Mature results of a phase 2 pilot study of radium-223 and radiotherapy in untreated hormone-naïve men with oligometastatic prostate cancer to bone.
Authors: Tward Jonathan David , Johnson Skyler B , Kokeny Kristine E. , Lloyd Shane , Cannon Donald Maurice , Dechet Christopher B. , ONeil Brock , Stephenson Robert A , Boucher Kenneth M. , Kohli Manish , Gupta Sumati , Swami Umang , Maughan Benjamin L. , Agarwal Neeraj 
Published: January 2024

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Background: We hypothesized that treatment with Radium-223 (Ra223) and to ≤5 sites of bony metastases could safely delay the time to start androgen deprivation therapy (ADT) and maintain quality of life (QoL). Methods: 20 men previously treated with surgery, radiation, or both for M0 PCa later developed ≤5 bone-only mets were eligible for this prospective trial. Inclusion: testosterone ≥ 100 ng/dL and mets on conventional bone scan, validated by a CT, MRI, or PET/CT. Exclusion: LHRH therapies after initial treatment or N1 disease at diagnosis of bone mets. Therapy was 6 cycles of Ra223 and SBRT (30 Gy in 5 fractions between cycles 1-2). Bone scan was performed at baseline and q3 months. PSA was evaluated monthly during the Ra223 course and q3 months after. Therapeutic effectiveness was defined as ≥20% of patients meeting the primary endpoint of freedom from ADT (FFAdt) use at 15 months. Discontinuation of study therapy occurred if: PSA rise > 10% if baseline PSA >20ng/ml, PSA>20 if baseline PSA <20 ng/ml, radiographic progression or a skeletal-related event (SRE). All endpoints were timed from the Cycle 1 radium date. Patients were followed for 2 years. Clinically significant changes in patient-reported outcome (PRO) measures were defined as >1/2 standard deviation from the mean baseline value and were censored after the time of ADT use. Continuous and categorical covariates were compared using the Wilcoxon rank sum and Pearson’s Chi2 tests and univariate Cox regression. Statistical significance was considered at P<0.05. Results: The median number of Ra223 cycles was 6. 6 patients had <6 cycles (range 2-5) due to progression. FFAdt at 15 and 24 months was 50.0% and 40.0%, respectively (p<0.001). Median time to ADT was 15 months. 11 (55%) and 5 (25%) patients had a PSA decline exceeding 50% and 90%, respectively. Two patients had undetectable (PSA<0.01) at 2 years. There were no significant changes from baseline in any PRO QoL domain (physical functioning, anxiety, depression, fatigue, satisfaction with participation in social roles, sleep disturbance, and pain interference). There were 2 patients with Grade 3 SREs (bone fracture, pain). Grade 2+ events attributed as possible or likely to Ra-223 were seen in 4 patients (bone pain, fatigue, fracture, decreased WBC count, and other). Grade 2+ events attributed as possible or likely to EBRT were seen in 2 patients, including fatigue and other pain. No differences were noted for age, baseline PSA, days from primary treatment, NCCN risk group, TNM stage, ISUP grade group, BMI, or # of lesions in those who met or failed the primary endpoint (all p>0.05). Conclusions: In this prospective pilot study, the first-line use of Ra223 and SBRT to conventionally imaged oligomets in hormone-naïve men resulted in a significant delay in ADT use compared to historical control. The therapy is well tolerated, maintains QoL, and may result in undetectable PSA. Clinical trial information: NCT03304418 .