LBA13 - Phase III trial of [177Lu]Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (PSMAfore)

Background

[¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu-PSMA-617) prolongs rPFS and OS in patients (pts) with mCRPC and prior ARPI and taxane therapy. PSMAfore (NCT04689828) examined ¹⁷⁷Lu-PSMA-617 in taxane-naive pts.

Methods

Eligible adults had mCRPC, were candidates for ARPI change after one progression on prior ARPI, and had ≥1 PSMA+ and no exclusionary PSMA– lesions by [⁶⁸Ga]Ga-PSMA-11 PET/CT. Candidates for PARP inhibition and pts with prior systemic radiotherapy (<6 months ago), immunotherapy (except sipuleucel-T), or chemotherapy (except [neo]adjuvant >12 months ago) were ineligible. Randomization was 1:1 to open-label ¹⁷⁷Lu-PSMA-617 (7.4 GBq q6w; 6 cycles) or ARPI change (abiraterone/enzalutamide). Pts randomized to ARPI could crossover to ¹⁷⁷Lu-PSMA-617 following centrally reviewed radiographic progression (rPD). Endpoints included: rPFS (PCWG3/RECIST v1.1; primary), OS (key secondary) (both overall α=0.025, one-sided), FACT-P (secondary) and ORR/DOR (exploratory). Primary analysis was to occur at ∼156 rPFS events and second OS interim analysis (IA) at ∼125 deaths. Crossover-adjusted analysis was the prespecified method for OS by rank-preserving structural failure time (RPSFT).

Results

468 pts were randomized. At primary analysis (median follow-up, 7.3 months; N = 467), the primary endpoint of rPFS was met (HR, 0.41; 95% CI: 0.29, 0.56; p<0.0001); this was similar at second IA (table). At second IA (45.1% of target deaths), 123/146 (84.2%) pts with rPD who discontinued ARPI crossed over; there was a positive OS trend in favour of ¹⁷⁷Lu-PSMA-617 per RPFST but not per unadjusted OS analysis. FACT-P and ORR/DOR favoured the ¹⁷⁷Lu-PSMA-617 arm (table). For ¹⁷⁷Lu-PSMA-617 vs ARPI change, incidence of grade ≥3 AEs was 34% (most common: anaemia, dry mouth) vs 44%, serious AEs 20% vs 28%, and AEs leading to discontinuation 5.7% vs 5.2%. Table: LBA13

^aRadiographic progression or death ^bTime to worsening in FACT-P Total, clinical disease progression, or death ^cSoft tissue only NE, not estimable.

Conclusions

¹⁷⁷Lu-PSMA-617 prolonged rPFS vs ARPI change in taxane-naive pts with PSMA+ mCRPC, with a favourable safety profile.

Drs. O. Sartor, M.J. Morris and K. Fizazi have equally contributed to the study.

Clinical trial identification

EudraCT 2020-003969-19. NCT04689828. Protocol release date: 13 January 2022.

Editorial acknowledgement

Under direction of the authors, Katie Willetts, PhD, Sarah Sabir, PhD and Matt Cottingham, PhD, of Oxford PharmaGenesis, Oxford, UK provided medical writing support, which was funded by Novartis, in accordance with Good Publication Practice (GPP 2022) guidelines.

Legal entity responsible for the study

Novartis.

Funding

Novartis.

