Background

AAP or ENZ added to ADT improves outcomes for mHSPC. Any benefit of combining ENZ & AAP in this disease setting is uncertain.

Methods

STAMPEDE is a multi-arm, multi-stage (MAMS), platform protocol conducted at 117 sites in the UK & Switzerland. 2 trials with no overlapping controls randomised mHSPC patients (pts) 1:1 to ADT +/- AAP (1000mg od AA + 5mg od P) or AAP + ENZ (160mg od). Treatment was continued to progression. From Jan 2016 docetaxel 75mg/m² 3-weekly with P 10mg od was permitted + ADT. Using meta-analysis methods, we tested for evidence of a difference in OS and secondary outcomes (as described previously: failure-free, metastatic progression-free, progression-free & prostate cancer specific survival) across the 2 trials using data frozen 3 Jul 2022. All confidence intervals (CI) 95%. Restricted mean survival times (RMST) restricted to 84 months (m).

Results

Between Nov 2011 & Jan 2014, 1003 pts were randomised ADT +/- AAP & between Jul 2014 & Mar 2016, 916 pts were randomised ADT +/- AAP + ENZ. Randomised groups were well balanced across both trials. Pt cohort: age, median 68 years (yr), IQR 63, 72; PSA prior to ADT, median 95.7 ng/ml, IQR 26.5, 346; de novo 94%, relapsed after radical treatment, 6%. In AAP + ENZ trial, 9% had docetaxel + ADT. OS benefit in AAP + ENZ trial, HR 0.65 (CI 0.55‒0.77) p = 1.4×10^-6; in AAP trial, HR 0.62 (0.53, 0.73) p = 1.6×10^-9. No evidence of a difference in treatment effect (interaction HR 1.05 CI 0.83‒1.32, p = 0.71) or between-trial heterogeneity (I² p = 0.70). Same for secondary end-points. % (CI) of pts reporting grade 3-5 toxicity in 1^st 5 yr: AAP trial, ADT: 38.5 (34.2-42.8), + AAP: 54.4 (50.0-58.8); AAP + ENZ trial, ADT: 45.2 (40.6 – 49.8), + AAP + ENZ: 67.9 (63.5 – 72.2); most frequently increased with AAP or AAP + ENZ = liver derangement, hypertension. At 7 yr in AAP trial (median follow-up: 95.8m), % (CI) pts alive with ADT: 30 (26, 34) versus with ADT + AAP: 48 (43, 52); RMST: ADT: 50.4m, ADT + AAP: 60.6m, p = 6.6 x 10^-9.

Conclusions

ENZ + AAP need not be combined for mHSPC. Clinically important improvements in OS when adding AAP to ADT are maintained at 7 yr.

Clinical trial identification

NCT00268476.

Legal entity responsible for the study

Medical Research Council Clinical Trials Unit at University College London.

Funding

Cancer Research UK, Medical Research Council, Janssen, Astellas.

