Margaret McJannett

BACKGROUND: Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer. METHODS: In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events. RESULTS: A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P = 0.002). Kaplan-Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P<0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P<0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group. CONCLUSIONS: Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.).

Objective To assess the activity and safety of cabazitaxel chemotherapy vs that of treatment with 177 Lu‐ PSMA ‐617, a novel radiolabelled small molecule that binds with high affinity to prostate‐specific membrane antigen ( PSMA ), in men with metastatic castration‐resistant prostate cancer ( mCRPC ) who have received prior docetaxel treatment. Patients and methods The TheraP trial ( ANZUP 1603) is an open‐label, randomized, stratified, two‐arm multicentre phase 2 trial comparing the activity and safety of cabazitaxel chemotherapy vs 177 Lu‐ PSMA ‐617 therapy in the treatment of men with mCRPC . Key eligibility criteria include prior docetaxel chemotherapy, rising prostate‐specific antigen ( PSA ) level, sufficient PSMA avidity, as defined by centrally reviewed 68 Ga‐ PSMA ‐11 and fluorodeoxyglucose ( FDG )‐positron emission tomography ( PET )/computed tomography ( CT ) with no discordant FDG ‐avid PSMA ‐negative sites of disease. Patients in the control group receive standard treatment with cabazitaxel (20 mg/m 2 ) i.v. every 3 weeks with prednisolone 10 mg daily orally, for a maximum of 10 cycles. Patients in the experimental group receive 177 Lu‐ PSMA ‐617 (8.5 GB q decreasing by 0.5 GB q per cycle) i.v. every 6 weeks, for up to a maximum of six cycles. In the event of an exceptional response as defined on centrally reviewed post‐therapy single‐photon emission CT imaging, treatment will be suspended but can recommence on progression. The trial aims to include 200 patients who will be centrally randomized to one of the two treatment groups, in a 1:1 ratio. The primary endpoint is PSA response. Secondary endpoints are overall survival, progression‐free survival ( PFS ), radiographic PFS , PSA PFS , objective tumour response, pain response, pain PFS , health‐related quality of life, and frequency and severity of adverse events. The treatment and outcomes of patients excluded on the basis of low PSMA avidity or discordant FDG ‐avid disease on screening 68 Ga‐ PSMA ‐11 and Fluorine‐18 ( 18 F)‐ FDG ‐ PET / CT scan will also be assessed. Enrolment in the study commenced on 29 January 2018. Results and Conclusions 177 Lu‐ PSMA ‐617 offers a potential additional life‐prolonging treatment option for men with mCRPC . The results of this trial will determine, for the first time in a randomized design, the activity and safety of 177 Lu‐ PSMA ‐617, as compared with cabazitaxel chemotherapy in men with progressive mCRPC .