Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Early M-Protein Dynamics Predicts Progression-Free Survival in Patients With Relapsed/Refractory Multiple Myeloma

This study aimed to predict long-term progression-free survival (PFS) using early M-protein dynamic measurements in patients with relapsed/refractory multiple myeloma (MM). The PFS was modeled based on dynamic M-protein data from two phase III studies, POLLUX and CASTOR, which included 569 and 498 patients with relapsed/refractory MM, respectively. Both studies compared active controls (lenalidomide and dexamethasone, and bortezomib and dexamethasone, respectively) alone vs. in combination with daratumumab. Three M-protein dynamic features from the longitudinal M-protein data were evaluated up to different time cutoffs (1, 2, 3, and 6 months). The abilities of early M-protein dynamic measurements to predict the PFS were evaluated using Cox proportional hazards survival models. Both univariate and multivariable analyses suggest that maximum reduction of M-protein (i.e., depth of response) was the most predictive of PFS. Despite the statistical significance, the baseline covariates provided very limited predictive value regarding the treatment effect of daratumumab. However, M-protein dynamic features obtained within the first 2 months reasonably predicted PFS and the associated treatment effect of daratumumab. Specifically, the areas under the time-varying receiver operating characteristic curves for the model with the first 2 months of M-protein dynamic data were ~ 0.8 and 0.85 for POLLUX and CASTOR, respectively. Early M-protein data within the first 2 months can provide a prospective and reasonable prediction of future long-term clinical benefit for patients with MM. © 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics

Evaluating serum-free light chain ratio as a biomarker for multiple myeloma

8047 Background: In 2014, the definition of multiple myeloma was updated to include serum free light chain (FLC) ratio ≥100 as a myeloma defining biomarker, based on retrospective data indicating a 2-year progression rate of 80% and a median time to progression (TTP) of 12 months associated with this marker. However, two recent studies have reported lower 2-year progression rates, 30-44%, and longer median TTP of 40 months in patients with FLC ratio ≥100. Because of the disparity in risk prediction by FLC ratio across studies, we were motivated to assess the risk of progression in patients with SMM and a FLC ratio ≥100. Methods: We performed a retrospective analysis of patients diagnosed with SMM at Memorial Sloan Kettering Cancer Center between January 2000 and December 2017. Diagnosis of SMM and progression to MM was defined according to the International Myeloma Working Group (IMWG) criteria at the time of diagnosis. Kaplan-Meier method was used to assess TTP and generate survival curves, with log-rank test for comparison between groups. Results: A total of 438 patients were included in the study, with a median follow-up time of 52 months. While all patients with a FLC ratio ≥100 (n = 66) had elevated involved FLC levels, 35 (53%) had an involved FLC concentration > 100 mg/L. Per current diagnostic criteria, we only included patients with an involved FLC concentration > 100 mg/L in the FLC ratio ≥100 group, and found a median TTP of 31 months (95% confidence interval [CI] 16-59 months) and a 2-year progression rate of 49% (CI 28-63%). In a sensitivity analysis including all 66 cases with FLC ratio ≥100 (independent of involved FLC concentration), we found the median TTP to be 41 months (CI 30-72 months), compared to 101 months for those with a FLC ratio 4 years, among whom 12 patients had an involved FLC level > 100 mg/L. Ten patients (7 with involved FLC level > 100 mg/L) were followed over a period ranging from 4 to 8.5 years before eventually progressing, and 12 patients (5 with involved FLC level > 100 mg/L) were followed between 4 and 8 years and did not progress during the study period. Conclusions: While FLC ratio ≥100 is associated with a high risk of progression in patients with SMM, it does not infer an imminent risk of progression, defined by the IMWG as median TTP of 12 months and 2-year progression rate of at least 80%. On the contrary, select patients with FLC ratio ≥100 can be followed for many years without progressing and some may never progress despite long-term follow-up. These findings suggest that in patients where FLC ratio ≥100 is the only myeloma-defining event, other high-risk features as well as the evolution of FLCs over time should be considered in the decision to start a patient on treatment

African American patients with smoldering multiple myeloma may have a lower risk of progression compared to White patients

8045 Background: The incidence of multiple myeloma (MM) is two to threefold higher in African Americans (AAs) compared to whites when adjusted for socioeconomics, age, and sex. However, there is limited information on whether racial background affects the risk of progression from smoldering MM (SMM) to MM. Methods: Patients with SMM presenting to Memorial Sloan Kettering Cancer Center between the years 2000 and 2019 and who identified as either AA or white were included in the study. Baseline characteristics were collected at the time of diagnosis including laboratory, imaging, and pathology reports. Differences in distributions of continuous and discrete characteristics were assessed by Kruskal-Wallis and chi-square tests. Time to progression (TTP) was assessed using the Kaplan-Meier method with log-rank test for comparisons. Univariate and multivariate Cox proportional hazard models were used to estimate effects of risk factors on TTP with hazard ratios (HR) and 95% confidence intervals (CI). Results: A total of 576 patients were included (70 were AA, 12%). Median follow-up time was 3 years in AAs and 4 years in whites. Differences in baseline characteristics between AAs and whites included median age (60 years in AAs vs 64 years in whites, p = 0.01), median hemoglobin level (12.3g/dL in AA vs 12.8g/dL in whites, p = 0.02), and immunoparesis including 1 or 2 uninvolved immunoglobulins (31% and 10% in AAs vs 56% and 27% in whites, p = 0.002). There was no difference in bone marrow plasma cells, M-spike, free light chain ratio, or Mayo-2018 SMM risk score. AA race was associated with a significantly decreased risk of progression in the univariate model (HR 0.57, CI 0.34-0.94). In the multivariate model adjusting for age, sex, and variables associated with an increased risk of progression in the univariate model (bone marrow plasma cells, M-spike, free light chain ratio, immunoparesis and low albumin), AA race remained associated with a decreased risk of progression (HR 0.39, CI 0.16-0.95). Overall, AA patients with SMM had a significantly (p = 0.027) longer median TTP (9.7 vs 6.2 years), and a lower 2-year (12.6% vs 20.1%) and 5-year (34% vs 44.6%) progression rate than whites. Because AA patients were younger at diagnosis, we stratified patients by age group, < 65 vs ≥65 years. In patients < 65 years, there was no difference in progression rate. In patients aged ≥65 years, AA patients continued to have a longer TTP than whites (9.8 vs 5.2 years, p = 0.02). Conclusions: In our retrospective single institution experience, AA patients with SMM had a lower risk of progression to MM compared to whites. Both groups had similar Mayo-2018 risk scores, however, AA patients had a lower degree of immunoparesis at baseline. Future studies are needed to better understand if these differences are explained by differences in disease biology including genomic mechanisms, immune microenvironment, and systemic immune response