A real-world evaluation of radium-223 in combination with abiraterone or enzalutamide for the treatment of metastatic castration-resistant prostate cancer

Introduction Radium-223, abiraterone, and enzalutamide have each been shown to significantly improve survival as monotherapy in patients with metastatic castration-resistant prostate cancer. However, effects of combination radium-223 plus abiraterone or enzalutamide on survival and safety remain unclear. Patients and methods This single-center retrospective cohort study used electronic health record data of patients with metastatic castration-resistant prostate cancer and bone metastases who were treated with radium-223 between April 1, 2014 and February 19, 2019. Patients who received radium-223 monotherapy were compared to patients who received a combination of radium-223 plus either abiraterone or enzalutamide. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, time to symptomatic skeletal event, symptomatic skeletal event-free survival, and incidence of drug-related adverse events. Time-to-event analyses were estimated by log rank tests using Kaplan-Meier curves. Hazard ratios and 95% confidence intervals were derived from Cox proportional hazards models. Chi-square tests evaluated difference in serious adverse events between the two arms. Results A total of 60 patients met inclusion criteria (n = 41 in the monotherapy arm, n = 19 in the combination arm). Differences in median overall survival were not observed (12.7 vs. 12.8 months; HR 1.15, 95% CI 0.59–2.23; P = 0.68), but median progression-free survival was significantly longer in the combination arm (7.6 vs. 4.9 months; HR 1.94, 95% CI 1.11–3.40; P = 0.02). Significant differences were not observed in time to first SSE (P = 0.97), SSE-free survival (P = 0.16), or in the overall incidence of serious adverse events (P = 0.45). Conclusion Combination radium-223 plus abiraterone or enzalutamide did not improve overall survival, but prolonged progression-free survival without increasing the incidence of serious adverse events in metastatic castration-resistant prostate cancer patients with bone metastases. However, these results are limited by small numbers and patient selection inherent in retrospective analysis.

RADTHYR: an open-label, single-arm, prospective multicenter phase II trial of Radium-223 for the treatment of bone metastases from radioactive iodine refractory differentiated thyroid cancer

Purpose This is the first prospective trial evaluating the efficacy of alpha emitter Radium-223 in patients with bone metastases from radioactive iodine (RAI) refractory (RAIR) differentiated thyroid cancer. Methods RADTHYR is a multicenter, single-arm prospective Simon two-stage phase II trial (NCT02390934). The primary objective was to establish the efficacy of three administrations of 55 kBq/kg of Radium-223 by 18F-FDG PET/CT according to PERCIST criteria. Secondary objectives were to establish the efficacy of six administrations of Radium-223 by 18F-FDG PET/CT, 99mTc-HMDP bone scan and 18FNa PET/CT, clinical benefits, changes in serum bone markers, thyroglobulin levels, and safety. Results Ten patients were enrolled between July 2015 and December 2017 (4 M; median age 74 years). Prior to Radium-223 administration, patients received a median RAI cumulative activity of 15 GBq (7.4–35.6), external radiation therapy (n = 9), bone surgery (n = 8), cimentoplasty (n = 5), and cryoablation (n = 2). 18F-FDG PET/CT showed stable disease (SD) in 4/10 and progressive disease (PD) in 6/10 cases after three administrations and SD in 4/10, PD in 5/10 cases, and 1/10 non-evaluable (NE) case after six administrations. After six injections, 99mTc-HMDP bone scan showed SD in 9 cases and was NE in 1 case; 18FNa PET/CT showed SD in 8 cases, partial response (PR) in 1 case, and was NE in 1 case. No significant clinical benefits were reported during the study. A skeletal event occurred in 6 patients (median time without skeletal event of 12.1 months). Seventy-seven adverse events were reported during treatment (7 of grade 3–4). Three patients developed an acute myeloid, a promyelocytic, and a chronic myeloid leukemia after the last Radium-223 administration considered as drug-related. Conclusion The trial was stopped after interim analysis for lack of response of bone metastases from RAIR thyroid cancer to Radium-223. Severe hematological toxicity was observed in patients heavily pretreated with RAI and external radiation. Trial registration number NCT02390934. Registration date 18.03.2015.

