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 Identifiers: NCT01212991 and NCT00974311.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Armstrong reported receiving honoraria from Dendreon, Janssen Oncology, and Sanofi; serving as a consultant for Dendreon, Sanofi, Astellas, Bayer, Janssen Biotech, Medivation, Novartis, and Pfizer; serving as a member of the speakers’ bureaus for Dendreon, Sanofi, and Bayer; receiving money for travel/accommodations expenses from Dendreon, Astellas, Bayer, and Janssen Biotech; receiving research funding from Dendreon, Medivation, Novartis, Pfizer, Active Biotech, Astellas, Bristol-Myers Squibb, Gilead Sciences, and Roche-Genentech; receiving grant money from Janssen Oncology; and receiving research support (to Duke) from Merck, Constellation, and AstraZeneca. Dr Al-Adhami reported being an employee of Pfizer Inc and having stock ownership in Pfizer Inc. Dr Lin reported being a former employee of Pfizer Inc and having stock ownership in Pfizer Inc. Dr Parli reported being a former employee of Pfizer Inc and having stock ownership in Pfizer Inc. Ms Sugg reported being an employee of Astellas Pharma Inc and having stock ownership in AstraZeneca. Dr Steinberg reported being an employee of Astellas Pharma Inc and having an immediate family member with stock ownership in Amgen. Dr Tombal reported receiving honoraria from Amgen, Astellas, Bayer, Ferring, Janssen, Pfizer, and Sanofi; serving as a consultant for Bayer, Ferring, Janssen, Sanofi, Astellas, Steba Biotech, and Takeda; receiving money for travel/accommodation expenses from Bayer, Ferring, Janssen, Sanofi, and Astellas; and receiving research funding from Ferring. Dr Sternberg reported serving as a consultant for Janssen, Astellas, Sanofi, Novartis, Bayer, and AstraZeneca; and receiving prior institutional funding from Cougar Biotechnology (now Janssen), Medivation (now Pfizer), Clovis Oncology, and Roche-Genentech. Dr De Bono reported receiving honoraria from Astellas, AstraZeneca, Genentech-Roche, Pfizer, Sanofi, Bayer, Boehringer Ingelheim, Merck Serono, and Merck Sharp & Dohme; receiving money for travel/accommodations expenses from AstraZeneca, Sanofi, Genmab, GlaxoSmithKline, Orion Pharma GmbH, Qiagen, Taiho Pharmaceutical, and Vertex; receiving research funding from AstraZeneca and Sanofi; and receiving royalties from Abiraterone rewards to inventors and PARP inhibitors and DNA repair defects. Dr Scher reported serving as a consultant for and receiving money for travel/accommodations expenses from Ambry Genetics, ESSA Pharma, Konica Minolta, Medivation, Menarini Silicon, OncLive Insights, Physicians’ Education Resource, Sanofi Aventis, and WCG Oncology; serving as a consultant for Janssen Biotech and Janssen Research & Development; receiving money for travel/accommodations expenses from Asterias Biotherapeutics, Clovis Oncology, Prostate Cancer Foundation, and Sanofi; receiving research funding (grants) from Epic Sciences, Illumina, Innocrin Pharmaceuticals, Janssen, Medivation, Menarini Silicon, and Thermo Fisher Scientific; and holding leadership or stock ownership in Asterias Biotherapeutics. Dr Beer reported serving as a consultant for AbbVie, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Clovis Oncology, GlaxoSmithKline, Janssen Biotech, Janssen Japan, Merck, and Pfizer; receiving research funding from Boehringer Ingelheim, Alliance Foundation Trials, Corcept Therapeutics, Endocyte, Janssen Research & Development, Medivation-Astellas, OncoGenex, Sotio, and Theraclone Sciences-OncoResponse; and holding stock ownership in Salarius Pharmaceuticals. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagrams for PREVAIL and AFFIRM

CR indicates complete response; ENZA, enzalutamide; PR, partial response; PSA, prostate-specific antigen; and SD, stable disease. aEarly was defined as new lesions detected on the first posttreatment scan (week 9 in PREVAIL, week 13 in AFFIRM). bLate was defined as new lesions detected on the second posttreatment scan (week 17 or later in PREVAIL, week 25 or later in AFFIRM).

Figure 2.. Radiographic Progression-Free Survival (rPFS) in PREVAIL and AFFIRM Among Men Treated With Enzalutamide Who Had a Decrease in Prostate-Specific Antigen Level or an Objective Soft-Tissue Response, With or Without New Unconfirmed Lesions Detected on Follow-up Bone Scans Over Time

A, Median rPFS in PREVAIL among men with new unconfirmed bone lesions (n = 177), not reached (NR [95% CI, 12.3 months to NR]); and median rPFS in PREVAIL among men with no new unconfirmed bone lesions (n = 466), NR (95% CI, 14.1 months to NR); hazard ratio, 1.37 (95% CI, 0.81-2.30); P = .23. B, Median rPFS in AFFIRM among men with new unconfirmed bone lesions (n = 73), 13.6 months (95% CI, 11.1-16.5 months); and median rPFS in AFFIRM among men with no new unconfirmed bone lesions (n = 331), 13.9 months (95% CI, 13.6-16.5 months); hazard ratio, 1.21 (95% CI, 0.83-1.75); P = .32. Horizontal dashed lines indicate the median.

Figure 3.. Overall Survival (OS) in PREVAIL and AFFIRM Among Men Treated With Enzalutamide Who Had a Decrease in Prostate-Specific Antigen Level or an Objective Soft-Tissue Response, With or Without New Unconfirmed Lesions Detected on Follow-up Bone Scans Over Time

A, Median OS in PREVAIL among men with new unconfirmed bone lesions (n = 177), not reached (NR [95% CI, NR to NR]); and median OS in PREVAIL among men with no new unconfirmed bone lesions (n = 466), 32.4 months (95% CI, 31.5 months to NR); hazard ratio, 1.25 (95% CI, 0.85-1.83). B, Median OS in AFFIRM among men with new unconfirmed bone lesions (n = 73), NR (95% CI, 16.5 months to NR); and median OS in AFFIRM among men with no new unconfirmed bone lesions (n = 331), NR; hazard ratio, 1.94 (95% CI, 1.10-3.44). Horizontal dashed lines indicate the median.