Association between New Unconfirmed Bone Lesions and Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer Treated with Enzalutamide: Secondary Analysis of the PREVAIL and AFFIRM Randomized Clinical Trials

Andrew J. Armstrong, Mohammed Al-Adhami, Ping Lin, Teresa Parli, Jennifer Sugg, Joyce Steinberg, Bertrand Tombal, Cora N. Sternberg, Johann De Bono, Howard I. Scher, Tomasz M. Beer

    Research output: Contribution to journalArticle

    1 Citation (Scopus)

    Abstract

    Importance: For men with metastatic castration-resistant prostate cancer (mCRPC) whose condition is responding to enzalutamide, new unconfirmed bone lesions detected at posttreatment scinitigraphy may reflect an osteoblastic reaction that represents healing, known as pseudoprogression, which can lead to premature discontinuation of therapy. Objective: To determine the association between new unconfirmed lesions detected on a follow-up bone scintigram (bone scan) and outcomes in enzalutamide-treated men with mCRPC. Design, Setting, and Participants: This post hoc, retrospective secondary analysis of 1672 enzalutamide-treated men from 2 phase 3, randomized mCRPC studies (PREVAIL and AFFIRM) before or after treatment with docetaxel was conducted from April 12, 2018, to July 25, 2019. Participants were men from the enzalutamide groups of the 2 studies with a decrease in prostate-specific antigen level at any time or with stable disease or soft-tissue disease responding to treatment based onradiologic findings. Intervention: Enzalutamide, 160 mg once daily. Main Outcomes and Measures: The clinical significance of new lesions detected on the first (early) or second (late) posttreatment bone scan, without an unfavorable change in prostate-specific antigen level or soft-tissue progression, was investigated. Associations of new unconfirmed lesions with radiographic progression-free survival, overall survival, decrease in prostate-specific antigen level, objective response in soft tissue, and quality of life were evaluated. Results: Among the 643 men (median age, 72 years [range, 43-93 years]) in PREVAIL, early and late unconfirmed lesions were observed in 177 men (27.5%) with stable disease or disease responding to enzalutamide. Among the 404 men (median age, 70 years [range, 41-88 years]) in AFFIRM, early and late unconfirmed lesions were observed in 73 men (18.1%) with stable disease or disease responding to enzalutamide. In PREVAIL, men with new unconfirmed lesions had median radiographic progression-free survival (hazard ratio [HR], 1.37 [95% CI, 0.81-2.30]; P =.23) and median overall survival (HR, 1.25 [95% CI, 0.85-1.83]) in the chemotherapy-naive setting similar to men those of men without such new lesions. In AFFIRM, the median overall survival (HR, 1.94 [95% CI, 1.10-3.44]) was reduced among men with unconfirmed bone lesions, but the median radiographic progression-free survival was not reduced (HR, 1.21 [95% CI, 0.83-1.75]; P =.32). Quality of life over time was similar regardless of the presence of new unconfirmed lesions detected on a follow-up bone scan in either setting. Conclusions and Relevance: These results suggest that new unconfirmed lesions detected on follow-up bone scans may represent pseudoprogression in men with mCRPC and are indicative of a favorable treatment response to enzalutamide. The detection of new unconfirmed bone lesions in men with mCRPC that responded to treatment with enzalutamide after docetaxel appears to be associated with worse overall survival and may represent true progression, thus highlighting the need for improved functional bone metastasis imaging. Trial Registration: ClinicalTrials.gov identifier: NCT01212991 and NCT00974311.

    Original languageEnglish (US)
    JournalJAMA Oncology
    DOIs
    StateAccepted/In press - Jan 1 2019

    Fingerprint

    Castration
    Prostatic Neoplasms
    Randomized Controlled Trials
    Bone and Bones
    docetaxel
    Prostate-Specific Antigen
    Disease-Free Survival
    Survival
    MDV 3100
    Quality of Life
    Therapeutics

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Association between New Unconfirmed Bone Lesions and Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer Treated with Enzalutamide : Secondary Analysis of the PREVAIL and AFFIRM Randomized Clinical Trials. / Armstrong, Andrew J.; Al-Adhami, Mohammed; Lin, Ping; Parli, Teresa; Sugg, Jennifer; Steinberg, Joyce; Tombal, Bertrand; Sternberg, Cora N.; De Bono, Johann; Scher, Howard I.; Beer, Tomasz M.

