Abstract 1374P
Background
Earlier time-to-event (TTE) endpoints than overall survival (OS) are needed to accelerate drug development and regulatory approval in metastatic castration-resistant prostate cancer (mCRPC). In the phase 3 VISION trial, [177Lu]Lu-PSMA-617 (lutetium (177Lu) vipivotide tetraxetan) plus SoC prolonged PCWG3-defined radiographic progression-free survival (rPFS) and OS, and delayed time to first symptomatic skeletal event (SSE) or death in patients with mCRPC. This post hoc analysis aimed to estimate correlations between these TTE endpoints and provide further evidence for rPFS as an early endpoint for regulatory approval, in the context of radioligand therapy (RLT).
Methods
Because censoring prevented observation of events, three Spearman’s rank correlation methods adapted to TTE endpoints were used to estimate the strength of association between rPFS, OS and time to first SSE. Correlation estimations were used for both VISION protocol data (as is) and imputed data. For the latter, imputation methods were used for rPFS and OS to adjust for informative censoring; for time to first SSE, patients were censored at 30 days after first treatment change or death (Table).
Results
The three Spearman’s rank correlation methods provided similar results (Table). The correlation between rPFS and OS was moderate-to-strong using both protocol and imputed data, with estimates of ∼0.7 or higher. Stronger associations between rPFS/OS and SSE were observed for protocol vs. imputed data; however, SSE data mainly contained information on OS for the protocol data (data not shown). Table: 1374P
Spearman’s correlation between TTE endpoints
| TTE endpoints | Restricted | Highest rank | Iterative multiple imputation |
| rPFS a and OS a | 0.69 (0.58, 0.80) | 0.69 (0.63, 0.74) | 0.74 (0.70, 0.77) |
| rPFS b and OS b | 0.71 (0.59, 0.79) | 0.76 (0.69, 0.82) | 0.76 (0.72, 0.81) |
| rPFS a and SSE c | 0.19 (0.09, 0.30) | 0.11 (0.06, 0.17) | 0.23 (0.08, 0.36) |
| OS a and SSE c | 0.27 (0.15, 0.42) | 0.16 (0.10, 0.23) | 0.31 (0.15, 0.45) |
Estimates (95% confidence interval). Imputed data were used for the correlation between rPFS/OS and SSE.aEarly censored data imputed; bProtocol data; cPatients censored at 30 days after first treatment change or death.
Conclusions
This analysis, the first for an RLT, shows a moderate-to-strong correlation between rPFS and OS, indicating that rPFS, as defined by PCWG3, may be relevant as an early endpoint for regulatory approval and clinical trial design in this context. Correlations between TTE endpoints and PRO scores will complement this analysis.
Clinical trial identification
NCT03511664, 30 April 2018.
Editorial acknowledgement
Under the guidance of the authors, Karim Bensaad, PhD from Oxford PharmaGenesis (Oxford, UK) provided medical writing support for this abstract, with funding from Advanced Accelerator Applications, a Novartis Company.
Legal entity responsible for the study
Advanced Accelerator Applications, a Novartis Company.
Funding
Advanced Accelerator Applications, a Novartis Company.
Disclosure
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. J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Financial Interests, Institutional, Advisory Board: Harpoon; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Vertex Pharmaceuticals, Sanofi Aventis, Sierra Oncology, Taiho, Crescendo Biologics; Non-Financial Interests, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Non-Financial Interests, Institutional, Product Samples: Daiichi, Bayer, Pfizer, Merck Serono, AstraZeneca, Harpoon, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GlaxoSmithKline. J. Nagarajah: Financial Interests, Personal, Advisory Board: Novartis, Curium. X.X. Wei: Financial Interests, Institutional, Principal Investigator: BMS. V.S. Koshkin: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Board: Clovis, Janssen, Pfizer, EMD Serono, Seagen, Astellas, Dendreon, Guidepoint, GLG, ExpertConnect; Financial Interests, Institutional, Research Grant: Endocyte, Nektar, Clovis, Janssen, Taiho; Financial Interests, Institutional, Funding: Prostate Cancer Foundation. A. Vickers: Other, Institutional, Funding: AAA. R. Ghouse: Financial Interests, Personal, Stocks/Shares: Advanced Accelerator Applications, International S.A. 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. K. Fizazi: Financial Interests, Institutional, Advisory Board: Astellas, Bayer, Janssen, AAA, MSD, AstraZeneca, Novartis/AAA, Pfizer; 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; 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. All other authors have declared no conflicts of interest.