Disclosure

G. Attard: Financial Interests, Personal, Invited Speaker: Janssen, Astellas, AstraZeneca; Financial Interests, Personal, Advisory Board: Janssen, Astellas, Novartis, Bayer, AstraZeneca, Pfizer, Sanofi, Sapience, Orion; Financial Interests, Personal, Royalties, Included in list of rewards to discoverers of abiraterone: Institute of Cancer Research; Financial Interests, Institutional, Research Grant: Janssen, Astellas; Non-Financial Interests, Principal Investigator: Janssen, Astellas; Non-Financial Interests, Advisory Role: Janssen, AstraZeneca. W.R. Cross: Financial Interests, Personal, Invited Speaker, Speaker fee: Myriad Genetics, Janssen, Astellas; Financial Interests, Personal, Advisory Board, Advisory Board fee: Bayer; Financial Interests, Institutional, Research Grant, Research grant: Myriad Genetics. S. Gillessen: Financial Interests, Personal, Advisory Board, 2018: Sanofi, Roche; Financial Interests, Personal, Advisory Board, 2018, 2019: Orion; Financial Interests, Personal, Invited Speaker, 2019 Speaker's Bureau: Janssen Cilag; Financial Interests, Personal, Advisory Board, 2020: Amgen; Financial Interests, Personal, Invited Speaker, 2020: ESMO; Financial Interests, Personal, Other, Travel Grant 2020: ProteoMEdiX; Financial Interests, Institutional, Advisory Board, 2018, 2019, 2022: Bayer; Financial Interests, Institutional, Advisory Board, 2020: Janssen Cilag, Roche, MSD Merck Sharp & Dohme, Pfizer; Financial Interests, Institutional, Advisory Board, 2018: AAA International, Menarini Silicon Biosystems; Financial Interests, Institutional, Advisory Board, 2019, 2020: Astellas Pharma; Financial Interests, Institutional, Advisory Board, 2019: Tolero Pharmaceuticals; Financial Interests, Personal, Invited Speaker, 2021, 2022: SAKK, DESO; Financial Interests, Institutional, Advisory Board, 2021: Telixpharma, BMS, AAA International, Novartis, Modra Pharmaceuticas Holding B.V.; Financial Interests, Institutional, Other, Steering Committee 2021: Amgen; Financial Interests, Institutional, Advisory Board, 2021, 2022: Orion, Bayer; Financial Interests, Personal, Invited Speaker, 2021: SAKK, SAKK, SAMO - IBCSG (Swiss Academy of Multidisciplinary oncology); Financial Interests, Personal, Advisory Board, 2021: MSD Merck Sharp & Dhome; Financial Interests, Personal, 2021: RSI (Televisione Svizzera Italiana); Financial Interests, Institutional, Invited Speaker, 2021: Silvio Grasso Consulting; Financial Interests, Institutional, Other, Faculty activity 2022: WebMD-Medscape; Financial Interests, Institutional, Advisory Board, 2022: Myriad genetics, AstraZeneca; Financial Interests, Institutional, Invited Speaker, 2022: TOLREMO; Financial Interests, Personal, Other, Travel support 2022: AstraZeneca; Financial Interests, Institutional, Funding, 2021, Unrestricted grant for a Covid related study as co-investigator: Astellas; Non-Financial Interests, Advisory Role, 2019: Menarini Silicon Biosystems, Aranda; Non-Financial Interests, Advisory Role, Continuing: ProteoMediX. C. Pezaro: Financial Interests, Personal, Advisory Board, Ad board Dec 2020: Advanced Accelerator Applications; Financial Interests, Personal, Advisory Board, Aug 2021: Astellas; Financial Interests, Personal, Advisory Board, Oct 2021: Bayer; Financial Interests, Personal, Invited Speaker, Sept-Oct 2020: AstraZeneca; Financial Interests, Personal, Invited Speaker, Oct 2020: Janssen; Financial Interests, Personal, Advisory Board, July-Sept 2022: Pfizer. Z. Malik: Financial Interests, Personal, Advisory Board, advisry board for new hormonal therapy for breast cancer: sanofi; Financial Interests, Institutional, Invited Speaker, research grant for CHROME study: sanofi; Other, Other, support to attend meetings or advisory boards in the past: Astellas,Jaansen,Bayer; Other, Other, Sponsorship to attend ASCO meeting 2022: Bayer. 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, 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; 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. 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. 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, Expert Testimony, Assisted with submissions regarding licencing for abiraterone: Janssen; Financial Interests, Personal, Advisory Board, Docetaxel: Sanofi; Financial Interests, Institutional, Expert Testimony, 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, Invited Speaker, Funding for STAMPEDE trial: Janssen, Astellas; Financial Interests, Institutional, Invited Speaker, Funding for RADIO trial bladder cancer: AstraZeneca. All other authors have declared no conflicts of interest.

