Reply to Potential underestimation of cerebrovascular events in the PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data
Year: 2020
Type: letter
Abstract: We thank Dores et al for their interest in our recently published report describing results from the PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED) registry.1 This prospective registry was required by the US Food and Drug Administration to evaluate a potential cerebrovascular event (CVE) signal observed in the sipuleucel-T clinical program through the use of prespecified methodology with which to assess CVEs in a larger population.2 With respect to their concern about study methodology, men could be enrolled either prospectively before receiving sipuleucel-T or “retrospectively,” which was defined as “within 6 months after the first leukapheresis.” Retrospective enrollment was allowed mainly to enhance timely accrual to the registry by allowing patients who had initiated sipuleucel-T but were not enrolled in the registry to be included. In all, 711 men (27%) were retrospectively and 1191 men (73%) were prospectively enrolled. Of those who enrolled retrospectively, approximately one-half enrolled within 28 days after the first leukapheresis, 75% enrolled within 69 days, and only 1 patient enrolled 199 days after the first infusion. Understanding this distribution should lessen concern that patients who enrolled retrospectively would have passed the usual time frame in which CVEs have been noted (ie, 6-7 months after infusion of sipuleucel-T). Furthermore, CVE rates per 100 person-years were found to be similar for those enrolled prospectively or retrospectively at 1.293 (95% CI, 0.810-1.958) and 1.376 (95% CI, 0.974-1.889), respectively. Another concern raised by Dores et al was the definition of CVE beyond that described in our article.1 Unlike previous studies, CVEs in PROCEED were defined prospectively in the protocol as was the adjudication process: “…CVEs will include all completed strokes, both ischemic and hemorrhagic in etiology, intracranial hemorrhage and transient ischemic attacks (TIA)…”3 The adjudicator applied similar, prospectively defined criteria: major, nonfatal CVE, nonfatal stroke (acute, focal neurologic event that persisted for >24 hours ideally confirmed by imaging) with evaluation of ischemic stroke subtypes as per TOAST criteria4 and primary intracranial hemorrhage as per Stroke Data Bank criteria5; and nonmajor CVEs including TIAs without acute infarction and fatal CVEs. Hence, embolic strokes were included; however, bleeding due to head trauma or metastatic lesions and neurological symptoms due to anoxia or hypoxia were not considered to be CVEs. The third concern relates to the impact of the adjudication process on the reported CVE rate. The adjudication algorithm was prespecified and all CVEs and serious adverse events that might have been a CVE were reviewed. The adjudicator received relevant source documentation and could request additional details to be able to identify whether the event was a CVE. We agree that retrospective case review can be challenging and further that some individual cases might be equivocal. Nonetheless, the adjudicator was an independent, internationally recognized expert in stroke with experience in the adjudication process and his analysis was accepted by regulatory authorities. Dores et al correctly note that a comparison of CVE rates with the preceding phase 3 sipuleucel-T trials has limitations, which is why we compared rates with outcomes from a Surveillance, Epidemiology, and End Results–Medicare database analysis of >10,000 men with metastatic prostate cancer who were castrate. The PROCEED CVE rate of 2.8% was identical to that of the Surveillance, Epidemiology, and End Results analysis and therefore we concluded that the CVE rate associated with sipuleucel-T treatment was no different from that observed in a similar population of men with metastatic prostate cancer who were not treated with sipuleucel-T. These findings are of particular interest because there currently is growing awareness of excess cardiovascular toxicities related to the other treatment options for metastatic castration-resistant prostate cancer such as abiraterone and enzalutamide. PROCEED was funded by Dendreon Pharmaceuticals LLC. Work conducted at Memorial Sloan Kettering Cancer Center was funded in part through the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748. This response was developed with the medical writing assistance of Helen M Wilfehrt, PhD, CMPP, of Dendreon Pharmaceuticals, LLC. Celestia S. Higano has served as a paid member of the advisory board for Aptevo, Asana, Astellas, Bayer, Blue Earth Diagnostics, Churchill Pharma, Clovis Oncology, Dendreon, Endocyte, Ferring, Hinova, Janssen, Myriad, Medivation, Orion Corporation, Pfizer, Novartis, and Merck and has participated in sponsored research for Aptevo, Bayer, Clovis, Aragon Pharma, Astellas, AstraZeneca, Dendreon, eFFECTOR Therapeutics, Emergent Biosolutions, Ferring, Genentech, Hoffman-LaRoche, Medivation, Sanofi, and Pfizer for work performed outside of the current study. In addition, Dr Higano's spouse was in a leadership role for CTI Biopharma. Andrew J. Armstrong has received grants and personal fees from Dendreon, Pfizer/Astellas, Janssen, Bayer, and Sanofi-Aventis for work performed as part of the current study and has acted as a paid consultant/advisor and member of the Speakers' Bureau, received research funding to Duke, and received travel expenses from Bayer; received grants from Novartis, Gilead, Bristol-Myers Squibb, Genentech/Roche, and