Research UK, Medical Research Council, The Jean Shanks Foundation, The Pathological Society of Great Britain & Ireland, Janssen, Sanofi.

Disclosure

C.T.A. Parker: Financial Interests, Institutional, Licensing Fees, My employer (UCL) may gain commercially from licensing data to Artera: Artera AI. V. Liu: Financial Interests, Personal, Full or part-time Employment, I am currently employed by ArteraAI: ArteraAI; Financial Interests, Personal, Stocks/Shares, I have stocks/shares as part of my compensation, but none have vested/I have not exercised my rights as of today's date (May 5/2023): ArteraAI; Other, Other, I was previously employed (in the last 2 years) by Decipher Biosciences/Veracyte Inc: Decipher Biosciences. D. Van der Wal: Financial Interests, Personal, Full or part-time Employment: Artera AI. J.R. Griffin: Financial Interests, Institutional, Full or part-time Employment: ArteraAI; Financial Interests, Institutional, Stocks/Shares: ArteraAI; Non-Financial Interests, Leadership Role: ArteraAI; Non-Financial Interests, Institutional, Proprietary Information: ArteraAI. E. Chen: Financial Interests, Institutional, Full or part-time Employment: Artera; Financial Interests, Institutional, Stocks/Shares: Artera. P.T. Tran: Financial Interests, Personal, Advisory Board: Janssen, Myovant, AstraZeneca, Natsar Pharmaceuticals, RefleXion Medical, Bayer, Regeneron, Lantheus; Financial Interests, Personal, Royalties: Natsar Pharmaceuticals; Financial Interests, Institutional, Funding: Bayer, Janssen, Medivation Inc-Astellas Pharma Inc; Non-Financial Interests, Leadership Role: NRG Oncology, ASTRO, Movember; Non-Financial Interests, Institutional, Proprietary Information: Veracyte, Artera. M.K. Parmar: Financial Interests, Institutional, Full or part-time Employment, Director at MRC Clinical Trials Unit at UCL: Medical Research Council Clinical Trials Unit at UCL; Financial Interests, Institutional, Research Grant: AstraZeneca, Astellas, Janssen, Clovis; Non-Financial Interests, Advisory Role, Euro Ewing Consortium: University College London; Non-Financial Interests, Advisory Role, rEECur: University of Birmingham; Non-Financial Interests, Advisory Role, CompARE Trial: University of Birmingham. M.R. Sydes: Financial Interests, Personal, Invited Speaker, Speaker fees at clinical trial statistics training sessions for clinicians (no discussion of particular drugs): Janssen; Financial Interests, Personal, Invited Speaker, Speaker fees at clinical trial statistics training session for clinicians (no discussion of particular drugs): Eli Lilly; Financial Interests, Personal, Other, Educational lecture not associated with any products: Eisai; Financial Interests, Institutional, Research Grant, Educational grant and drug for STAMPEDE trial: Astellas, Janssen, Novartis, Pfizer, Sanofi; Financial Interests, Institutional, Research Grant, Educational grant and biomarker costs for STAMPEDE trial: Clovis Oncology. L.C. Brown: Financial Interests, Institutional, Research Grant, £170k educational grant for the FOCUS4-C Trial from June 2017 to Dec 2021: AstraZeneca; Financial Interests, Institutional, Funding, Various grants awarded to my institution for work undertaken as part of the STAMPEDE Trial: Janssen pharmaceuticals; Financial Interests, Institutional, Funding, Grant funding to my institution for the STAMPEDE2 trial: Novartis AAA; Non-Financial Interests, Other, I am a member of the CRUK CERP funding advisory panel and my Institution also receive grant funding from CRUK for the STAMPEDE and FOCUS4 trials: Cancer Research UK. A. Esteva: Financial Interests, Personal, Officer, CEO: Artera AI. F. Feng: Financial Interests, Personal, Advisory Role: Artera AI. N.D. James: Financial Interests, Personal, Advisory Board, Advice around PARP inhibitors: AstraZeneca; Financial Interests, Personal, Advisory Board, Prostate cancer therapies: Janssen, Clovis, Novartis; Financial Interests, Institutional, Advisory Board, Assisted with submissions regarding licensing for abiraterone: Janssen; Financial Interests, Personal, Advisory Board, Docetaxel: Sanofi; Financial Interests, Institutional, Advisory Board, Providing STAMPEDE trial data to facilitate license extensions internationally for docetaxel: Sanofi; Financial Interests, Personal, Advisory Board, Bladder cancer therapy: Merck; Financial Interests, Personal, Advisory Board, Advice around novel hormone therapies for prostate cancer: Bayer; Financial Interests, Personal, Invited Speaker, Lecture tour in Brazil August 2022 - speaking on therapy for advanced prostate cancer: Merck Sharp & Dohme (UK) Limited; Financial Interests, Institutional, Coordinating PI, Funding for STAMPEDE trial: Janssen, Astellas; Financial Interests, Institutional, Coordinating PI, Funding for RADIO trial bladder cancer: AstraZeneca. G. Attard: Financial Interests, Personal, Invited Speaker: Janssen, Astellas, AstraZeneca; Financial Interests, Personal, Advisory Board: Janssen, Astellas, Novartis, Bayer, AstraZeneca, Pfizer, Sanofi, Sapience, Orion, Novartis; Financial Interests, Personal, Royalties, Included in list of rewards to discoverers of abiraterone: Institute of Cancer Research; Financial Interests, Institutional, Advisory Board: Artera, Veracyte; Financial Interests, Institutional, Research Grant: Janssen, Astellas, Novartis; Financial Interests, Institutional, Coordinating PI: Janssen; Financial Interests, Institutional, Local PI: Novartis, Pfizer; Non-Financial Interests, Principal Investigator: Janssen, Astellas; Non-Financial Interests, Advisory Role: Janssen, AstraZeneca; Non-Financial Interests, Project Lead: Artera, Veracyte. All other authors have declared no conflicts of interest.

