Background

The optimal timing of RT after RP for prostate cancer is uncertain. RADICALS-RT compared the efficacy and safety of adjuvant RT (aRT) versus an observation policy with salvage RT for early PSA failure (Obs+sRT). We previously reported an early outcome measure (OM): bPFS, and now have enough events to report on the primary OM, freedom from distant metastases (FFDM).

Methods

Patients with post-op PSA≤0.2ng/ml and ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, or pre-op PSA≥10ng/ml) were randomised ≤22wk after RP to aRT or Obs+sRT for PSA failure: PSA ≥0.1ng/ml or 3 consecutive rises. Stratification factors were Gleason score, margin status, planned RT volume (prostate bed only, prostate bed + pelvis), RT schedule (52.5Gy/20f, 66Gy/33f) and centre. The primary OM was FFDM with >1200 pts needed for 80% power to detect an improvement from 90% to 95% at 10yr with aRT. Secondary OMs include overall survival, safety & patient reported OMs (1, 5, 10yr). Standard survival analysis methods were used.

Results

1396 pts were randomised (697 aRT, 699 Obs+sRT) from Oct-2007 to Dec-2016 (82% UK, 13% Denmark, 4% Canada, 1% Ireland). Median age was 65yrs and 37% (517/1396) had a CAPRA-S score of 6+. Data were frozen May 2022 and median follow-up was 8yrs. 93% (650/697) aRT started RT within 5mo; 39% (270/699) Obs+sRT started RT. Median PSA at time of sRT was 0.2ng/ml. 24% (156/650) aRT and 27% (72/270) Obs+sRT reported HT with their RT. With 80 events, FFDM at 10 yrs was 93% for aRT v 90% for Obs+sRT (HR= 0.68 (95%CI 0·43-1·07, p=0·095). Overall survival at 10-yrs was 88% vs 87% (HR=0.98 (95%CI 0.67 to 1.44, p=0.92). Self-reported urinary incontinence and faecal incontinence were worse at 1yr for aRT (p<0.001).

Conclusions

RADICALS-RT is the largest study ever conducted addressing the value of adjuvant RT in prostate cancer. Final results from RADICALS-RT show no evidence of a meaningful benefit for aRT after RP in this patient group. Adjuvant RT increases risk of urinary & bowel morbidity. An observation policy with salvage RT for PSA failure should be the current standard after RP.

Clinical trial identification

NCT00541047.

Editorial acknowledgement

None

Legal entity responsible for the study

UCL.

Funding

No companies involved.

Disclosure

C. Parker: Financial Interests, Personal, Advisory Board: ITM Radiopharma; Financial Interests, Institutional, Advisory Board: AAA. N. Clarke: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Bayer. W. Cross: Financial Interests, Personal, Advisory Board: Janssen, Bayer. C. Catton: Financial Interests, Institutional, Funding: Canadian Cancer Trials Group, AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer, AbbVie, Janssen, Astellas. H.A. Payne: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Ferring, Ipsen. 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. H. Lindberg: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Bayer, Sanofi-Aventis, Roche; Non-Financial Interests, Personal, Other: Janssen, Astellas, Bayer, Sanofi-Aventis. A. Zarkar: Financial Interests, Personal, Other: Bayer; Financial Interests, Personal, Advisory Board: Astellas, Amgen, Pfizer, EUSA Pharma. 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. All other authors have declared no conflicts of interest.

Background

Xaluritamig is a novel bispecific XmAb® 2+1 T-cell engager with two STEAP1 binding sites designed to facilitate T-cell–mediated lysis of STEAP1-expressing cells. We report results from the dose exploration of xaluritamig monotherapy in a first-in-human study for patients (pts) with mCRPC.

Methods

Eligible pts had mCRPC refractory to prior novel hormonal therapy and 1–2 taxane regimens, ECOG 0–1, and adequate organ function. Xaluritamig was administered as an IV weekly (QW) or Q2W with various dose levels/schedules (DLs). Study objectives were to evaluate safety, tolerability, antitumor activity, PK, and determine the MTD and RP2D.