Constellation; received honoraria from, acted as a paid consultant/advisor for, and received research funding to Duke and travel expenses from Janssen; and acted as paid consultant/advisor for and received research funding to Duke from Merck, AstraZeneca, Janssen, and Pfizer/Astellas for work performed outside of the current study. Oliver Sartor served as a consultant for and received personal fees from Advanced Accelerator Applications, Astellas, AstraZeneca, Bavarian Nordic Immunotherapies, Bayer, Bellicum, Blue Earth Diagnostics, Celgene, Clovis, Constellation, Dendreon, EMD Serono, Endocyte, Johnson & Johnson, Bristol-Myers Squibb, Myovant, Pfizer, Progenics, Novartis, Janssen, Sanofi, Teva, Myriad, and Hinova; has acted as a paid consultant and provided expert testimony for Sanofi; and has acted as co-chairman of the Genitourinary Committee for NRG and as a consultant for the Board of Scientific Counselors for the National Cancer Institute for work performed as part of the current study. Dr Sartor has also received grants from AstraZeneca, Bayer, Constellation, Dendreon, Endocyte, Johnson & Johnson, Bristol-Myers Squibb, Progenics, Sanofi, Innocrin, Invitae, Merck, Roche, and Sotio. Nicholas J. Vogelzang has received personal fees from Bayer, Caris, Sanofi Aventis, Janssen, Pfizer, and Merck for work performed outside of the current study. Philip W. Kantoff has received personal fees from Astellas, Bayer, Bellicum, BIND Biosciences, Bavarian Nordic Immunotherapies, DRGT (in which he currently has an investment interest), Genentech/Roche, Ipsen Pharmaceuticals, Janssen, Metamark, Merck, Millennium/Prometrika, MTG, Omnitura, OncoCellMDX, OncoGenex, Progenity, Sanofi, Tarveda Pharmaceuticals (in which he previously held an investment interest), Thermo Fisher, GE Healthcare, Context Therapeutics (for which he acts as a board member and currently holds an investment interest), New England Research Institutes, SEER Biosciences (in which he currently has an investment interest), and Placon (in which he currently has an investment interest). David G. McLeod has received other fees from Dendreon for work performed outside of the current study. Christopher M. Pieczonka has received personal fees as a consultant for Dendreon, Bayer, Janssen, and Pfizer, as well as serving as an investigator for Dendreon, Bayer, Janssen, Pfizer, Merck, AstraZeneca, Taiho, Innocrin, and Myovant for work performed outside of the current study. David F. Penson has received personal fees from Dendreon and Janssen, as well as a grant from the Vanderbilt University Research Center. Neal D. Shore has served as a paid consultant and received personal fees from Ferring, Bayer, Amgen, Janssen, Dendreon, Tolmar, Astellas, Pfizer, AstraZeneca, Genentech/Roche, Myovant Sciences, Merck, Pfizer, Sanofi-Genzyme, Bristol-Meyers Squibb, and Nymox for work performed outside of the current study. Jeffrey Vacirca has acted as the director/chair of the Science Committee for Spectrum Pharmaceuticals and as vice chairman and cofounder of Odonate Therapeutics. Raoul S. Concepcion has served in an advisory role for Dendreon and received personal fees for work performed outside of the current study. David I. Quinn has been involved in payments to the University of Southern California for trials conducted with Dendreon and has acted as a paid advisor for Dendreon, Bayer, Janssen, Pfizer, Astellas, Genzyme, Merck, Novartis, Clovis, and AstraZeneca. Vahan Kassabian has served as a consultant or speaker for Dendreon, Amgen, Astellas, Pfizer, Janssen, Bayer, UroGPO, Tolmar, and Genomic Health for work performed outside of the current study. Matt Harmon has stock ownership in Amgen. Robert C. Tyler has been an employee of Janssen, Dendreon, Medivation, Pfizer, and Innocrin. Nancy N. Chang was a full-time employee of Dendreon at the time of the analyses and drafting of this article. Hong Tang was a full-time employee of Dendreon at the time of the analyses and drafting of this article; is a non-executive director of OnQuality Pharmaceuticals; and owns stock in BeiGene, Nektar, Sangamo Therapeutics, Tesaro, Verastem, Editas Medicine, and CVS Health Corporation. Matthew R. Cooperberg has received personal fees in relation to a PROCEED trial steering committee as well as serving in an advisory or consultancy role for AbbVie, Janssen, Bayer, AstraZeneca, MDx Health, and Myriad Genetics and also has participated in a registry steering committee for Astellas.
Source: Cancer
DOI: 10.1002/cncr.32785
Authors: Celestia S. Higano, Andrew J. Armstrong, Oliver Sartor, Nicholas J. Vogelzang, Philip W. Kantoff, David G. McLeod, Christopher M. Pieczonka, David F. Penson, Neal D. Shore, Jeffrey Vacirca, Raoul S. Concepcion, Ronald F. Tutrone, Luke T. Nordquist, David I. Quinn, Vahan Kassabian, Mark C. Scholz, Matt Harmon, Robert C. Tyler, Nancy N. Chang, Hong Tang, Matthew R. Cooperberg
Institutions: University of Washington, Fred Hutch Cancer Center, Duke University, Duke Medical Center, Duke Cancer Institute, Tulane University, Comprehensive Cancer Centers of Nevada, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, Walter Reed National Military Medical Center, Vanderbilt University Medical Center, Carolina Urologic Research Center, Urology Associates, Chesapeake Urology Associates, University of Southern California, USC Norris Comprehensive Cancer Center, Dendreon (United States), University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center
Language: English
Subfield: Toxicology
Domain: Life Sciences
Open Access status: green
Award: Cancer Center Support Grant
OpenAlex ID: W3010677012