Real-world outcomes of radium-223 dichloride for metastatic castration resistant prostate cancer

Aim: Timing of radium-223 (Ra-223) in metastatic castration-resistant prostate cancer (mCRPC) remains challenging due to alternative options and short window of opportunity. Methods: Ra-223 treated patients in the CAPRI-registry were included. Outcomes were evaluated based on treatment line of Ra-223. Results: Out of 285 patients, 49% received Ra-223 in line ≥3. 51% completed six Ra-223 injections and 34% had a symptomatic skeletal event after first Ra-223 without differences between subgroups. After correction of known prognostic factors Ra-223 in line ≥3 (HR: 3.267; 95% CI: 1.689–6.317; p < 0.01) remained associated with worse OS. Conclusion: In the Netherlands, Ra-223 was mainly started as second or third mCRPC-treatment in 2014–2018. Later timing of Ra-223 did affect OS, but not treatment completion and occurrence of symptomatic skeletal events.

Phase II trial of combination therapy with intravenous bevacizumab (B), oral satraplatin (S), and prednisone (P) in docetaxel-pretreated (DP) metastatic castrate-resistant prostate cancer (CRPC).

152 Background: Satraplatin is an oral platinum that has demonstrated efficacy and tolerability in metastatic CRPC. Bevacizumab has revealed safety and efficacy in advanced prostate cancer, and synergy was noted between platinum based chemotherapy and B. Methods: Primary endpoint was time to progression (TTP). Latter wasdefined per RECIST 1.0 or onset of a skeletal event, or > 2 new areas of bone metastases. DP metastatic CRPC patients were eligible. S 80mg/m2 orally on days 1-5, P 5 mg twice daily, and B 10mg/kg on day 1, and 15mg/kg on day 15 were administered in 35 day cycles. Results: 31 patients enrolled (13 African American and 18 Caucasian) to complete accrual. Median age was 67 years (range 50-85 years) and 21 patients (68%) were > 65 years of age. Median pretherapy PSA was 180.7 ng/ml (range 4.7-1,433 ng/ml). 21 (68%) had bone pain, Gleason score was > 8 in 20 (65%) patients. Pretherapy 12 patients had measurable disease progression, 17 (55%) had bone scan progression, and 8 had PSA only progression. 176 cycles have been administered; median 4 cycles (range 0-12 cycles). Grade 4 toxicities noted were, pulmonary embolism in 2 patients and thrombocytopenia in 1 patient. Grade 3 toxicities observed were neutropenia and hypertension in 3, anemia in 7 and , thrombocytopenia and diarrhea in 2 patients each. No treatment related deaths. 29 patients are response evaluable to date; 10 (34%) had a ≥30% PSA decline and 3 (10%) had a > 90% PSA decline. Of 12 patients with MD, 2 had a response and 7 had stable disease. Median TTP was 7.4 months (90% CI 4.8-12.8 months) and median survival was 11.2 months (90% CI 9.1-18.3 months). 47% of patients were alive at 12 months. Genotype characterization for excision repair cross-complementation group 1 (ERCC1) polymorphism was performed in 17 patients with 9 having homozygous (CC), 3 with heterozygous, (CT) and 2 patients with absence of ERCC expression respectively. Conclusions: The combination was tolerable and revealed promising efficacy in metastatic CRPC. ERCC1 testing will be correlated with outcome endpoints. Supported in part by Genentech Inc and GPC Biotech. [Table: see text]

Randomised Study on Prophylactic Pamidronate 30 mg vs. 90 mg in Multiple Myeloma (Nordic Myeloma Study Group).