Results

As of 23 March 2023, 97 pts in 15 DLs received ≥1 dose of xaluritamig. Median (range) age was 67 (40–86) years; 67 pts (69.1%) had received > 3 prior lines of therapy. Treatment emergent adverse events (TEAEs) were reported in 100% of pts (grade ≥3, 74.2%); 95.9% reported treatment-related AEs (TRAEs) (grade ≥3, 52.6%). The most common AEs were cytokine release syndrome (CRS; 72.2%), fatigue (52.6%), anemia (45.4%), pyrexia (40.2%), and myalgia (39.2%). CRS was primarily grade 1 or 2, one event being grade 3 (no grade 4/5 CRS; cycle 1). In the DL15 QW cohort, 3 of 6 DLT evaluable subjects experienced DLTs, defining DL14 QW as the MTD. TRAEs leading to discontinuation occurred in 17.5% of pts. PSA50 (≥ 50% PSA decline) responses occurred in 42 pts (47.2%); PSA90, in 24 pts (27.0%) (Table). PSA responses were more frequent at higher DLs (DL8–15) than in lower DLs (DL1–7). Overall, RECIST responses included 15 (22.7%) confirmed PR and 30 (45.5%) SD. At higher DLs, 14 pts (38.9%) had confirmed PR and 12 (33.3%) SD. Preliminary PK showed dose-proportional increase in exposure with a mean terminal half-life of approximately 3-4 days.

Table: 1765O

Conclusions

Xaluritamig was tolerable with low-grade CRS (occurring primarily cycle 1) with encouraging preliminary efficacy in heavily pretreated pts with mCRPC.

Clinical trial identification

NCT04221542.

Legal entity responsible for the study

Amgen.

Funding

Amgen.