    In: JAMA Oncology, 01.01.2019.

    Research output: Contribution to journalArticle

    Armstrong, Andrew J. ; Al-Adhami, Mohammed ; Lin, Ping ; Parli, Teresa ; Sugg, Jennifer ; Steinberg, Joyce ; Tombal, Bertrand ; Sternberg, Cora N. ; De Bono, Johann ; Scher, Howard I. ; Beer, Tomasz M. / Association between New Unconfirmed Bone Lesions and Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer Treated with Enzalutamide : Secondary Analysis of the PREVAIL and AFFIRM Randomized Clinical Trials. In: JAMA Oncology. 2019.
    @article{3a468a419d3f4cf1bfbb96e0a571340e,
    title = "Association between New Unconfirmed Bone Lesions and Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer Treated with Enzalutamide: Secondary Analysis of the PREVAIL and AFFIRM Randomized Clinical Trials",
    abstract = "Importance: For men with metastatic castration-resistant prostate cancer (mCRPC) whose condition is responding to enzalutamide, new unconfirmed bone lesions detected at posttreatment scinitigraphy may reflect an osteoblastic reaction that represents healing, known as pseudoprogression, which can lead to premature discontinuation of therapy. Objective: To determine the association between new unconfirmed lesions detected on a follow-up bone scintigram (bone scan) and outcomes in enzalutamide-treated men with mCRPC. Design, Setting, and Participants: This post hoc, retrospective secondary analysis of 1672 enzalutamide-treated men from 2 phase 3, randomized mCRPC studies (PREVAIL and AFFIRM) before or after treatment with docetaxel was conducted from April 12, 2018, to July 25, 2019. Participants were men from the enzalutamide groups of the 2 studies with a decrease in prostate-specific antigen level at any time or with stable disease or soft-tissue disease responding to treatment based onradiologic findings. Intervention: Enzalutamide, 160 mg once daily. Main Outcomes and Measures: The clinical significance of new lesions detected on the first (early) or second (late) posttreatment bone scan, without an unfavorable change in prostate-specific antigen level or soft-tissue progression, was investigated. Associations of new unconfirmed lesions with radiographic progression-free survival, overall survival, decrease in prostate-specific antigen level, objective response in soft tissue, and quality of life were evaluated. Results: Among the 643 men (median age, 72 years [range, 43-93 years]) in PREVAIL, early and late unconfirmed lesions were observed in 177 men (27.5{\%}) with stable disease or disease responding to enzalutamide. Among the 404 men (median age, 70 years [range, 41-88 years]) in AFFIRM, early and late unconfirmed lesions were observed in 73 men (18.1{\%}) with stable disease or disease responding to enzalutamide. In PREVAIL, men with new unconfirmed lesions had median radiographic progression-free survival (hazard ratio [HR], 1.37 [95{\%} CI, 0.81-2.30]; P =.23) and median overall survival (HR, 1.25 [95{\%} CI, 0.85-1.83]) in the chemotherapy-naive setting similar to men those of men without such new lesions. In AFFIRM, the median overall survival (HR, 1.94 [95{\%} CI, 1.10-3.44]) was reduced among men with unconfirmed bone lesions, but the median radiographic progression-free survival was not reduced (HR, 1.21 [95{\%} CI, 0.83-1.75]; P =.32). Quality of life over time was similar regardless of the presence of new unconfirmed lesions detected on a follow-up bone scan in either setting. Conclusions and Relevance: These results suggest that new unconfirmed lesions detected on follow-up bone scans may represent pseudoprogression in men with mCRPC and are indicative of a favorable treatment response to enzalutamide. The detection of new unconfirmed bone lesions in men with mCRPC that responded to treatment with enzalutamide after docetaxel appears to be associated with worse overall survival and may represent true progression, thus highlighting the need for improved functional bone metastasis imaging. Trial Registration: ClinicalTrials.gov identifier: NCT01212991 and NCT00974311.",
    author = "Armstrong, {Andrew J.} and Mohammed Al-Adhami and Ping Lin and Teresa Parli and Jennifer Sugg and Joyce Steinberg and Bertrand Tombal and Sternberg, {Cora N.} and {De Bono}, Johann and Scher, {Howard I.} and Beer, {Tomasz M.}",
    year = "2019",
    month = "1",
    day = "1",
    doi = "10.1001/jamaoncol.2019.4636",
    language = "English (US)",
    journal = "JAMA oncology",
    issn = "2374-2437",
    publisher = "American Medical Association",