Background

Addition of AAP to ADT is standard of care for APC (metastatic, M1 and high-risk non-metastatic, M0). We tested transcriptome signatures as prognostic and predictive biomarkers for patients (pt) starting ADT +/- AAP.

Methods

Whole transcriptome profiling was performed using a clinical test (Decipher, Veracyte, San Diego) on tumor index core mRNA from pt randomised 1:1 ADT:ADT+AAP in STAMPEDE. A pre-specified statistical analysis plan was approved by the trial oversight groups. Cox models were fit with mRNA signature, AAP (+/-), age, WHO PS, pre-ADT PSA, NSAIDs/aspirin use, Gleason score, and disease burden (M0N0 vs M0N1 vs M1 low volume vs M1 high volume) as covariates. Primary analyses included Decipher genomic classifier (GC, continuous) for prognosis and AR-activity (AR-A, average vs low) for prediction. AAP trial closed to follow up Nov 2021.

Results

Of 1917 pt (full trial cohort, FTC) enrolled Nov 2011 - Jan 2014, 1824 consented to tumor analysis; 1298 (71%) reviewed centrally, 974 (75%) gave transcriptomes; 781 (80%) passed QC. Of 781, 50% vs 52% in FTC were M1; other clinical variables, well balanced. Median follow-up = 94 months (IQR: 84 - 97). GC was strongly prognostic in APC (per 0.1 increment, M1 OS (HR [95% CI] 1.17 [1.09 - 1.26], p < 0.001), M0 MFS (HR 1.20 [1.09 - 1.31], p < 0.001), Table. AR-A showed no interaction with AAP (interaction HR 0.86 [0.56 - 1.33], p = 0.5). Secondary analyses showed consistent effect of AAP across PAM50, PSC and GC and worse outcome for low AR-A (M1, OS HR: 1.30 [0.99 - 1.70], p = 0.06; M0, MFS HR: 1.56 [1.08 - 2.27], p = 0.02). Table: 1358O

Conclusions

Decipher GC is strongly prognostic in APC treated with ADT +/- AAP. AAP effect is consistent across AR-A, PAM50, PSC and GC categories but absolute benefit varied. We clinically qualify mRNA signatures for potential use in treatment intensification/de-intensification of pt treated with ADT + AAP.

Clinical trial identification

NCT00268476, ISRCTN78818544.

Legal entity responsible for the study

Medical Research Council Clinical Trials Unit at University College London.

Funding

Prostate Cancer UK, Prostate Cancer Foundation, Cancer Research UK, Medical Research Council, Janssen, Veracyte.