Background

Androgen deprivation therapy (ADT) is the mainstay medical treatment for men with locally advanced (M0) and metastatic hormone sensitive prostate cancer (M1 mHSPC): bone loss and increased fracture risk are recognised complications. The STAMPEDE trial compared patients (pts) treated with ADT ± docetaxel (Doc) ± zoledronic acid (ZA). No survival benefit was demonstrated with the addition of ZA however, long term effects on bone health and fracture risk were not formally collected within the trial. Health systems data through Hospital Episode Statistics (HES) for pts in England provides data with demonstrated integrity and provenance beyond standard trial follow up permitting evaluation of fracture risk.

Methods

HES data were obtained (up to Mar 2021) for pts randomised to ADT (Arm A), ADT+ZA (Arm B), ADT+Doc (Arm C) and ADT+Doc+ZA (Arm E). ZA (4mg) was given as six 3 weekly cycles, then 4 weekly for 2 years. Fracture related hospitalisations (FRH) were identified using a prespecified coding framework of ICD10 diagnosis and OPCS procedure codes. Flexible parametric competing risks models were used to estimate 5- and 10yr cumulative incidence of FRH and subdistribution hazard ratios (SDHR).

Results

Linked data were available for 2,042 (734 M0, 1,308 M1) out of 2,140 eligible pts (95%). The 5-year cumulative incidence of FRH for M1 and M0 pts treated with ADT were 23% (95% CI 19-28%) and 11% (95% CI 8-15%) respectively. The 10-year cumulative incidence with ADT in M0 pts was 26% (95% CI 20-33%). Addition of ZA significantly reduced the incidence of FRH in M1 pts (SDHR 0.73, 95% CI 0.55-0.97; p=0.015). Data were inconclusive in M0 pts (SDHR 0.88, 95% CI 0.59-1.32, p=0.549). Doc had no significant effect on FRH in both M1 (p=0.264) and M0 (p=0.570), with no evidence of interaction between ZA and Doc in both M1 (p=0.526) and M0 (p=0.805).

Conclusions

High incidence of 10yr fracture related hospitalisations was observed in STAMPEDE trial participants with either M0 or M1 prostate cancer. Addition of ZA reduced risk of FRH in people with M1 disease but not with M0 disease. These data support the use of bone protection agents to reduce fracture risk in men with mHSPC.

Clinical trial identification

NCT00268476.

Legal entity responsible for the study

MRC Clinical Trials Unit UCL.

Funding

Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis.

Disclosure

C. Jones: Financial Interests, Personal, Invited Speaker: Janssen. P. Dutey-Magni, M.K. Parmar, L.C. Brown: Financial Interests, Institutional, Research Funding: Janssen, Astellas, Novartis, Sanofi, and Clovis. J.E. Brown: Financial Interests, Institutional, Research Grant: AstraZeneca; Non-Financial Interests, Institutional, Other, Drug donation: Bayer; Financial Interests, Personal, Speaker’s Bureau: Ipsen. N.D. James: Financial Interests, Personal, Advisory Board, Advice around PARP inhibitors: AstraZeneca; Financial Interests, Personal, Advisory Board, Prostate cancer therapies: Janssen, Clovis, Novartis; Financial Interests, Institutional, Advisory Board, Assisted with submissions regarding licencing for abiraterone: Janssen; Financial Interests, Personal, Advisory Board, Docetaxel: Sanofi; Financial Interests, Institutional, Advisory Board, Providing STAMPEDE trial data to facilitate licence extensions internationally for docetaxel: Sanofi; Financial Interests, Personal, Advisory Board, Bladder cancer therapy: Merck; Financial Interests, Personal, Advisory Board, Advice around novel hormone therapies for prostate cancer: Bayer; Financial Interests, Personal, Invited Speaker, Lecture tour in Brazil August 2022 - speaking on therapy for advanced prostate cancer: Merck Sharp & Dohme (UK) Limited; Financial Interests, Institutional, Coordinating PI, Funding for STAMPEDE trial: Janssen, Astellas; Financial Interests, Institutional, Coordinating PI, Funding for RADIO trial bladder cancer: AstraZeneca. M.R. Sydes: Financial Interests, Personal, Invited Speaker, Speaker fees at clinical trial statistics training sessions for clinicians (no discussion of particular drugs): Janssen; Financial Interests, Personal, Invited Speaker, Speaker fees at clinical trial statistics training session for clinicians (no discussion of particular drugs): Eli Lilly; Financial Interests, Personal, Other, Educational lecture not associated with any products: Eisai; Financial Interests, Institutional, Research Grant, Educational grant and drug for STAMPEDE trial: Astellas, Janssen, Novartis, Pfizer, Sanofi; Financial Interests, Institutional, Research Grant, Educational grant and biomarker costs for STAMPEDE trial: Clovis Oncology. N.W. Clarke: Financial Interests, Personal, Invited Speaker: Janssen, Astellas. All other authors have declared no conflicts of interest.

