Association of Bone Metastatic Burden With Survival Benefit From Prostate Radiotherapy in Patients With Newly Diagnosed Metastatic Prostate Cancer: A Secondary Analysis of a Randomized Clinical Trial

Abstract

Importance: Prostate radiotherapy (RT) improves survival in men with low-burden metastatic prostate cancer. However, owing to the dichotomized nature of metastatic burden criteria, it is not clear how this benefit varies with bone metastasis counts and metastatic site.

Objective: To evaluate the association of bone metastasis count and location with survival benefit from prostate RT.

Design, setting, and participants: This exploratory analysis of treatment outcomes based on metastatic site and extent as determined by conventional imaging (computed tomography/magnetic resonance imaging and bone scan) evaluated patients with newly diagnosed metastatic prostate cancer randomized within the STAMPEDE trial's metastasis M1 RT comparison. The association of baseline bone metastasis counts with overall survival (OS) and failure-free survival (FFS) was assessed using a multivariable fractional polynomial interaction procedure. Further analysis was conducted in subgroups.

Interventions: Patients were randomized to receive either standard of care (androgen deprivation therapy with or without docetaxel) or standard of care and prostate RT.

Main outcomes and measures: The primary outcomes were OS and FFS.

Results: A total of 1939 of 2061 men were included (median [interquartile range] age, 68 [63-73] years); 1732 (89%) had bone metastases. Bone metastasis counts were associated with OS and FFS benefit from prostate RT. Survival benefit decreased continuously as the number of bone metastases increased, with benefit most pronounced up to 3 bone metastases. A plot of estimated treatment effect indicated that the upper 95% CI crossed the line of equivalence (hazard ratio [HR], 1) above 3 bone metastases without a detectable change point. Further analysis based on subgroups showed that the magnitude of benefit from the addition of prostate RT was greater in patients with low metastatic burden with only nonregional lymph nodes (M1a) or 3 or fewer bone metastases without visceral metastasis (HR for OS, 0.62; 95% CI, 0.46-0.83; HR for FFS, 0.57; 95% CI, 0.47-0.70) than among patients with 4 or more bone metastases or any visceral/other metastasis (HR for OS, 1.08; 95% CI, 0.91-1.28; interaction P = .003; HR for FFS, 0.87; 95% CI, 0.76-0.99; interaction P = .002).

Conclusions and relevance: In this exploratory analysis of a randomized clinical trial, bone metastasis count and metastasis location based on conventional imaging were associated with OS and FFS benefit from prostate RT in M1 disease.

Trial registration: ClinicalTrials.gov Identifier: NCT00268476; ISRCTN.com Identifier: ISRCTN78818544.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Mason reported receiving personal fees from Endocyte and Clovis outside the submitted work. Dr Dearnaley reported receiving personal fees from The Institute of Cancer Research, Janssen, Takeda, Amgen, Astellas, and Sandoz outside the submitted work; in addition, Dr Dearnaley reported having a patent EP1933709B issued. Dr Attard reported receiving grants, personal fees, nonfinancial support, and speaker fees from Janssen, Astellas, and Sanofi; personal fees, nonfinancial support, and speaker fees from AstraZeneca; and personal fees from Novartis and Bayer outside the submitted work; in addition, Dr Attard reported having a patent (GB1915469.9; blood signatures for prostate cancer detection) pending and is on the Institute of Cancer Research list of rewards to inventors for abiraterone acetate. Dr Gillessen reported an advisory board for institution from Bayer, Menarini Silicon Biosystems, AAA International, Tolero Pharmaceuticals, Astellas, Janssen, Merck Sharp & Dohme, and Roche; personal fees for advisory boards from Sanofi, Orion, Roche, and Amgen; and personal fees for speakers bureaus from Janssen Speakers Bureau outside the submitted work; in addition, Dr Gillessen reported having a patent for WO2009138392 issued. Dr Sydes reported receiving grants and drug from Astellas, Janssen, Novartis, Pfizer, and Sanofi for the STAMPEDE trial outside of this work; grants from Clovis Oncology for biomarker work in the STAMPEDE trial outside of this work; and personal (speaker) fees from Lilly Oncology and Janssen (no discussion of particular drugs) outside the submitted work. Dr James reported receiving grants from Cancer Research UK to support trial conduct and grants and personal fees from Sanofi, Janssen, and Astellas during the conduct of the study. Dr Clarke reported receiving personal speaker and advisory fees from Astellas, AstraZeneca, Ferring, and Janssen outside the submitted work and additional research grants from AstraZeneca outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Flowchart Showing Inclusion of Patients for Bone Metastatic Burden Analysis

RT indicates radiotherapy; SOC, standard of care.

Figure 2.. Treatment Effect Plots for Bone Metastasis Count

Estimated treatment effect (solid line) with pointwise 95% CI (shaded area) is shown for overall survival (A) and failure-free survival (B). The horizontal gray line at hazard ratio 1.00 denotes equivalence of treatment effects, with values below 1.00 favoring prostate radiotherapy. MFPI indicates multivariable fractional polynomial interaction.

Figure 3.. Kaplan-Meier Curves for Overall and Failure-Free Survival by Treatment in 1587 Patients With Bone Metastases

Overall and failure-free survival by treatment in 1587 patients with bone metastases with or without nonregional lymph node metastasis (NRLN) metastasis stratified by ≤3 (A and B) and ≥4 (C and D) bone metastases. RT indicates radiotherapy; SOC, standard of care.

Figure 4.. Kaplan-Meier Curves for Overall Survival (OS) and Failure-Free Survival (FFS) by Treatment in Patients With Only Nonregional Lymph Node (NRLN) Metastasis (M1a) and Any Visceral or Other Metastasis

Overall and failure-free survival by treatment in patients with only NRLN metastasis (M1a) (A and B) and any visceral or other metastasis (C and D). RT indicates radiotherapy; SOC, standard of care.