Disclosure

J.A. Proudfoot: Financial Interests, Personal, Full or part-time Employment: Veracyte Inc.; Financial Interests, Personal, Stocks/Shares: Veracyte, Inc. Y. Liu: Financial Interests, Personal, Full or part-time Employment: Veracyte; Financial Interests, Personal, Stocks/Shares: Veracyte, Inc. 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, 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. R. Jones: Financial Interests, Personal, Advisory Board, advisory board attendance: AstraZeneca, Astellas; Financial Interests, Personal, Invited Speaker, Honoraria for speaking: Astellas; Financial Interests, Personal, Advisory Board: Bayer, Clovis, Exelixis, Ipsen, Bristol Myers Squipp, Merck Serono, Merck Sharpe Dome, Roche, Janssen, Novartis / AAA; Financial Interests, Personal, Invited Speaker: Bayer, Ipsen, Bristol Myers Squibb, Merck Serono, Merck Sharpe Dome, Pfizer, Roche, Janssen; Financial Interests, Institutional, Other, IDMC membership: Roche; Financial Interests, Institutional, Other, IDMC member: Stab; Financial Interests, Institutional, Invited Speaker: Janssen, Pfizer, Tail, AstraZeneca, BioXcel, Bristol Myers Squibb, Novartis/AAA, Roche, MSK. 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. F. Feng: Financial Interests, Personal, Advisory Role: Astellas, Bayer, BMS, Foundation Medicine, Janssen, Myovant, Novartis, Roivant; Financial Interests, Personal, Advisory Board: Artera, BlueStar Genomics, SerImmune. C.J. Sweeney: Financial Interests, Personal, Advisory Board, Consultancy: Genentech, Roche, Bayer, Astellas, Pfizer, Pfizer, Sanofi, Lilly; Financial Interests, Personal, Other, Consultancy: Janssen; Financial Interests, Personal, Stocks/Shares: Leuchemix; Financial Interests, Institutional, Research Grant: Bayer, Janssen, Astellas, Pfizer, Dendreon, Sanofi. N. Clarke: Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Principal Investigator: AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca, Astellas, Janssen, Bayer; Financial Interests, Personal, Speaker’s Bureau: Janssen, AstraZeneca, Astellas; Financial Interests, Personal, Advisory Board: AstraZeneca, Janssen, Pfizer, NICE; Financial Interests, Personal, Funding: AstraZeneca, Astellas, Janssen, Bayer. E. Davicioni: Financial Interests, Personal, Full or part-time Employment: Veracyte Inc.; Financial Interests, Personal, Stocks/Shares: Veracyte, Inc. N.D. James: Financial Interests, Personal, Funding: Sanofi, Novartis, Janssen, Astellas, Bayer. L. 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; 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. G. Attard: Financial Interests, Personal, Invited Speaker: Janssen, Astellas, AstraZeneca; Financial Interests, Personal, Advisory Board: Janssen, Astellas, Novartis, Bayer, AstraZeneca, Pfizer, Sanofi, Sapience, Orion; Financial Interests, Personal, Royalties, Included in List of Rewards to Discoverers of Abiraterone: Institute of Cancer Research; Financial Interests, Institutional, Research Grant: Janssen, Astellas; Non-Financial Interests, Principal Investigator: Janssen, Astellas; Non-Financial Interests, Advisory Role: Janssen, AstraZeneca. All other authors have declared no conflicts of interest.

Background

At the primary analysis of PROpel (NCT03732820; data cut-off [DCO]: 30/07/21), abi + ola significantly prolonged radiographic progression-free survival (rPFS) vs pbo + abi in 1L mCRPC (HR 0.66, 95% CI 0.54–0.81; P<0.0001). Overall survival (OS) trended towards a benefit with abi + ola vs abi + pbo (28.6% maturity; HR 0.86, 95% CI 0.66–1.12). We report biomarker analysis from the primary analysis and updated overall survival and safety data from a planned OS interim analysis (DCO2).

Methods

PROpel is a double-blind, pbo-controlled trial. 796 pts were randomized 1:1 to ola (300 mg twice daily [bid]) or pbo, and abi (1000 mg once daily) + prednisone or prednisolone (5 mg bid), irrespective of homologous recombination repair gene mutation (HRRm) status. The primary endpoint was rPFS by investigator assessment. OS was a key secondary endpoint. Aggregated results from tumour tissue (FoundationOne®CDx) and circulating tumour DNA (FoundationOne®Liquid CDx) tests were used to classify pts HRRm status.

Results

Pts with HRRm, including BRCAm, were balanced between treatment arms and rPFS favoured abi + ola for all biomarker subgroups, including pts with non-HRRm, HRRm and BRCAm status (HR 0.76, 0.50 and 0.23 respectively; Table). Sensitivity analysis of rPFS by blinded independent central review was consistent. At DCO2 (14/03/22) rPFS was consistent with the primary analysis (25.0 vs 16.4 months; HR 0.67, 95% CI 0.56–0.81). A trend towards improved OS with abi + ola vs abi + pbo continued (maturity 40%; HR 0.83; 95% CI 0.66–1.03). Safety and tolerability results remained stable.

Conclusions

Meaningful rPFS improvement of ≥5 months was observed with abi + ola vs abi + pbo in all assessed biomarker subgroups. Updated results show a continuing trend towards improved OS and support a superior clinical benefit with abi + ola vs abi + pbo as 1L therapy for pts with mCRPC.