Background

Pts with mCRPC with progressive disease (PD) during 2^nd generation hormonal agent therapy typically receive chemo next. Additional therapies are needed in this setting. Pembro + enza had antitumor activity in pretreated mCRPC in early phase studies. KEYNOTE-641 (NCT03834493) evaluated pembro + enza vs placebo (pbo) + enza in pts with chemo-naïve mCRPC with/without prior abiraterone (abi).

Methods

Eligible pts were male, aged ≥18 years, had ECOG PS ≤1, had confirmed mCRPC with no prior chemo except docetaxel in the hormone-sensitive setting, and had intolerance to or PD during prior abi or no prior abi. Pts were randomized 1:1 to pembro 200 mg or pbo IV Q3W for ≤35 cycles + enza 160 mg orally daily. Dual primary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS) per PCWG-modified RECIST 1.1 by blinded independent central review. Time to initiation of first subsequent anticancer therapy (TFST) was a key secondary endpoint. Safety/tolerability was a secondary endpoint.

Results

1244 pts were enrolled between Aug 21, 2019, and Jun 10, 2022 (n=621 to pembro + enza; n=623 to pbo + enza). As of Dec 12, 2022, the median (range) follow-up time at first prespecified interim analysis was 27.6 mo (6.1–39.8). 60.9% of all pts had prior abi and 29.1% had prior docetaxel, balanced between arms. The dual primary endpoints of rPFS (median 10.4 mo with pembro + enza vs 9.0 mo with pbo + enza; HR 0.98, 95% CI 0.84−1.14; P=0.41) and OS (median 24.7 mo vs 27.3 mo; HR 1.04, 95% CI 0.88−1.22; P=0.66) were not met. The prespecified boundary for futility for OS was crossed and the study was stopped. Median TFST was 13.2 mo vs 12.6 mo, respectively (HR 0.95, 95% CI 0.83−1.09). Any-grade and grade ≥3 treatment-related AEs occurred in 77.9% and 31.2% of 615 pts with ≥1 dose pembro + enza and 61.6% and 10.8% of 620 pts with ≥1 dose pbo + enza. 3 treatment-related deaths occurred with pembro + enza and none with pbo + enza.

Conclusions

Pembro + enza did not significantly improve efficacy outcomes vs pbo + enza in pts with mCRPC with/without prior abi. Pembro + enza was associated with more treatment-related AEs vs pbo + enza; no new safety signals were observed.

Clinical trial identification

NCT03834493.

Editorial acknowledgement

Writing assistance was provided by Ina Nikolaeva of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Astellas provided the enzalutamide for this study.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding

Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

J.N. Graff: Financial Interests, Personal, Invited Speaker, CME vendor: P3; Financial Interests, Personal, Invited Speaker, CME: Binaytara Foundation; Financial Interests, Personal, Other, Testicular cancer chair- make around $7,000 USD per year: Elsevier; Financial Interests, Personal, Other, Testicular cancer chair: Elsevier; Financial Interests, Institutional, Coordinating PI, Two Investigator initiated, lead in a phase 3 trial (KN 641), local PI for several studies: Merck Sharpe Dohme; Financial Interests, Institutional, Steering Committee Member: Janssen, Curium; Financial Interests, Institutional, Coordinating PI: Sanofi; Non-Financial Interests, Leadership Role: Veterans Affairs Hospital. M. Burotto: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS; Financial Interests, Personal, Advisory Board: Merck & Co., Inc., Roche. P.C. Fong: Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Other, Oncology meeting attendance/Accommodation: Pfizer; Non-Financial Interests, Advisory Role: New Zealand Prostate Cancer Foundation. D. Pook: Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Advisory Board: BMS, MSD, Ipsen, Pfizer, Eisai, Astellas; Financial Interests, Institutional, Invited Speaker: BMS, Astellas, Pfizer, Roche, Ipsen, MSD, Amgen. R. Manneh Kopp: Financial Interests, Personal, Invited Speaker: MSD, AstraZeneca, BMS, Janssen, Astellas, Pfizer, Bayer, Eli Lilly, Roche, Tecnofarma, Procaps; Financial Interests, Personal, Advisory Board: MSD, Bayer, Tecnofarma; Financial Interests, Personal and Institutional, Invited Speaker: MSD, Bayer, BMS, Roche, Pfizer, Novartis, AstraZeneca; Non-Financial Interests, Leadership Role: Asociación Colombiana de Hematología y Oncología. G. Kramer: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Bayer, Janssen, Pfizer, Sandoz; Financial Interests, Personal, Advisory Role: Ferring, MSD, Novartis; Financial Interests, Personal, Other, Travel Expenses: Astellas, AstraZeneca, Bayer, Janssen, MSD, Novartis. R. Ratta: Financial Interests, Personal, Invited Speaker: Ipsen, Astellas; Financial Interests, Personal, Advisory Board: Pfizer, Merck, BMS, AstraZeneca. M. Kwiatkowski: Financial Interests, Personal, Invited Speaker: Janssen Cilag, Novartis, Roche; Non-Financial Interests, Principal Investigator, Clinical Trials: MSD, BMS; Non-Financial Interests, Principal Investigator, Clinical trials: AstraZeneca, Roche, Hengrui, Janssen Cilag, BeiGene, Shanghai Jinshu, Bayer. M. Retz: Financial Interests, Personal, Research Grant: BMS. J.A. Arranz Arija: Financial Interests, Personal, Advisory Board: Astellas, BMS, Merck, Pfizer, Bayer, MSD, Eisai; Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Institutional, Invited Speaker, SOGUG: BMS. H.P. Gurney: Financial Interests, Personal, Advisory Board: Merck, Pfizer, AstraZeneca, BMS, MSD, Ipsen, Astellas. N. Matsubara: Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Institutional, Invited Speaker: Janssen, AstraZeneca, Bayer, Roche, MSD, Taiho, Astellas, Amgen, Eisai, Eli Lilly, Pfizer, Chugai, AbbVie. L.W. Liang, J. Todoric, K. Imai: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. A. Stenzl: Financial Interests, Personal, Advisory Board: Astellas, Pfizer, Bayer, Ipsen Pharma, Roche Pharma, AstraZeneca, Cystotech, GSK, MSD; Non-Financial Interests, Other, Preparation of an official project related to connection between Hospitals/doctors and Industry in general, Z.I.M.T: BioRegioSTERN; Non-Financial Interests, Leadership Role, Secretary General: European Assoc. of Urology (EAU); Non-Financial Interests, Leadership Role, Member Board of Directors: European Cancer Organisation. All other authors have declared no conflicts of interest.