    }

    TY - JOUR

    T1 - Association between New Unconfirmed Bone Lesions and Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer Treated with Enzalutamide

    T2 - Secondary Analysis of the PREVAIL and AFFIRM Randomized Clinical Trials

    AU - Armstrong, Andrew J.

    AU - Al-Adhami, Mohammed

    AU - Lin, Ping

    AU - Parli, Teresa

    AU - Sugg, Jennifer

    AU - Steinberg, Joyce

    AU - Tombal, Bertrand

    AU - Sternberg, Cora N.

    AU - De Bono, Johann

    AU - Scher, Howard I.

    AU - Beer, Tomasz M.

    PY - 2019/1/1

    Y1 - 2019/1/1

    N2 - Importance: For men with metastatic castration-resistant prostate cancer (mCRPC) whose condition is responding to enzalutamide, new unconfirmed bone lesions detected at posttreatment scinitigraphy may reflect an osteoblastic reaction that represents healing, known as pseudoprogression, which can lead to premature discontinuation of therapy. Objective: To determine the association between new unconfirmed lesions detected on a follow-up bone scintigram (bone scan) and outcomes in enzalutamide-treated men with mCRPC. Design, Setting, and Participants: This post hoc, retrospective secondary analysis of 1672 enzalutamide-treated men from 2 phase 3, randomized mCRPC studies (PREVAIL and AFFIRM) before or after treatment with docetaxel was conducted from April 12, 2018, to July 25, 2019. Participants were men from the enzalutamide groups of the 2 studies with a decrease in prostate-specific antigen level at any time or with stable disease or soft-tissue disease responding to treatment based onradiologic findings. Intervention: Enzalutamide, 160 mg once daily. Main Outcomes and Measures: The clinical significance of new lesions detected on the first (early) or second (late) posttreatment bone scan, without an unfavorable change in prostate-specific antigen level or soft-tissue progression, was investigated. Associations of new unconfirmed lesions with radiographic progression-free survival, overall survival, decrease in prostate-specific antigen level, objective response in soft tissue, and quality of life were evaluated. Results: Among the 643 men (median age, 72 years [range, 43-93 years]) in PREVAIL, early and late unconfirmed lesions were observed in 177 men (27.5%) with stable disease or disease responding to enzalutamide. Among the 404 men (median age, 70 years [range, 41-88 years]) in AFFIRM, early and late unconfirmed lesions were observed in 73 men (18.1%) with stable disease or disease responding to enzalutamide. In PREVAIL, men with new unconfirmed lesions had median radiographic progression-free survival (hazard ratio [HR], 1.37 [95% CI, 0.81-2.30]; P =.23) and median overall survival (HR, 1.25 [95% CI, 0.85-1.83]) in the chemotherapy-naive setting similar to men those of men without such new lesions. In AFFIRM, the median overall survival (HR, 1.94 [95% CI, 1.10-3.44]) was reduced among men with unconfirmed bone lesions, but the median radiographic progression-free survival was not reduced (HR, 1.21 [95% CI, 0.83-1.75]; P =.32). Quality of life over time was similar regardless of the presence of new unconfirmed lesions detected on a follow-up bone scan in either setting. Conclusions and Relevance: These results suggest that new unconfirmed lesions detected on follow-up bone scans may represent pseudoprogression in men with mCRPC and are indicative of a favorable treatment response to enzalutamide. The detection of new unconfirmed bone lesions in men with mCRPC that responded to treatment with enzalutamide after docetaxel appears to be associated with worse overall survival and may represent true progression, thus highlighting the need for improved functional bone metastasis imaging. Trial Registration: ClinicalTrials.gov identifier: NCT01212991 and NCT00974311.

