Association Between Androgen Deprivation Therapy and Mortality Among Patients With Prostate Cancer and COVID-19 | Oncology | JAMA Network Open | JAMA Network
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    3 Comments for this article
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    Refined analysis is needed particularly for ARI
    Carlos Wambier, MD, PhD | Department of Dermatology - Warren Alpert Medical School of Brown University
    In addition to the primary analysis, the authors performed an interesting sensitivity analysis comparison between "ADT" vs "non-ADT+ARI" -- they included patients receiving ARI that didn't undergo surgical or chemical castration in the "non-ADT" group (n=7): 3 patients were receiving 1st Generation Androgen Receptor Inhibitor (ARI-1) such as bicalutamide and flutamide, 2 patients were receiving 2nd generation androgen receptor inhibitor (ARI-2) such as enzalutamide, darolutamide, or apalutamide, and 2 patients were receiving abiraterone acetate, according to supplement eTable 1.

    Considering the clinically significant protective effect seen on all-cause 30-day mortality (OR, 0.77, 95% CI 0.42-1.42, a difference that did
    not reach statistical significance); it is prudent to reanalyse the data with the correction of ADT per definition of use of antiandrogen medications such as the extremely potent ARI. As seen on table 4, there was further increased protection seen with ARI-1 and ARI-2 (aOR, 0.64, 95% CI 0.26-1.58, a difference that did not reach statistical significance), when compared to the rest of the ADT group.

    In my view, the most important analysis, given the trends for protection specific to ARI is to perform a specific analysis of prostate cancer patients under ARI vs "non-ADT".

    Given the age of the men of the study, it is also important to exclude patients taking 5-alpha reductase inhibitors, such as dutasteride, finasteride, or perform a sub-analysis of such group, as these medications are also antiandrogens, and block TMPRSS2 expression. Spironolactone, a commonly used diuretic for patients with hepatic and cardiac failure, is another antiandrogen and its use could be controlled for refined analysis of the impact of TMPRSS2 inhibition on COVID-19 severity and mortality.

    Another point is that "3 months before COVID-19 diagnosis" may not be a good temporal parameter for evaluating use of ARI during COVID-19 diagnosis. An alternative analysis that would be insightful is to evaluate the use of such medications during hospitalization, which is a controlled environment, to evaluate the impact of 2nd generation ARI such as apalutamide, enzalutamide, and darolutamide on the survival and hospitalization days.

    It is interesting that the authors conclude that "ADT use was not associated with decreased mortality from SARS-CoV-2 infection," since it is not clear that the study was enough powered to test the observed reduction of 23% of the odds of 30-day all-cause mortality with ADT that excluded ARI monotherapy and accounted ARI in the control group (a difference that did not reach statistical significance). It would be valuable if the raw data was available for further analysis of each ARI.



    CONFLICT OF INTEREST: None Reported
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    Confirming no association between ADT and COVID-19 outcomes
    Rolf Gedeborg, MD, PhD, and Pär Stattin, MD, PhD | Dept Surgical Sciences, Uppsal University, Sweden
    Andrew Schmidt and co-authors should be congratulated for publishing a negative report questioning the protective effect of ADT on COVID-19 mortality, a hypothesis that has already sparked a number of RCTs, despite little clinical evidence in its support.

    It is not easy to publish a negative report; unfortunately our submission was not accepted here.  

    In our paper, which we  published on 7 October 2021, we analyzed a population-based cohort in Sweden of 110,371 men with prevalent prostate cancer during March–June 2020, of whom 23,727 were on ADT, with 913 deaths during the period (1).

    The adjusted
    relative mortality rate ratio comparing the increase in March–June 2020 vs. the same period in 2015-2019 for men on ADT compared to men not on ADT was 0.96 (95% CI: 0.87 to 1.06). 

    The replication by application of different analytical approaches to data from different healthcare systems and demographic context, strengthens the conclusion that there is little support for a protective effect of ADT on COVID-19 outcomes.

    This is important information considering the both the initiation of randomized trials based on limited support (2) and risks associated with ADT, and makes us reflect how publication bias of negative reports might be avoided.

    REFERENCES

    1. Gedeborg R, Styrke J, Loeb S, Garmo H, Stattin P. Androgen deprivation therapy and excess mortality in men with prostate cancer during the initial phase of the COVID-19 pandemic. PLoS One 2021;16: e0255966.

    2. ClinicalTrials.gov: The National Library of Medicine at the National Institutes of Health: COVID-19 and androgen deprivation therapy

    CONFLICT OF INTEREST: None Reported
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    Explanation for Author Omitted Information on Coauthor, Group Name, Collaborators, and Grant
    Rana R. McKay, MD |
    This manuscript includes several omissions which are currently being submitted as an erratum including:
    1. Addition of Dimpy P. Shah as a co-author.
    2. Addition of name of group Covid-19 and Cancer Consortium to the byline.
    3. Inclusion in supplement of all non-author contributors as part of the consortium.
    4. Update to the funding statement.