Background

New therapeutic options are needed to delay disease progression for pts with mHSPC. The combination of pembro + enza has shown antitumor activity in pts with metastatic prostate cancer. The phase 3 KEYNOTE-991 study (NCT04191096) investigated pembro or placebo (pbo) + enza + ADT in pts with next-generation hormonal agent (NHA)-naïve mHSPC.

Methods

Eligible pts (aged ≥18 yrs, ECOG PS ≤1) had confirmed mHSPC (≥2 bone lesions and/or visceral disease, verified centrally), no prior NHA, and had completed any prior docetaxel (≤6 cycles) ≤2 mo from randomization. Pts were randomized 1:1 to receive pembro 200 mg or pbo IV Q3W for ≤35 cycles + enza 160 mg orally daily + continuous ADT (if no history of bilateral orchiectomy). Dual primary endpoints were radiographic progression-free survival (rPFS) per PCWG-modified RECIST 1.1 by blinded independent central review and overall survival (OS). Key secondary endpoints included time to initiation of first subsequent anticancer therapy (TFST) and time to first symptomatic skeletal-related event (TTSSRE). Safety was a secondary endpoint.

Results

Between Mar 2, 2020, and Aug 9, 2021, 626 pts were randomized to pembro + enza and 625 to pbo + enza. As of Oct 31, 2022, the median (range) follow-up time at first prespecified interim analysis was 21.1 mo (14.8−32.0). Baseline characteristics were generally balanced between arms; ∼10% of pts received prior docetaxel in each arm. The primary endpoint of rPFS for pembro + enza vs pbo + enza was not met (median not reached [NR] vs NR, HR 1.20, 95% CI 0.96−1.49, P=0.95). Median OS was NR vs NR (HR 1.16, 95% CI 0.88−1.53). Median TFST was NR in both arms (HR 1.24, 95% CI 1.01−1.54). Median TTSSRE was NR in both arms (HR 0.89, 95% CI 0.61−1.30). Serious AEs occurred in 40.3% vs 23.2% of pts with pembro + enza vs pbo + enza. Any-grade and grade ≥3 treatment-related AEs occurred in 88.0% vs 67.0% and 41.8% vs 13.9% of pts, respectively.

Conclusions

The study was stopped for futility. The addition of pembro to enza plus ADT did not improve rPFS or OS in pts with NHA-naïve mHSPC and was associated with more serious and treatment-related AEs vs enza plus ADT.

Clinical trial identification

NCT04191096.

Editorial acknowledgement

Writing assistance was provided by Ina Nikolaeva of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Astellas provided the enzalutamide for this study.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding

Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

C.J. Gratzke: Financial Interests, Personal, Advisory Board: Astellas Pharma, Bayer, GSK, MSD, AstraZeneca, Janssen, Steba Biotech; Financial Interests, Personal, Invited Speaker: Astellas Pharma, Bayer, MSD, MSD, Bayer, Recordati, Amgen, AstraZeneca, AstraZeneca, Ipsen, Janssen, Janssen, Novartis, Pfizer; Financial Interests, Personal and Institutional, Invited Speaker: MSD, MSD; Financial Interests, Personal and Institutional, Funding: MSD; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Invited Speaker: Bayer, Janssen, Lilly, AstraZeneca; Non-Financial Interests, Principal Investigator: MSD; Non-Financial Interests, Project Lead: Janssen, Bayer; Non-Financial Interests, Advisory Role: STEBA. M. Ozguroglu: Financial Interests, Personal, Advisory Board, prostate cancer: Astellas; Financial Interests, Personal, Invited Speaker, travel and accommodation: Regeneron; Financial Interests, Personal, Advisory Board, lung cancer meeting: Sanofi. A. Peer: Financial Interests, Personal, Advisory Board, and Invited speaker: MSD; Financial Interests, Personal, Advisory Board, And invited speaker: BMS; Financial Interests, Personal, Expert Testimony, and invited speaker: Roche; Financial Interests, Personal, Advisory Board, and invited speaker: Astellas; Financial Interests, Personal, Advisory Board: Janssen, Bayer, Teva, Takeda, Medison pharma; Financial Interests, Personal, Invited Speaker: Exelixis; Financial Interests, Institutional, Research Grant: Sanofi aventis. M.A.N. Sendur: Financial Interests, Personal, Advisory Board: BMS, Pfizer, Takeda, Roche, Astellas; Financial Interests, Personal, Invited Speaker: Astellas, Pfizer, BMS, MSD, Roche. M. Retz: Financial Interests, Personal, Research Grant: BMS. J.C.H. Goh: Financial Interests, Personal, Advisory Board, Prior member of the BMS RCC Advisory Board: BMS; Financial Interests, Personal, Advisory Board, Uterine Cancer Advisory Board: GSK; Financial Interests, Personal, Other, Chairing RCC meeting: Ipsen; Financial Interests, Personal, Invited Speaker, Speaking @ MSD sponsored event on Gynaecological cancerSpeaking at MSD sponsored event on RCC: MSD; Financial Interests, Personal, Advisory Board, Met RCC Advisory Board: MSD/ Eisai; Financial Interests, Personal, Other, 1. Asia-Pacific Advisory Board member for prostate cancer2. Invited Speaker at AZ sponsored molecular/genomic testing meeting: AstraZeneca; Financial Interests, Personal, Stocks/Shares, Private Cancer Centres in Australia: ICON Cancer Centres; Financial Interests, Institutional, Funding, Funding for phase 2 metastatic cervical cancer trial: BeiGene; Non-Financial Interests, Principal Investigator, local PI for CHECKMATE-914, CHECKMATE-9KD trial, CHECKMATE-7DX & CHECKMATE-9ER trials: BMS. G. Jayram: Financial Interests, Personal, Advisory Board: Merck, AstraZeneca; Financial Interests, Personal, Invited Speaker: Photocure, BMS; Financial Interests, Institutional, Invited Speaker: Janssen, Merck. S. Byun: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Clinical trial investigator: Astellas, MSD; Financial Interests, Personal, Other, Clinical trial investigator: Pfizer; Financial Interests, Personal, Invited Speaker, Clinical trial investigator: Janssen; Financial Interests, Personal, Officer, CEO: Inivites Biocore; Financial Interests, Personal, Stocks/Shares: PROCAGEN; Non-Financial Interests, Leadership Role, President: Korean Urological Research Society. M. Kwiatkowski: Financial Interests, Personal, Invited Speaker: Janssen Cilag, Novartis, Roche; Non-Financial Interests, Principal Investigator, Clinical Trials: MSD, BMS; Non-Financial Interests, Principal Investigator, Clinical trials: AstraZeneca, Roche, Hengrui, Janssen Cilag, BeiGene, Shanghai Jinshu, Bayer. R. Manneh Kopp: Financial Interests, Personal, Invited Speaker: MSD, AstraZeneca, BMS, Janssen, Astellas, Pfizer, Bayer, Eli Lilly, Roche, Tecnofarma, Procaps; Financial Interests, Personal, Advisory Board: MSD, Bayer, Tecnofarma; Financial Interests, Personal and Institutional, Invited Speaker: MSD, Bayer, BMS, Roche, Pfizer, Novartis, AstraZeneca; Non-Financial Interests, Leadership Role: Asociación Colombiana de Hematología y Oncología. J.C. Vazquez Limon: Financial Interests, Institutional, Full or part-time Employment, Attending physician and chief of oncology service: Hospital Civil de Guadalajara; Financial Interests, Personal and Institutional, Local PI: BMS, MSD, Novartis, Janssen, AstraZeneca, Roche, Regeneron, AbbVie, GSK; Non-Financial Interests, Advisory Role: Janssen; Non-Financial Interests, Institutional, Product Samples: GSK. J.F. Escobar Penagos: Financial Interests, Personal, Invited Speaker, Participate like principal investigator in clinical trials: AstraZeneca; Financial Interests, Personal, Invited Speaker, principal investigator in clinical trial: BMS; Financial Interests, Personal, Invited Speaker, principal investigator in clinical trials: MSD. U.F.F. De Giorgi: Financial Interests, Personal, Advisory Board: Pfizer, BMS, MSD, PharmaMar, Astellas, Bayer, Ipsen, Novartis, Eisai, Janssen; Financial Interests, Personal, Invited Speaker: Roche, BMS, Clovis Oncology, AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca, Sanofi, Roche. K.M.D. Trindade: Financial Interests, Personal, Invited Speaker: Janssen, Merck, Astellas, AstraZeneca, Adium; Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Merck; Financial Interests, Institutional, Invited Speaker: MSD, Janssen, BMS, Roche. C. Niu: Financial Interests, Personal, Full or part-time Employment: MSD China; Financial Interests, Personal, Stocks/Shares: MSD China. Y. Liu, C.H. Poehlein: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. J.M. Piulats Rodriguez: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Roche, BMS, MSD, BeiGene, VCN, AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: BMS, Pfizer, Janssen, BeiGene, Mirati. All other authors have declared no conflicts of interest.