Disclosure

O. Sartor: Financial Interests, Personal, Speaker, Consultant, Advisor: Advanced Accelerator Applications, Amgen, ArtBio, Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Clarity, Clovis, Constellation, Convergent, Dendreon, EMD Serono, Foundation Medicine, Fusion, Hengrui, Isotopen Technologien Meunchen, Janssen, Merck, Morphimmune, Myovant, Myriad, NorthStar, Novartis, PointBiopharma, Pfizer, Ratio, Sanofi, Telix, Theragnostics; Financial Interests, Institutional, Research Grant: Advanced Accelerator Applications, Amgen, Janssen, Merck; Financial Interests, Institutional, Research Funding: Bayer, Constellation; Non-Financial Interests, Institutional, Research Grant: Endocyte, Invitae, Progenics, Tenebio; Non-Financial Interests, Personal, Speaker, Consultant, Advisor: Genzyme, Noria Therapeutics, Inc, Noxopharm, Progenics, Tenebio, Tessa, Z-alpha; Financial Interests, Personal, Stocks/Shares: Ratio, Tellix. D.E. Castellano Gauna: Financial Interests, Personal, Advisory Board: Pfizer, Roche, BMS, Janssen, Astellas, MSD, Ipsen, AstraZeneca, Novartis, GSK; Financial Interests, Institutional, Local PI: Pfizer, Roche, MSD, BMS, AstraZeneca, Janssen, Astellas, Ipsen, Exelisis, Eisai, Lilly, Bayer, GSK, Clovis, QED Therapeutics; Non-Financial Interests, Personal, Other, Executive member: SOGUG (Spanish Oncology Genito-Urinary Group) Foundation. K. Herrmann: Financial Interests, Personal, Advisory Board: Bayer, Adacap/Novartis, Curium, Boston Scientific, GE Healthcare, AstraZeneca; Financial Interests, Personal, Invited Speaker: Sirtex, Siemens Healthineers, Monrol; Financial Interests, Personal, Other, Consultant: Amgen; Financial Interests, Personal, Other, DMSB: ymabs; Financial Interests, Personal, Advisory Board, Scientific Advisor: AdvanceCell; Financial Interests, Personal, Advisory Board, Advisor, Consultant: Janssen; Financial Interests, Personal, Advisory Board, Consultant: Eco1R, Fusion Pharmaceuticals, Genentech; Financial Interests, Personal, Member of Board of Directors: Sofie Biosciences, Pharma 15; Financial Interests, Personal, Ownership Interest: Sofie Biosciences; Financial Interests, Personal, Stocks/Shares: Aktis Oncology, AdvanCell, Convergent Therapeutics; Non-Financial Interests, Leadership Role, Chair Oncology&Theragnostics Committee: EANM. J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals, Menarini Silicon Biosystems, ImCheck Therapeutics, Crescendo; Financial Interests, Institutional, Advisory Board: Harpoon; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GSK, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, Crescendo Biologics, Menarini Silicon Biosystems; Non-Financial Interests, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, Menarini Silicon Biosystems, GSK, Harpoon, Janssen, Pfizer, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals, Crescendo, ImCheck Therapeutics; Non-Financial Interests, Institutional, Product Samples: Daiichi, Bayer, Merck Serono, AstraZeneca, Harpoon, Pfizer, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GSK. N.D. Shore: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, 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, Genetech, Guardant, Ferring, Foundation Medicine, Immunitybio, Incyte, Minomic, NGM, Nonagen, Novartis, PlatformQ, Profound, Promaxo, Protara, Vessi; Financial Interests, Personal, Member of Board of Directors: Photocure. 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. 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. A. Flechon: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Bayer, Jannssen, Loxo, Pfizer; Financial Interests, Personal, Advisory Role: Astellas; Financial Interests, Personal, Ownership Interest: Novartis, Astellas, AstraZeneca, Bayer, Janssen, Loxo, Pfizer. X.X. Wei: Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Institutional, Coordinating PI: Bristol Myers Squibb. H. Mahammedi: Financial Interests, Personal, Advisory Board: BMS, Bayer, Janssen, MSD, Astellas, Pfizer; Financial Interests, Personal, Invited Speaker: Novartis, Amgen; Financial Interests, Institutional, Advisory Board: Merck; Financial Interests, Personal, Steering Committee Member: curium; Non-Financial Interests, Principal Investigator: BMS, Janssen, Roche, MSD, Pfizer, Novartis, curium, Exelixis, AstraZeneca. 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. H. Studentova: Financial Interests, Personal, Advisory Board: Novartis, Bayer, Janssen, Astellas, Ipsen, MSD, Pfizer, Merck, BMS; Financial Interests, Personal, Principal Investigator: Novartis, MSD; Financial Interests, Personal, Invited Speaker: Janssen, Ipsen, MSD, Novartis, Merck, BMS. S. Ghebremariam: Financial Interests, Personal, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks/Shares: Novartis. E. Kpamegan: Financial Interests, Personal, Full or part-time Employment: Novartis. N. Delgoshaie: Financial Interests, Personal, Full or part-time Employment: Novartis. K. Lehnhoff: Financial Interests, Personal, Full or part-time Employment: Novartis. M.J. Morris: Financial Interests, Personal, Advisory Board: Oric, Pfizer, Exelixis, Lantheus, AstraZeneca, Amgen, Daiichi, Convergent, Clarity Pharmaceuticals, Blue Earth Diagnostics, POINT Biopharma, Telix, Z-alpha; Financial Interests, Personal, Stocks/Shares: Doximity; Financial Interests, Personal, Invited Speaker: Progenics, ITM Isotope Technologies; Financial Interests, Institutional, Coordinating PI: Novartis, Celgen; Financial Interests, Institutional, Local PI: Corcept, Janssen, Astellas; Non-Financial Interests, Advisory Role: Bayer, Janssen Oncology, Novartis; Other, Travel/lodging at conference: APCCC; Other, Travel to conference: AstraZeneca. K. Fizazi: Financial Interests, Institutional, Advisory Board: Astellas, Bayer, Janssen, AAA, MSD, AstraZeneca, Novartis/AAA, Pfizer, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Astellas, Bayer, Janssen, Sanofi, MSD, AstraZeneca, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Curevac, Orion; Financial Interests, Institutional, Research Grant, Trial chair: Pfizer, Bayer, AstraZeneca, Orion, MSD, BMS, Janssen; Financial Interests, Personal, Advisory Board, February 2022: Arvinas; Financial Interests, Personal, Advisory Board, April 2022: Macrogenics; Non-Financial Interests, Principal Investigator, Chair of the 7DX phase 3 trial: BMS; Non-Financial Interests, Principal Investigator, Chair of the Docetaxel-pembrolizumab phase 3 trial: Merck; Non-Financial Interests, Principal Investigator, Chair of the Darolutamide BCR phase 3 trial: Bayer; Non-Financial Interests, Principal Investigator, Chair of the PSMAfore phase 3 trial: AAA/Novartis; Non-Financial Interests, Principal Investigator, Chair of the CYPIDES ODM-208 Phase I-II trial: Orion; Non-Financial Interests, Principal Investigator, Chair of the STESIDES ODM-209 Phase I-II trial: Orion; Non-Financial Interests, Principal Investigator, Chair of the CAPITELLO 281 phase 3 trial: AstraZeneca; Non-Financial Interests, Principal Investigator, Chair of the TRITON-3 phase 3 trial: Clovis; Non-Financial Interests, Principal Investigator, Chair of the TALAPRO-2 and TALAPRO-3 phase 3 trials: Pfizer; Non-Financial Interests, Principal Investigator, Chair of the RADIANT phase 3 trial: Bayer. All other authors have declared no conflicts of interest.