    We apologize for the inconvenience this may have caused and are resolving the errors. There are not changes being made to any of the factual content of the text of the manuscript.
    CONFLICT OF INTEREST: Dr McKay reported research funding from Bayer, Pfizer, and Tempus; and personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Calithera, Caris, Dendreon, Exelixis, Janssen, Johnson and Johnson, Merck & Co, Myovant, Novartis, Pfizer, Sanofi, Sorrento Therapeutics, Tempus, and Vividion.
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    Original Investigation
    Urology
    November 12, 2021

    Association Between Androgen Deprivation Therapy and Mortality Among Patients With Prostate Cancer and COVID-19

    Author Affiliations
    • 1Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
    • 2Vanderbilt University Medical Center, Nashville, Tennessee
    • 3Duke Cancer Institute Center for Prostate and Urologic Cancer, Duke University, Durham, North Carolina
    • 4Oregon Health and Science University Knight Cancer Institute, Portland
    • 5UPMC Western Maryland, Cumberland
    • 6Winship Cancer Institute of Emory University, Atlanta, Georgia
    • 7Penn State Cancer Institute, Hershey, Pennsylvania
    • 8Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
    • 9Missouri Baptist Medical Center, St Louis
    • 10Massachusetts General Hospital, Boston
    • 11Montefiore Einstein College of Medicine, Bronx, New York
    • 12Intermountain Healthcare, Salt Lake City, Utah
    • 13University of Cincinnati College of Medicine, Cincinnati, Ohio
    • 14Henry Ford Cancer Institute, Henry Ford Hospital, Detroit, Michigan
    • 15University of Washington, Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Seattle
    • 16Stanford University, Stanford, California
    • 17Memorial Sloan Kettering Cancer Center, New York, New York
    • 18Virtua Health Network, Marlton, New Jersey
    • 19Tallahassee Memorial Healthcare, Tallahassee, Florida
    • 20University of Texas Health Science Center at San Antonio, San Antonio
    • 21Moores Cancer Center, University of California, San Diego
    • 22University of Kansas Medical Center, Westwood
    JAMA Netw Open. 2021;4(11):e2134330. doi:10.1001/jamanetworkopen.2021.34330
    Key Points

    Question  Given the higher COVID-19–related mortality rate observed among men than among women, is androgen deprivation therapy associated with decreased rate of 30-day mortality from COVID-19 among patients with prostate cancer?

    Findings  In this cohort study of 1106 patients, no statistically significant difference was found in the rates of all cause 30-day mortality following COVID-19 infection among men with prostate cancer receiving androgen deprivation therapy (15%) vs those not receiving androgen deprivation therapy (14%).

    Meaning  The findings of this cohort study do not support an association between androgen deprivation therapy and 30-day mortality among patients with COVID-19 infection.

    Abstract

    Importance  Androgen deprivation therapy (ADT) has been theorized to decrease the severity of SARS-CoV-2 infection in patients with prostate cancer owing to a potential decrease in the tissue-based expression of the SARS-CoV-2 coreceptor transmembrane protease, serine 2 (TMPRSS2).

    Objective  To examine whether ADT is associated with a decreased rate of 30-day mortality from SARS-CoV-2 infection among patients with prostate cancer.

    Design, Setting, and Participants  This cohort study analyzed patient data recorded in the COVID-19 and Cancer Consortium registry between March 17, 2020, and February 11, 2021. The consortium maintains a centralized multi-institution registry of patients with a current or past diagnosis of cancer who developed COVID-19. Data were collected and managed using REDCap software hosted at Vanderbilt University Medical Center in Nashville, Tennessee. Initially, 1228 patients aged 18 years or older with prostate cancer listed as their primary malignant neoplasm were included; 122 patients with a second malignant neoplasm, insufficient follow-up, or low-quality data were excluded. Propensity matching was performed using the nearest-neighbor method with a 1:3 ratio of treated units to control units, adjusted for age, body mass index, race and ethnicity, Eastern Cooperative Oncology Group performance status score, smoking status, comorbidities (cardiovascular, pulmonary, kidney disease, and diabetes), cancer status, baseline steroid use, COVID-19 treatment, and presence of metastatic disease.

    Exposures  Androgen deprivation therapy use was defined as prior bilateral orchiectomy or pharmacologic ADT administered within the prior 3 months of presentation with COVID-19.

    Main Outcomes and Measures  The primary outcome was the rate of all-cause 30-day mortality after COVID-19 diagnosis for patients receiving ADT compared with patients not receiving ADT after propensity matching.

    Results  After exclusions, 1106 patients with prostate cancer (before propensity score matching: median age, 73 years [IQR, 65-79 years]; 561 (51%) self-identified as non-Hispanic White) were included for analysis. Of these patients, 477 were included for propensity score matching (169 who received ADT and 308 who did not receive ADT). After propensity matching, there was no significant difference in the primary end point of the rate of all-cause 30-day mortality (OR, 0.77; 95% CI, 0.42-1.42).

    Conclusions and Relevance  Findings from this cohort study suggest that ADT use was not associated with decreased mortality from SARS-CoV-2 infection. However, large ongoing clinical trials will provide further evidence on the role of ADT or other androgen-targeted therapies in reducing COVID-19 infection severity.

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