Background

In the phase 3 MAGNITUDE study (NCT03748641), NIRA + AAP significantly improved radiographic progression-free survival in BRCA-mutant (BRCA+) pts. Here we present the FA of MAGNITUDE, a phase 3 study with the largest population of 1L BRCA+ mCRPC pts, reporting mature overall survival (OS) data and prespecified multivariate analysis (MVA) for OS, addressing baseline imbalances.

Methods

Eligible pts (N = 423) with HRR+ mCRPC were randomized 1:1 to NIRA + AAP (n = 212) or placebo (PBO) + AAP (n = 211) as 1L therapy. At this FA, secondary endpoints of OS and time to cytotoxic chemotherapy (TCC) were formally assessed. Updates to time to symptomatic progression (TSP) and patient-reported outcomes (PROs) in BRCA+ pts and to safety for all HRR+ pts are also reported.

Results

At FA, 225 BRCA+ pts were evaluated; 113 pts received NIRA + AAP. Median follow-up was 35.9 months. In the NIRA + AAP and PBO + AAP arms, 70% and 86% of pts received subsequent life-prolonging therapy. OS favored NIRA + AAP over PBO + AAP (Table). A prespecified MVA adjusting for baseline imbalances showed an OS benefit favoring NIRA + AAP. Continued improvement in TSP and a clinically meaningful improvement in TCC were observed with NIRA + AAP. Time to worst pain progression and time to pain interference progression also favored NIRA + AAP. No new safety signals were observed with additional treatment exposure. Pulmonary embolism occurred in 4.7% and 1.4% of pts in NIRA + AAP and PBO + AAP arms, with no cases of myelodysplastic syndrome or acute myeloid leukemia in the NIRA + AAP arm. Table: LBA85

Endpoints at FA in pts withBRCA+ mCRPC, NIRA + AAP vs PBO + AAP

Conclusions

OS favored NIRA + AAP for pts with BRCA+ mCRPC. NIRA + AAP led to improvements in TSP, TCC, and PROs. The positive benefit-risk profile supports 1L NIRA + AAP as a new standard of care for pts with BRCA+ mCRPC.

Clinical trial identification

NCT03748641.

Editorial acknowledgement

Brittany Carson, PhD, MEDiSTRAVA.

Legal entity responsible for the study

Janssen Research & Development, LLC.

Funding

Janssen Research & Development, LLC.