    AB - Importance: For men with metastatic castration-resistant prostate cancer (mCRPC) whose condition is responding to enzalutamide, new unconfirmed bone lesions detected at posttreatment scinitigraphy may reflect an osteoblastic reaction that represents healing, known as pseudoprogression, which can lead to premature discontinuation of therapy. Objective: To determine the association between new unconfirmed lesions detected on a follow-up bone scintigram (bone scan) and outcomes in enzalutamide-treated men with mCRPC. Design, Setting, and Participants: This post hoc, retrospective secondary analysis of 1672 enzalutamide-treated men from 2 phase 3, randomized mCRPC studies (PREVAIL and AFFIRM) before or after treatment with docetaxel was conducted from April 12, 2018, to July 25, 2019. Participants were men from the enzalutamide groups of the 2 studies with a decrease in prostate-specific antigen level at any time or with stable disease or soft-tissue disease responding to treatment based onradiologic findings. Intervention: Enzalutamide, 160 mg once daily. Main Outcomes and Measures: The clinical significance of new lesions detected on the first (early) or second (late) posttreatment bone scan, without an unfavorable change in prostate-specific antigen level or soft-tissue progression, was investigated. Associations of new unconfirmed lesions with radiographic progression-free survival, overall survival, decrease in prostate-specific antigen level, objective response in soft tissue, and quality of life were evaluated. Results: Among the 643 men (median age, 72 years [range, 43-93 years]) in PREVAIL, early and late unconfirmed lesions were observed in 177 men (27.5%) with stable disease or disease responding to enzalutamide. Among the 404 men (median age, 70 years [range, 41-88 years]) in AFFIRM, early and late unconfirmed lesions were observed in 73 men (18.1%) with stable disease or disease responding to enzalutamide. In PREVAIL, men with new unconfirmed lesions had median radiographic progression-free survival (hazard ratio [HR], 1.37 [95% CI, 0.81-2.30]; P =.23) and median overall survival (HR, 1.25 [95% CI, 0.85-1.83]) in the chemotherapy-naive setting similar to men those of men without such new lesions. In AFFIRM, the median overall survival (HR, 1.94 [95% CI, 1.10-3.44]) was reduced among men with unconfirmed bone lesions, but the median radiographic progression-free survival was not reduced (HR, 1.21 [95% CI, 0.83-1.75]; P =.32). Quality of life over time was similar regardless of the presence of new unconfirmed lesions detected on a follow-up bone scan in either setting. Conclusions and Relevance: These results suggest that new unconfirmed lesions detected on follow-up bone scans may represent pseudoprogression in men with mCRPC and are indicative of a favorable treatment response to enzalutamide. The detection of new unconfirmed bone lesions in men with mCRPC that responded to treatment with enzalutamide after docetaxel appears to be associated with worse overall survival and may represent true progression, thus highlighting the need for improved functional bone metastasis imaging. Trial Registration: ClinicalTrials.gov identifier: NCT01212991 and NCT00974311.

    UR - http://www.scopus.com/inward/record.url?scp=85076628122&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=85076628122&partnerID=8YFLogxK

    U2 - 10.1001/jamaoncol.2019.4636

    DO - 10.1001/jamaoncol.2019.4636

    M3 - Article

    C2 - 31830211

    AN - SCOPUS:85076628122

    JO - JAMA oncology

    JF - JAMA oncology

    SN - 2374-2437

    ER -