Disclosure

W. Kelly: Financial Interests, Personal, Invited Speaker: Janssen Oncology; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Institutional, Research Funding: Novartis, Janssen Oncology, Bayer, Exelixis, Seattle Genetics, Endocyte, Amgen, BioClin Therapeutics, Sarah Cannon Research Institute, Hoffman-LaRoche, Regeneron; Financial Interests, Personal, Other, Travel, accommodations, expenses: Janssen Oncology. D. Danila: Financial Interests, Institutional, Research Grant: US Department of Defense, American Society of Clinical Oncology, American Society of Clinical Oncology, Stand Up 2 Cancer (MSKCC), Amgen (MSKCC), Janssen Research & Development (MSKCC), Astellas (MSKCC), Medivation (MSKCC), Medivation (MSKCC), Genentech (MSKCC), CreaTV (MSKCC); Financial Interests, Personal, Advisory Role: Angle LLT, Axiom LLT, Janssen Research & Development, AstraZeneca, BioView LTD, Clovis, Astellas, Medivation, Pfizer, Agensys, Merck. C. Lin: Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, Eli Lilly, Novartis, Roche; Financial Interests, Personal, Advisory Role: AbbVie, Bayer, Blueprint Medicines, Boehringer-Ingelheim, BMS, Daiichi Sankyo, Merck KGaA, Novartis, PharmaEngine, Rakuten; Financial Interests, Personal, Other, Travel support: BeiGene, Eli Lilly, Impact. J. Lee: Financial Interests, Personal, Stocks/Shares: Johnson & Johnson, Amgen, Merck, Innovent Biologics, Black Diamond Therapeutics, Karyopharm Therapeutics, Zymeworks; Financial Interests, Institutional, Research Grant: Pfizer, Janssen, Novartis, BMS, Roche, Genentech, AstraZeneca, MSD, Bayer Schering Pharma, Seagen, GI Innovation, Amgen, Oscotec; Financial Interests, Personal, Advisory Role: Merck, AstraZeneca, Sanofi Korea, Oscotec, Astellas Korea. N. Matsubara: Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Advisory Role: Janssen, MSD, Eli Lilly; Financial Interests, Institutional, Research Grant: Janssen, AstraZeneca, Bayer, MSD, Taiho, Astellas, Amgen, Eisai, Eli Lilly, Takeda, Pfizer, Seagen, Chugai, AbbVie, Novartis. P. Ward: Financial Interests, Personal, Advisory Role: Amgen. A.J. Armstrong: Financial Interests, Institutional, Research Grant: Astellas, Pfizer, Bayer, Janssen, Dendreon, BMS, AstraZeneca, Merck, Forma, Celgene, Amgen; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Personal, Advisory Role: Astellas, Epic Sciences, Pfizer, Bayer, Janssen, Dendreon, BMS, AstraZeneca, Merck, Forma, Celgene, Clovis, Exact Sciences, Myovant, Exelixis, GoodRx, Novartis. D. Pook: Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Advisory Board: BMS, MSD, Ipsen, Pfizer, Eisai, Astellas; Financial Interests, Institutional, Local PI: BMS, Astellas, Roche, MSD, Amgen; Financial Interests, Institutional, Coordinating PI: Pfizer, Ipsen. M. Kim: Financial Interests, Personal, Invited Speaker: Astellas, MSD, Novartis; Financial Interests, Personal, Advisory Board: BMS/Ono Pharmaceutical, Eisai, Ipsen, MSD, Pfizer, Yuhan. T. Dorff: Financial Interests, Personal, Advisory Board: AstraZeneca, Janssen, Sanofi and Bayer. S. Fischer: Financial Interests, Institutional, Invited Speaker: Janssen; Financial Interests, Institutional, Advisory Role: Ipsen. L.G. Horvath: Financial Interests, Personal, Advisory Board, Honorarium donated back to Chris O'Brien Lifehouse (My hospital): Imagion Biosystems; Financial Interests, Institutional, Invited Speaker: Astellas, Janssen, Amgen; Financial Interests, Institutional, Advisory Board: Astellas, Bayer; Financial Interests, Personal, Member of Board of Directors, No payment: ANZUP (Australia and New Zealand Urogenital and Prostate) Clinical Trials Group; Financial Interests, Personal, Stocks/Shares, Stock options: Imagion Biosystems; Financial Interests, Personal, Stocks/Shares: My Emergency Doctor; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Local PI, MK7684-001MK3475-991: MSD; Financial Interests, Institutional, Local PI, AMG160 Phase 1AMG509 Phase 1AMG757 Phase 1: Amgen; Financial Interests, Institutional, Local PI, 9785-CL-0335 (ARCHES): Astellas; Financial Interests, Institutional, Local PI, SHR3680-002: Jiangsu Hengrui Medicines; Financial Interests, Institutional, Local PI, TALAPRO2, TALAPRO3: Pfizer; Financial Interests, Institutional, Local PI, CYCLONE-2, CYCLONE-3: Eli Lilly; Financial Interests, Institutional, Steering Committee Member, ENZAMET, ENZARAD, DASL-HiCAP, GUIDE, ANZAdapt: ANZUP; Financial Interests, Institutional, Local PI, GALAHADACIS Prevalence: Janssen Cilag; Financial Interests, Institutional, Local PI, GSK204697: GSK; Financial Interests, Institutional, Local PI, XL184-021: Exelexis; Financial Interests, Institutional, Local PI, BGB-A317BGB-283BGB-A317-290: BeiGene; Financial Interests, Institutional, Local PI, FPT155-001: Five Prime; Financial Interests, Institutional, Local PI, AB928CSP0003: ARCUS; Financial Interests, Institutional, Local PI, ATG-017 and ATG-019: Antagene; Financial Interests, Institutional, Local PI, JANUX007: Janux; Financial Interests, Institutional, Local PI, ENZAMET, ENZA-P, Upfront PSMA, ANZAdapt, GUIDE: ANZUP; Financial Interests, Institutional, Local PI, HP-518-CS-001: Hinova; Financial Interests, Institutional, Local PI, Petranha: AstraZeneca. Z. Yang, J. Connarn, J. Stieglmaier: Financial Interests, Personal, Full or part-time Employment: Amgen; Financial Interests, Personal, Stocks or ownership: Amgen. G. Jurida: Financial Interests, Personal, Full or part-time Employment: Amgen. H. Penny: Financial Interests, Full or part-time Employment: Amgen. L.J. Appleman: Financial Interests, Personal, Advisory Board: AADi; Financial Interests, Personal, Research Funding: Janssen Oncology; Financial Interests, Institutional, Research Funding: Pfizer, Exelixis, BMS, Astellas Pharma, Novartis, Bayer, Merck, Genentech/Roche, AVEO, Peloton Therapeutics, Calithera Biosciences, Seattle Genetics, Inovio Pharmaceuticals, Eisai, Lilly, Amgen, Surface Oncology, BioNTech AG, Epizyme, Ipsen, Arvinas; Financial Interests, Personal, Other: Pfizer; Non-Financial Interests, Personal, Other: Exelixis. All other authors have declared no conflicts of interest.

Background

Enzalutamide (ENZA) and Lutetium-177-prostate-specific membrane antigen-617 (LuPSMA) both improve overall survival (OS) in mCRPC. Preclinical and clinical data suggest synergy for LuPSMA with androgen receptor pathway inhibitors (ARPI) in mCRPC. We evaluated the activity and safety of combining ENZA with adaptive-dosing of LuPSMA vs ENZA alone as first-line treatment for mCRPC.