Disclosure

K.N.N. Chi: Financial Interests, Personal, Invited Speaker: Astellas, AstraZeneca, Janssen, Point Biopharma, Roche; Financial Interests, Personal, Advisory Board: AstraZeneca, AstraZeneca, Janssen, Merck, Novartis, Pfizer, Point Biopharma, Roche, BMS; Financial Interests, Institutional, Steering Committee Member: AstraZeneca, Janssen, Novartis, Roche; Financial Interests, Institutional, Trial Chair: AstraZeneca, Arvinas, Janssen, Novartis; Financial Interests, Institutional, Local PI: Arvinas. E. Castro: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Janssen, MSD, Bayer, Pfizer, Daiichi Sankyo, Lilly, Medscape, Novartis; Financial Interests, Personal, Invited Speaker: Astellas, AstraZeneca, Janssen, Clovis, Pfizer, Medscaoe; Financial Interests, Personal, Writing Engagement: Pfizer; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Research Grant: Janssen, Bayer, Pfizer; Financial Interests, Institutional, Local PI: Janssen, Pfizer, MSD. G. Attard: Financial Interests, Personal, Invited Speaker: Janssen, Astellas, AstraZeneca; Financial Interests, Personal, Advisory Board: Janssen, Astellas, Novartis, Bayer, AstraZeneca, Pfizer, Sanofi, Sapience, Orion, Novartis; Financial Interests, Personal, Royalties, Included in list of rewards to discoverers of abiraterone: Institute of Cancer Research; Financial Interests, Institutional, Advisory Board: Artera, Veracyte; Financial Interests, Institutional, Research Grant: Janssen, Astellas, Novartis; Financial Interests, Institutional, Coordinating PI: Janssen; Financial Interests, Institutional, Local PI: Novartis, Pfizer; Non-Financial Interests, Principal Investigator: Janssen, Astellas; Non-Financial Interests, Advisory Role: Janssen, AstraZeneca; Non-Financial Interests, Project Lead: Artera, Veracyte. M.R. Smith: Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen, Astellas Pharma, Bayer, Eli Lilly and Company, Janssen Biotech, Pfizer, Novartis; Financial Interests, Institutional, Research Funding: Janssen Oncology, Bayer, Lilly, ESSA, Oric Pharmaceuticals. S.K. Sandhu: Financial Interests, Institutional, Advisory Board, I have served on advisory boards for BMS. The contracts for my role are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre.: Bristol Myer Squib; Financial Interests, Institutional, Advisory Board, I have served on advisory boards for MSD. The e contracts for my role are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre.: Merck Sharp and Dohme; Financial Interests, Institutional, Advisory Board, I have served on advisory boards for AstraZeneca. The contracts for my role as an advisor are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre.: AstraZeneca; Financial Interests, Institutional, Advisory Board, I have served on advisory boards for Novartis. The contracts for my role as an advisor are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre.: Novartis; Financial Interests, Institutional, Advisory Board, I have served on an advisory board for Merck Serono. The contracts for my service are set up with the institution and funds go into a research fund at the Peter MacCallum Cancer Centre.: Merck Serono; Financial Interests, Institutional, Research Grant, My institution receives grant funding to run an investigator initiated trial that I lead.: Novartis, Genentech, Amgen, AstraZeneca, Merck Serono, Merck Sharp and Dohme; Financial Interests, Institutional, Funding, Pfizer are providing funding to my institution for the conduct of an investigator initiated clinical trial.: Pfizer; Non-Financial Interests, Principal Investigator, I am a principal investigator on several of Janssen sponsored studies and don't receive any renumeration for this.: Janssen; Non-Financial Interests, Principal Investigator, I am a principal investigator on several Novartis sponsored studies and dont receive any renumeration for this.: Novartis; Non-Financial Interests, Principal Investigator, I am a principal investigator on several of Genentech sponsored studies and don't receive any renumeration for this.: Genentech; Non-Financial Interests, Principal Investigator, I am a principal investigator on several of Bristol Myer Squibb sponsored studies and don't receive any renumeration for this.: Bristol Myer Squibb; Non-Financial Interests, Other, I serve on the Independent Safety and Data Monitoring committee for 2 of Novartis sponsored studies and don’t receive any compensation for this.: Novartis; Non-Financial Interests, Principal Investigator, I am the Priincipal Investigator for several AstraZeneca sponsored studies and am not remunerated for this.: AstraZeneca; Non-Financial Interests, Other, I serve on the steering committee for several Janssen sponsored trials and i do not receive compensation for this.: Janssen; Non-Financial Interests, Other, I serve on the steering committee for one AstraZeneca sponsored trial and I do not receive compensation for this.: AstraZeneca; Non-Financial Interests, Other, I serve on the steering committee for one Genentech sponsored trials and I do not receive compensation for this.: Genentech; Non-Financial Interests, Other, I serve on the steering committee for a Bristol Myer Squibb sponsored trial and I do not receive renumeration for this.: Bristol Myer Squibb. E. Efstathiou: Financial Interests, Personal, Speaker, Consultant, Advisor: Janssen, Sanofi, Takeda, Bayer, Merck, Pfizer, Myovant, AstraZeneca, Astellas, Tokai Pharmaceuticals; Financial Interests, Institutional, Research Funding: Janssen-Cilag. G. Roubaud: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Bayer; Financial Interests, Institutional, Advisory Board: Pfizer, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Coordinating PI: Bayer. E.J.J. Small: Financial Interests, Personal, Stocks/Shares: Fortis, Harpoon, Teon; Financial Interests, Personal, Speaker, Consultant, Advisor: J&J; Financial Interests, Personal, Advisory Board: Janssen, Fortis. A.J.P.D.S. Gomes: Financial Interests, Personal, Invited Speaker: Astellas, Bayer, Janssen, AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer, Janssen. D. Rathkopf: Financial Interests, Trial Chair: Janssen; Financial Interests, Steering Committee Member: Janssen, Genentech; Financial Interests, Institutional, Research Grant, Clinical Trial Grant: Genentech; Non-Financial Interests, Advisory Role: Janssen, Genentech, AstraZeneca, Myovant, Bayer, BMS; Non-Financial Interests, Principal Investigator: Janssen, Genentech, Promontory, Celgene/BMS. M. Saad: Financial Interests, Personal, Invited Speaker: Johnson&Johnson, MSD, Ipsen, Eisai, Amgen, Pfizer; Financial Interests, Personal, Advisory Board: Johnson&Johnson, MSD, Ipsen, Eisai, Merck, AstraZeneca; Financial Interests, Personal, Writing Engagement: Johson&Johnson, Ipsen; Financial Interests, Personal and Institutional, Local PI: Johson&Johnson, MSD; Non-Financial Interests, Advisory Role: Johnson&Johnson, Amgen. H.P. Gurney: Financial Interests, Personal, Advisory Board: Merck, Pfizer, AstraZeneca, BMS, MSD, Ipsen, Astellas. G.E. Mason: Financial Interests, Personal, Full or part-time Employment: Janssen; Financial Interests, Personal, Stocks/Shares: Janssen. S. Dibaj: Financial Interests, Personal, Full or part-time Employment: Janssen; Financial Interests, Personal, Stocks/Shares: Janssen. D. Wu: Financial Interests, Personal, Full or part-time Employment: Janssen; Financial Interests, Personal, Stocks/Shares: Janssen. B. Diorio: Financial Interests, Personal, Full or part-time Employment: Janssen; Financial Interests, Personal, Stocks/Shares: Janssen. A. Lopez-Gitlitz: Financial Interests, Personal, Full or part-time Employment: Janssen; Financial Interests, Personal, Stocks/Shares: Janssen. W. Kim: Financial Interests, Personal, Full or part-time Employment: Janssen. D. Olmos: Financial Interests, Personal, Financially compensated role: Janssen, Bayer; Financial Interests, Institutional, Financially compensated role: Astellas Pharma; Financial Interests, Institutional, Speaker, Consultant, Advisor: Janssen, AstraZeneca, Bayer; Financial Interests, Personal, Speaker, Consultant, Advisor: Clovis Oncology, Daiichi Sankyo, MSD Oncology; Financial Interests, Personal, Other, Travel, accommodations, expenses: Bayer, Janssen, Ipsen, Astellas Pharma, Roche, AstraZeneca Spain. All other authors have declared no conflicts of interest.