*Genes assessed were ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D and RAD54L
^†BRCA1 and/or BRCA2
ITT, intention-to-treat, NR, not reached
HRRm unknown pts (n=18) were excluded from the analysis.

Clinical trial identification

NCT03732820.

Editorial acknowledgement

Medical writing support was provided by Kirstin Spence, PhD, at Mudskipper Business Ltd., funded by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

AstraZeneca.

Funding

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

Disclosure

F. Saad: Financial Interests, Personal, Other, Honoraria: AbbVie; Advanced Accelerator Applications; Astellas Pharma; AstraZeneca; Bayer; BMS; Janssen Oncology; Knight Therapeutics; Merck; Myovant Sciences; Novartis; Pfizer; Sanofi; Financial Interests, Personal, Advisory Role: AbbVie; Advanced Accelerator Applications; Astellas Pharma; AstraZeneca/MedImmune; Bayer; Janssen Oncology; Knight Therapeutics; Myovant Sciences; Novartis; Pfizer; Sanofi; Financial Interests, Institutional, Funding: Advanced Accelerator Applications (Inst); Astellas Pharma (Inst); AstraZeneca (Inst); Bayer (Inst); Bristol Myers Squibb (Inst); Janssen Oncology (Inst); Merck (Inst); Novartis (Inst); Pfizer (Inst); Sanofi (Inst). A.J. Armstrong: Financial Interests, Personal, Advisory Role: Janssen; Novartis; Myovant Sciences; Bayer; Exelixis; Dendreon; Merck; GoodRx; AstraZeneca; FORMA Therapeutics; Astellas Scientific and Medical Affairs Inc.; Pfizer; Bristol Myers Squibb; Exelixis; Financial Interests, Institutional, Funding: Gilead Sciences (Inst); Roche/Genentech (Inst); Bristol Myers Squibb (Inst); AstraZeneca (Inst); FORMA Therapeutics (Inst); Astellas Pharma (Inst); Constellation Pharmaceuticals (Inst); Dendreon (Inst); Pfizer (Inst); Amgen (Inst); Novartis (Inst); Janssen; Financial Interests, Institutional, Royalties: Circulating Tumor Cell Novel Capture Technology (Inst); Financial Interests, Personal, Other, Travel/accommodation: Astellas Scientific and Medical Affairs Inc. A. Thiery-Vuillemin: Financial Interests, Personal, Advisory Board, & public speaking: Pfizer, AstraZeneca, Janssen, Ipsen, Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Sanofi, Novartis, Roche/Genentech, MSD, Astellas Pharma; Financial Interests, Institutional, Funding: Pfizer, Ipsen, Bayer; Financial Interests, Institutional, Invited Speaker: Pfizer, AstraZeneca, Sanofi, JNJ, Novartis, Ipsen, Roche, BMS, MSD, Astellas Pharma, excelixis, UNICANCER / GETUG, Incyte; Financial Interests, Invited Speaker: AstraZeneca, Novartis, BMS; Non-Financial Interests, Member: ASCO, GETUG; Other, Travel, Accommodations: Roche, MSD, JNJ, BMS, AstraZeneca, Pfizer, Astellas Pharma, Ipsen. M. Oya: Financial Interests, Personal, Other, Honoraria: Ayer; Bristol Myers Squibb; Novartis; Ono Pharmaceutical; Pfizer; AstraZeneca, Astellas and Takeda; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Funding: Novartis; Pfizer. N.D. Shore: Financial Interests, Personal, Advisory Role, Consultant/Independent Contractor: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BMS, Boston Scientific, Clarity, Clovis Oncology, Cold Genesys, Dendreon, Exact Imaging, Exact Sciences, FerGene, Foundation Medicine, Genesis Care, Invitae, Janssen, Lantheus, Lilly, MDxhealth, Merck, Myovant. G. Procopio: Financial Interests, Personal, Advisory Board, consultant fees: Astellas, AstraZeneca, Bayer, BMS, Janssen, Ipsen, Merck, MSD, Novartis, Pfizer; Financial Interests, Institutional, Research Grant, research Funding for No Profit Clinical Trial: Ipsen. C. Arslan: Financial Interests, Personal, Advisory Role: Amgen, AstraZeneca, Bristol Myers Squib, Janssen, Novartis, Pfizer, Teva; Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, Bristol Myers Squib, Janssen, Novartis, Pfizer, Teva; Financial Interests, Institutional, Funding: Amgen (Inst), AstraZeneca (Inst), Bristol Myers Squib (Inst), Incyte (Inst), Janssen (Inst), Henlius (Inst), Merck (Inst), Yuhan (Inst), Lilly (Inst), Novartis (Inst), Roche (Inst); Financial Interests, Personal, Other, Travel: Amgen, Astra Zeneca, Bristol Myers Squib, Janssen, Merck, Novartis, Pfizer, Teva. N. Mehra: Financial Interests, Personal, Advisory Board: Pfizer, Roche, MSD, AstraZeneca, Astellas, JNJ; Financial Interests, Institutional, Advisory Board: Janssen; Financial Interests, Institutional, Funding: Astellas, Pfizer; Financial Interests, Personal and Institutional, Funding: Janssen; Financial Interests, Institutional, Invited Speaker: BMS, Janssen, BMS; Financial Interests, Institutional, Research Grant: AstraZeneca, BMS; Non-Financial Interests, Leadership Role, Head of the Prostate Cancer Working group: Dutch Uro-Oncology Study Group; Non-Financial Interests, Principal Investigator, Co-PI: Prospective Bladder Cancer Infrastructure (Netherlands); Non-Financial Interests, Leadership Role: Castration-resistant Prostate Cancer Registry. F. Parnis: Financial Interests, Personal, Advisory Role: Ipsen; Janssen Oncology; Merck Serono. F. Constans Schlurmann: Financial Interests, Personal, Other, Honoraria: AAA, AstraZeneca; Astellas; Bayer; BMS; Janssen; MSD, Pfizer; Financial Interests, Personal, Advisory Role: AAA, AstraZeneca; Astellas; Bayer; BMS; Janssen; MSD, Pfizer; Financial Interests, Personal, Other, Travel: AAA, AstraZeneca; Astellas; Bayer; BMS; Janssen; MSD, Pfizer. M. Sugimoto: Financial Interests, Personal and Institutional, Funding, Honoraria; travel expenses: Janssen Pharmaceutical, AstraZeneca; Financial Interests, Personal, Other, Honoraria: Takeda Pharmaceutical; Financial Interests, Personal and Institutional, Funding, Honoraria, travel, accommodation and expenses: Astellas Pharma; Financial Interests, Personal, Funding, Travel expenses: BMS; Financial Interests, Personal and Institutional, Funding, Travel expenses: MSD; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Personal, Other, Travel expenses: Bayer. O. Sartor: Financial Interests, Personal, Advisory Role: Advanced Accelerator Applications (AAA), Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Inc., Bavarian Nordic, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis, Constellation, Dendreon, EMD Serono, Fusion, Isotopen Technologien Meunchen, Janss; Financial Interests, Personal, Research Grant: Advanced Accelerator Applications, Amgen, AstraZeneca, Bayer, Constellation, Endocyte, Invitae, Janssen, Lantheus, Merck, Progenics, Tenebio. Y. Liu, C. Desai, P.M.D. Del Rosario: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. Poehlein, C.H. Poehlein: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc. N. Clarke: Financial Interests, Personal, Other, Honoraria: Janssen; Bayer; AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Other, Consulting: AstraZeneca. All other authors have declared no conflicts of interest.