Methods

Participants (pts) had mCRPC not previously treated with chemotherapy or ARPI (prior abiraterone and/or docetaxel for hormone-sensitive disease were allowed), ⁶⁸Ga-PSMA-positive disease on positron emission tomography (PET), and at least 2 risk factors associated with early progression on ENZA. Pts were randomised (1:1) to either ENZA 160 mg daily (ENZA-alone), or ENZA 160 mg daily plus adaptive dosing LuPSMA 7.5 GBq on days 15 and 57, with 2 further doses of LuPSMA if persistent PSMA-positive disease on interim ⁶⁸Ga-PSMA PET (day 92) (ENZA+LuPSMA). The primary endpoint was PSA-progression free survival (PSA-PFS). Secondary endpoints include radiological PFS (rPFS), PSA50% and PSA90% response rates (PSA50RR, PSA90RR), adverse events (AE), and OS.

Results

We randomised 162 pts from Aug 2020 to Jul 2022: median age 71 (range 45-96), prior docetaxel in 54%, and prior abiraterone in 13%. Imaging screen failure rate was 18% (40/220). 16% (13) of pts received between 2-3 doses of LuPSMA and 81% (67) received 4 doses. The median follow up was 20 months (IQR 18-21). PSA-PFS was longer with ENZA+LuPSMA vs ENZA-alone (median 13 vs 7.8 months; HR 0.43 [95%CI 0.29-0.63], p<0.001). PSA50RR and PSA90RR were higher with ENZA+LuPSMA vs ENZA-alone: 93% (77/83) vs 68% (54/79) (p<0.001) and 78% (65/83) vs 37% (29/79) (p<0.001) respectively. Analysis of rPFS (ongoing) will be presented. SAE were reported in 33% (27/81) of pts assigned ENZA+LuPSMA vs 35% (28/79) ENZA-alone.

Conclusions

The addition of adaptive-dosing of LuPSMA (2-4 doses) to ENZA improved PSA-PFS, PSA50RR, and PSA90RR. Our data supports enhanced anti-cancer activity with the use of adaptive-dosed LuPSMA together with ENZA as first-line treatment in mCPRC.

Clinical trial identification

NCT04419402.

Legal entity responsible for the study

ANZUP Cancer Trials Group Limited.

Funding

Prostate Cancer Research Alliance (PCRA), Movember Foundation, Cancer Australia, Endocyte – a Novartis company, Astellas, Australasian Radiopharmaceutical Trials Network (ARTnet), St Vincent’s Clinic Foundation, Roy Morgan Research, GenesisCare, Australian Nuclear Science and Technology Organisation (ANSTO) and MIM Software

Disclosure

L. Emmett: Financial Interests, Personal, Invited Speaker: AstraZeneca, telix; Financial Interests, Institutional, Invited Speaker: astellas; Financial Interests, Personal, Advisory Board: Clarity Pharma; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Coordinating PI: Clovis. M. Crumbaker: Non-Financial Interests, Advisory Role, 1 off advisory board meeting - March 2023: Astellas. A.M. Joshua: Financial Interests, Personal, Stocks/Shares: Pricillium Therapeutics; Financial Interests, Institutional, Local PI, No financial interest: AstraZeneca, BMS, Eisai, Ipsen, Janssen, Merck Serono, Neolukin, Novartis, Noxopharm, Pfizer, Sanofi; Financial Interests, Institutional, Steering Committee Member, No financial interest: Iqvia; Non-Financial Interests, Advisory Role: AstraZeneca, Bayer, BMS, Corvus, Eli-Lilly, Janssen, Macrogenics, Mayne, Merck, Pfizer, Roche. A.J. Weickhardt: Financial Interests, Personal, Advisory Board: Merck, Ipsen, Pfizer; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Coordinating PI, PCR MIB funding: Merck. R.J. Francis: Financial Interests, Institutional, Other, Consultancy activities: AIQ Solutions; Financial Interests, Personal, Stocks/Shares, Declaration relates to family member (spouse): AIQ Solutions; Financial Interests, Institutional, Funding, Collaborative research agreement between University of Western Australia and AIQ Solutions.: AIQ Solutions. 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. D.A. Pattison: Financial Interests, Personal, Invited Speaker, Independent educational presentation on thyroid cancer.: Eisai; Financial Interests, Personal, Advisory Board: Ipsen. I.D. Kirkwood: Financial Interests, Institutional, Stocks/Shares: Sonic Healthcare, Resmed, CSL. 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 Principal 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. C. Gedye: Financial Interests, Personal, Advisory Board: Cadex Genomics, BCAL Diagnostics; Financial Interests, Institutional, Coordinating PI: Bristol Myers Squibb, Amgen, Merck Sharpe Dohme; Financial Interests, Institutional, Steering Committee Member: Ipsen. M. Hofman: Financial Interests, Personal, Invited Speaker: Astellas, AstraZeneca; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Institutional, Research Grant: Novartis, Isotopia Molecular Imaging, Bayer; Other, Research Support: Movember, Prostate Cancer Foundation (PCF), Prostate Cancer Foundation of Australia (PCFA). M.R. Stockler: Financial Interests, Institutional, Research Grant, DASL: Bayer; Financial Interests, Institutional, Research Grant, ENZAMET & ENZARAD: Astellas; Financial Interests, Institutional, Research Grant, KEYPAD: Amgen, MSD; Financial Interests, Institutional, Research Grant, NIVORAD: BMS; Financial Interests, Institutional, Research Grant: Pfizer, Roche; Financial Interests, Institutional, Research Grant, ADELE: BeiGene; Financial Interests, Institutional, Research Grant, PARAGON2: Novartis; Financial Interests, Institutional, Other, Study Drug for Cannabis CINV Trial: Tilray. I.D. Davis: Financial Interests, Personal, Full or part-time Employment, Professor of Medicine and Head of Eastern Health Clinical School: Monash University; Financial Interests, Personal, Full or part-time Employment, Professor of Medicine; Head, Eastern Health Clinical School; medical oncologist: Eastern Health; Financial Interests, Personal, Royalties, Authorship royalties for: Health Press; Financial Interests, Personal, Other, Remuneration for associate editor role in Therapeutic Advances in Medical Oncology: SAGE; Financial Interests, Institutional, Local PI, Institutional support for clinical research: Movember Foundation, Merck/MSD, Bristol Myers Squibb, Exelixis, Astellas, Pfizer, AstraZeneca, Roche / Genentech, Eisai, Bayer, Janssen, Ipsen, Seagen; Non-Financial Interests, Member of Board of Directors, Director and Chair: ANZUP Cancer Trials Group; Non-Financial Interests, Advisory Role, All honoraria and payments are made directly to ANZUP Cancer Trials Group with no pass-through payment: Roche, Eisai, Pio Therapeutics, Xennials Therapeutics, Telix Therapeutics; Non-Financial Interests, Other, Member of Council: Clinical Oncology Society of Australia; Non-Financial Interests, Member: ASCO, Clinical Oncology Society of Australia, Medical Oncology Group of Australia, American Association for Cancer Research, Australian Academy of Health and Medical Sciences. All other authors have declared no conflicts of interest.