Background

The Prostate Biomarker (ProBio) trial is an international biomarker-driven, randomized, outcome-adaptive platform trial in men with metastatic castrate resistant prostate cancer (mCRPC) evaluating multiple agents.

Methods

We used outcome-adaptive randomization to compare biomarker-driven treatment selection (experimental arms) against physician’s choice standard-of-care (SOC; control arm), and to compare agents against each other within the experimental treatment arms. Men with mCRPC were randomized based on genomic alterations in circulating tumor DNA in five biomarker signatures: (1) AR wt and TP53 wt; (2) TP53 mut; (3) DRD; (4) TMPRSS2:ERG fusion; (5) all biomarkers signatures combined. Androgen receptor pathway inhibitors (ARPi; abiraterone and enzalutamide) and taxanes (docetaxel and cabazitaxel) were evaluated, using progression-free survival, by no longer clinically benefiting per PCWG3 criteria (PFS), as primary endpoint. Enrollment in the experimental group was stopped when the Bayesian probability of superiority reached prespecified thresholds (“graduation”).

Results

In total, 219 men were randomized: 92 to SOC, vs. 76 and 51 to taxanes and ARPi, respectively, in the biomarker-driven arms. ARPi graduated in the “signature all”, i.e. a signature encompassing all biomarkers. The median estimated PFS was 11.3 months (90% Bayesian credible interval [CI], 9.8 to 13.1) for ARPi compared with 7.2 months (90% CI, 6.5 to 8.1) in the SOC arm, for a hazard ratio (HR) of 0.52 (90% CI 0.37 to 0.72). ARPi demonstrated superiority to taxanes within the experimental arms (HR 0.54; 90% CI 0.38 to 0.76). We observed suggestive differential treatment effects for patients with TP53 mut and TMPRSS2:ERG fusion disease. The median estimated overall survival (OS) was 37.3 months (CI, 27.7 to NA) for ARPi compared with 20.2 months (90% CI, 18.4 to 23.0) taxanes within the experimental arms.

Conclusions

ARPi increases PFS and OS both compared to SOC and taxanes in patients with mCRPC. These are directly randomized data for ARPi and taxanes, showing the first evidence of a difference in PFS and OS for these agents in the mCRPC setting.

Clinical trial identification

NCT03903835.

Legal entity responsible for the study

Karolinska Institutet.

Funding

Janssen Pharmaceuticals, AstraZeneca.

Disclosure

H. Grönberg: Financial Interests, Personal, Ownership Interest: A3P Biomedical; Financial Interests, Institutional, Funding: AstraZeneca, Janssen; Financial Interests, Personal, Invited Speaker: Janssen, Astellas, Bayer, AstraZeneca. A. Ullén: Financial Interests, Institutional, Funding: Merck KGaA; Financial Interests, Personal, Advisory Role: Merck KGaA, Astellas Pharma. A. Mortezavi: Financial Interests, Institutional, Funding: Janssen; Financial Interests, Personal, Stocks or ownership: STOICH GmbH; Financial Interests, Personal, Advisory Role: Janssen, Myriad; Financial Interests, Personal, Speaker’s Bureau: Janssen; Financial Interests, Personal, Other: Janssen. P. Ost: Financial Interests, Institutional, Funding: Varian; Financial Interests, Personal, Advisory Role: AAA, Bayer, Janssen, Novartis. G. Enblad: Financial Interests, Personal, Advisory Role: Gilead, Pierre Fabre. J. Oldenburg: Financial Interests, Personal, Other: Astellas Oncology, AstraZeneca, Name of Entity: Relationship: Delete : Name of Entity: Relationship: Delete : Astellas Oncology You ABayer Germany, Ipsen, BMS Norway, Eisai, Roche, Janssen Oncology, Merck, MSD; Financial Interests, Personal, Advisory Role: Merck, BMS Norway, Bayer Germany, Roche, Janssen, Eisai, AstraZeneca, Astellas Oncology; Financial Interests, Personal, Speaker’s Bureau: Astellas Oncology, Janssen, Bayer. J. Sandzén: Financial Interests, Institutional, Funding: Reassure. M.N. Vigmostad: Financial Interests, Personal, Other: Pfizer, Janssen, Dagens Medisin. M.E. Hjälm-Eriksson: Financial Interests, Personal, Advisory Role: Astellas. M. Eklund: Financial Interests, Personal, Stocks or ownership: A3P Biomedical AB; Financial Interests, Personal, Other: A3P Biomedical AB. All other authors have declared no conflicts of interest.