Background

Pts with biochemically relapsed prostate cancer (BRPC) following radical prostatectomy (RP) and a short PSA doubling time (PSADT) are at risk for distant metastases. Apalutamide (APA), an androgen receptor (AR) antagonist, and abiraterone acetate plus prednisone (AAP), prolong survival in the metastatic setting. We evaluated if intensification of androgen deprivation therapy (ADT) prolongs biochemical progression-free survival (bPFS) in BRPC.

Methods

PRESTO is a randomized phase III, open-label trial in pts with BRPC and PSADT ≤ 9 months (mo), without distant metastases on conventional imaging (NCT03009981). Pts were randomized 1:1:1 to receive a finite 52-week treatment course with ADT, ADT + APA, or ADT + APA + AAP, stratified by PSADT (< 3 vs 3–9 mo), with post-treatment follow-up. The primary endpoint of bPFS (serum PSA > 0.2 ng/mL following treatment) was compared for each experimental arm vs. control. Secondary endpoints included safety, patient-reported quality of life (QOL), time to testosterone (T) recovery (> 50 ng/dL) (TTTR), metastasis-free survival (MFS) and time to castration resistance (TTCR).

Results

504 pts were randomized to ADT alone (N = 167), ADT + APA (N = 168) or ADT + APA + AAP (N = 169). At first planned interim analysis, both experimental arms significantly prolonged bPFS compared to the control arm (median 24.9 mo for ADT + APA vs 20.3 mo for ADT, HR = 0.52 (95% CI: 0.35–0.77); median 26.0 mo for ADT + APA + AAP vs 20.0 mo for ADT, HR = 0.48 (95% CI: 0.32–0.71)). Median TTTR was 3.9, 3.8 and 4.7 mo in ADT, ADT + APA, and ADT + APA + AAP arms, respectively. The most common grade ≥ 2 adverse event (AE) was hypertension (19.4%, 23.4%, 30.4% in ADT, ADT + APA and ADT + APA + AAP arms, respectively). Eight pts (1.8%) across all treatment arms stopped treatment for AEs. Follow-up for analysis of QOL, MFS and TTCR is ongoing.

Conclusions

More complete AR blockade with APA in addition to ADT prolongs bPFS with a manageable safety profile, without impacting TTTR following a finite duration of treatment. More hypertension was seen in the AAP-containing treatment arm. Intensification of ADT should be considered in high-risk BRPC. Support: AFT, Janssen; https://acknowledgments.alliancefound.org.

Clinical trial identification

NCT03009981.

Legal entity responsible for the study

Alliance Foundation Trials, LLC.

Funding

Janssen.

Disclosure

R. Aggarwal: Financial Interests, Personal, Advisory Board: AstraZeneca, Merck, Novartis, Dendreon, Bayer, Modra, Exelixis, Jubilant Therapeutics, Pfizer; Financial Interests, Institutional, Research Grant: Janssen, Zenith Epigenetics, Amgen. S.T. Tagawa: Financial Interests, Personal, Advisory Board: Convergent Therapeutics, AIkido Pharma; Financial Interests, Personal, Other, Consultant: EMD Serono, Telix Pharma, Blue Earth Diagnostics, POINT Biopharma, Myovant, Bayer, 4D Pharma, Gilead, Pfizer, Janssen, Astellas, AbbVie, Novartis, Seagen, Clarity; Financial Interests, Personal, Stocks/Shares: AIkido Pharma; Financial Interests, Personal, Other, Patent co-inventor: Gilead; Financial Interests, Institutional, Invited Speaker: Medivation, Astellas, Janssen, Amgen, BMS, AstraZeneca, Bayer, Merck, Clovis, Seagen, Gilead, Novartis, POINT Biopharma, Clarity, Ambrx, Phosplatin. M.J. Morris: Financial Interests, Personal, Advisory Board: Oric, Pfizer, Exelixis, Lantheus, AstraZeneca, Amgen, Daiichi, Convergent; Financial Interests, Personal, Stocks/Shares: Doximity; Financial Interests, Institutional, Invited Speaker: Novartis, Corcept, Celgen, Janssen. All other authors have declared no conflicts of interest.