Background

RT + ltADT (18-36 months) is a standard-of-care in the treatment of HR/LA-PC. Efforts are ongoing to evaluate intensification of systemic therapy beyond ADT to further improve outcomes. We evaluated 5-year metastasis-free survival (MFS) rates in subgroups of patients (pts) with HR/LA-PC to define patients more likely to benefit from treatment intensification, and guide design and interpretation of adjuvant trials in HR/LA-PC.

Methods

IPD from patients with HR/LA-PC (as defined by any of the following 3 risk factors [RFs]: Gleason ≥8, ≥cT3, PSA >20; or cN1) treated with RT+ltADT in RCTs collated by ICECaP were pooled. 5-year MFS was calculated by Kaplan-Meier method in various risk-groups and by number of RFs. Multivariable Cox regression estimated hazard ratios (HR) for the 3 RFs and cN1 disease, stratified by trials and years of enrolment. MFS was defined as distant metastasis on conventional imaging or death from any cause.

Results

3604 pts with HR/LA-PC treated with RT+ltADT on 10 randomized trials between 1987-2016 were eligible. Median age was 68 and median PSA was 24 (IQR 12-48). 2602 (72%) were cT3/4, 1942 (54%) had Gleason 8-10 and 422 pts (12%) had cN1 disease. The HR for MFS was 1.5 (95% CI 1.4-1.7) for Gleason ≥8, 1.2 (1.1-1.4) for PSA>20, 1.2 (1.1-1.4) for cT3/T4, and 1.8 (1.5-2.1) for cN1. 5-year MFS (%, 95% CI) rate was 83 (81-85), 78 (75-80) and 77 (73-80) for pts with 1, 2 and 3 RFs respectively, and 68 (63-72) for cN1 disease. Table shows 5-yr MFS rates in various subgroups.

Table: 1770O

Conclusions

Pts with HR/LA-PC treated with RT+ltADT who had ≥2 RFs or cN1 disease had 5-yr MFS rates <80% and are the ones most likely to benefit from treatment intensification. This will guide patient counselling and the design and interpretation of adjuvant trials in HR/LA-PC.

Legal entity responsible for the study

The authors.

Funding

Sanofi; Dendreon; Janssen; Astellas/Pfizer; Bayer; PCF.

Disclosure

All authors have declared no conflicts of interest.