Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol.

BACKGROUND: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. METHODS: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0-2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). FINDINGS: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86-107) in the abiraterone trial and 72 months (61-74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8-86·9) in the abiraterone group versus 45·7 months (41·6-52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53-0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9-81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3-59·0) in the standard of care group (HR 0·65 [0·55-0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83-1·32]; pinteraction=0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3-5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial). INTERPRETATION: Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. FUNDING: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.

Radioembolization With Chemotherapy for Colorectal Liver Metastases: A Randomized, Open-Label, International, Multicenter, Phase III Trial.

PURPOSE: To study the impact of transarterial Yttrium-90 radioembolization (TARE) in combination with second-line systemic chemotherapy for colorectal liver metastases (CLM). METHODS: In this international, multicenter, open-label phase III trial, patients with CLM who progressed on oxaliplatin- or irinotecan-based first-line therapy were randomly assigned 1:1 to receive second-line chemotherapy with or without TARE. The two primary end points were progression-free survival (PFS) and hepatic PFS (hPFS), assessed by blinded independent central review. Random assignment was performed using a web- or voice-based system stratified by unilobar or bilobar disease, oxaliplatin- or irinotecan-based first-line chemotherapy, and KRAS mutation status. RESULTS: Four hundred twenty-eight patients from 95 centers in North America, Europe, and Asia were randomly assigned to chemotherapy with or without TARE; this represents the intention-to-treat population and included 215 patients in the TARE plus chemotherapy group and 213 patients in the chemotherapy alone group. The hazard ratio (HR) for PFS was 0.69 (95% CI, 0.54 to 0.88; 1-sided P = .0013), with a median PFS of 8.0 (95% CI, 7.2 to 9.2) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. The HR for hPFS was 0.59 (95% CI, 0.46 to 0.77; 1-sided P < .0001), with a median hPFS of 9.1 (95% CI, 7.8 to 9.7) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. Objective response rates were 34.0% (95% CI, 28.0 to 40.5) and 21.1% (95% CI, 16.2 to 27.1; 1-sided P = .0019) for the TARE and chemotherapy groups, respectively. Median overall survival was 14.0 (95% CI, 11.8 to 15.5) and 14.4 months (95% CI, 12.8 to 16.4; 1-sided P = .7229) with a HR of 1.07 (95% CI, 0.86 to 1.32) for TARE and chemotherapy groups, respectively. Grade 3 adverse events were reported more frequently with TARE (68.4% v 49.3%). Both groups received full chemotherapy dose intensity. CONCLUSION: The addition of TARE to systemic therapy for second-line CLM led to longer PFS and hPFS. Further subset analyses are needed to better define the ideal patient population that would benefit from TARE.

Oral sodium clodronate induced osteonecrosis of the jaw in a patient with myeloma.

Bisphosphonate therapy has been shown to significantly reduce the incidence of skeletal complications in patients with myeloma. Several recent reports have described osteonecrosis of the jaw (ONJ) associated with bisphosphonates. These reports mainly demonstrate an association between ONJ and potent i.v. bisphosphonates. We report a case of ONJ in a patient with myeloma, who had only been treated with oral sodium clodronate. While the degree of risk for osteonecrosis in patients taking oral bisphosphonates, such as clodronate, remains uncertain it would be prudent to consider carefully the indications for the use of these agents to minimise the risk of ONJ.