Background: Prophylactic bisphosphonates are used worldwide in multiple myeloma patients, and two randomised studies have shown significant effect of i.v. pamidronate 90 mg once a month (N Engl J Med 1996 Feb 22;334(8):488–931) and of oral clondronate 1600 mg daily compared to placebo (Br J Haematol 2001 Jun;113(4):1035–43). However, no larger clinical study has addressed the dose-efficacy question, which is of increasing importance in view of recent reports on the risk of renal toxicity and osteonecrosis of the jaw (ONJ). In 2000 we started a randomised double blind trial with i.v. pamidronate 30 mg versus 90 mg monthly for at least 3 years. Design: Patients with newly diagnosed symptomatic multiple myeloma were allocated to one of the two doses. Patients were stratified according to planned high dose therapy or conventional therapy and to the level of beta-2-microglobulin. Primary end-point was physical functioning at 12 months as measured by the EORTC QLQ-C30 quality of life questionnaire (QLQ), while secondary end-points were time to first objective skeletal event, cost-utility analysis, response of myeloma disease, response duration and survival, fatigue and pain determined by the QLQ. The patients were followed every third month with respect to skeletal event, toxicity and response, while the QLQ was mailed directly to the patients every third month. Skeletal x-rays were routinely performed before, and 9 and 24 months after start of pamidronate therapy. Results: 505 patients were randomised. Median age was 63,4 years (range: 35–92). Sixty percent of the patients were treated with high-dose therapy and 40 percent with melphalan-prednisone (MP) regimes. The median follow up time was 3,7 years (1.1 to 5.7 years). There was no significant difference between the two treatment arms with respect to age, proportion of high-dose treated patients, skeletal involvement, stage (both international staging system (ISS) and Durie and Salmon), or b-2-microglobulin. The initial analysis of QLQ data shows improvement of global health status, pain, fatigue and physical functioning after myeloma treatment in accordance with earlier publication (Eur J Haematol 2001 May;66(5):328–36), but no significant difference regarding the primary end-point between the two pamidronate dose groups. Time to first skeletal event was not different in the two arms. The results from the blinded review of all skeletal x-rays will be presented together with the final analysis of toxicity data (renal failure and ONJ). Conclusions:The initial analysis of the first prospective double blind trial on different doses of pamidronate as prophylactic treatment in multiple myeloma shows no significant difference between monthly infusions of 30 and 90 mg with respect to quality of life and time to first skeletal event. The final analysis will show whether the doses have any impact on the toxicity of the bisphosphonates. We recommend that the dose and type of bisphosphonate should be reconsidered in the prophylactic treatment of newly diagnosed myeloma patients. # ClinicalTrials.gov Identifier: NCT00376883

Analysis of skeletal morbidity in breast cancer (BC) patients treated with zoledronic acid (Zol) or placebo: Time to first pathologic fracture

10639 Background: We have previously reported that Zol significantly delayed time to first skeletal-related event (SRE) compared with placebo in BC patients with bone metastases in a multicenter randomized trial conducted in Japan. Patients with bone metastases from BC suffer from a range of skeletal complications, including pathologic fractures that can dramatically decrease mobility and adversely affect patient autonomy and quality of life. Methods: 228 women with bone metastases were randomized to 4 mg Zol (n = 114) or placebo (n = 114) every 4 weeks for 1 year. Time to first skeletal event was estimated using the Kaplan-Meier method for all individual types of event. Median time to individual skeletal events was not reached in either treatment group; therefore, data are presented as the incidence at 1 year, and the log-rank P value is from the Kaplan-Meier estimate of time to first event. Results: Median time to first SRE (including hypercalcemia) was not reached in the Zol group versus 360 days in the placebo group (P = .002). Time to first pathologic fracture (P = .022), spinal cord compression (P = .022), need for radiation therapy to palliate bone pain (P = .054), and hypercalcemia (P = .040) were all reduced in the Zol group compared with the placebo group. The incidence of each of these events at 1 year is shown in the table . Cox regression analysis (adjusting for stratification factors) also showed that treatment with Zol significantly reduced the risk of pathologic fractures by 39% compared with placebo (hazard ratio = 0.61; P = .041). Conclusions: This prospective analysis of time to first skeletal event demonstrates that treatment of BC patients with Zol significantly delays the onset and reduces the risk of skeletal complications, including pathologic fractures, which may help preserve independence and quality of life. [Table: see text] [Table: see text]

Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group.

PURPOSE To determine the efficacy and safety of 21 monthly cycles of pamidronate therapy in patients with advanced multiple myeloma. PATIENTS AND METHODS Patients with stage III myeloma and at least one lytic lesion received either placebo or pamidronate 90 mg intravenously administered as a 4-hour infusion monthly for 21 cycles. At study entry, the patients were stratified according to whether they were to receive first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy. Skeletal events (pathologic fracture, radiation or surgery to bone, and spinal cord compression) and hypercalcemia were assessed monthly. RESULTS The results of the first nine previously reported cycles are extended to 21 cycles. Of the 392 randomized patients, efficacy could be evaluated in 198 who received pamidronate and 179 who received placebo. After 21 cycles, the proportion of patients who developed any skeletal event was lower in the pamidronate-group (P = .015). The mean number of skeletal events per year was less in the pamidronate-group (1.3) than in placebo-treated patients (2.2; P = .008). Although survival was not different between the pamidronate-treated group and placebo patients overall, stratum 2 patients who received pamidronate lived longer than those who received placebo (14 v 21 months, P = .041). Pamidronate was safe and well tolerated during the 21 cycles of therapy. CONCLUSION Long-term monthly infusions of pamidronate as an adjunct to chemotherapy are superior to chemotherapy alone in reducing skeletal events in stage III multiple myeloma patients, and may improve the survival of patients on salvage therapy.