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Metastasis-directed therapy by stereotactic body radiotherapy (SBRT) has been shown to improve clinical outcomes in the oligometastatic prostate cancer setting. We aimed to investigate whether short-course androgen deprivation therapy (ADT) and SBRT at all oligometastatic sites versus SBRT alone improves clinical progression-free survival in men with metachronous oligorecurrent hormone-sensitive prostate cancer. The RADIOSA study was a single-centre, randomised, open-label, controlled phase 2 trial done in the European Institute of Oncology, IRCCS, Milan, Italy. Key eligibility criteria were histologically proven initial diagnosis of adenocarcinoma of the prostate, biochemical progression after radical local prostate treatment, nodal relapse in the pelvis, extra-regional nodal relapse, bone metastases at next-generation imaging with a maximum of three lesions, Eastern Cooperative Oncology Group (ECOG) performance status 0–1, and age 18 years or older. Participants were stratified according to prostate-specific membrane antigen doubling time (≤3 vs >3 months), metastases localisation (node vs bone), and diagnostic imaging (positron emission tomography vs MRI) and were randomly assigned (1:1) using a computer-generated random number to SBRT alone or SBRT in combination with 6 months of ADT. For SBRT treatment, a schedule of 30 Gy in three fractions every other day (with the equivalent dose in 2 Gy fractions being 98·6 Gy, considering α/β ratio of 1·5 Gy and biologically effective dose of >100 Gy), or equivalent regimens depending on disease site location, was administered. Patients in the SBRT with ADT group received 6 months of ADT with a luteinising hormone-releasing hormone analogue within 1 week before the start of SBRT. The allocated treatment was not masked. The primary outcome measure was clinical progression-free survival. All analyses followed a modified intention-to-treat principle, consisting of all patients assigned to a treatment group who had available data. The trial is registered at ClinicalTrials.gov, NCT02680587, and is complete. Between Aug 1, 2019, and April 30, 2023, 218 patients were assessed for eligibility, 113 were excluded, and 105 were enrolled and randomly assigned to an intervention (52 to SBRT only and 53 to SBRT with ADT). Three patients were lost to follow-up and 51 patients in each group were assessed for the primary outcome. The median age at study enrolment was 70 years (IQR 65–75); data on race and ethnicity were not collected. With a median follow-up of 31 months (IQR 16–36) for both groups, the median clinical progression-free survival was 15·1 months (95% CI 12·4–22·8) for the SBRT group versus 32·2 months (22·4–not reached) for the SBRT with ADT group (hazard ratio 0·43 [95% CI 0·26–0·72], p=0·0010]). One gastrointestinal grade 1 adverse event (SBRT group) and one genitourinary grade 3 adverse event (left ureter stenosis, SBRT with ADT group) were reported, with no late toxicities observed. 22 grade 1 ADT-related adverse events were reported, all of which had resolved at the last follow-up. No treatment-related deaths were recorded. To our knowledge, the RADIOSA trial represents the first randomised trial in the metachronous oligometastatic hormone-sensitive prostate cancer setting to report improved clinical progression-free survival with the combination of SBRT and a short course of ADT, although carefully selected patients might still benefit from SBRT alone. By demonstrating improved clinical progression-free survival, the RADIOSA trial reinforces the role of metastasis-directed therapy in delaying systemic treatment escalation. Additionally, it underscores the need for further studies to determine the optimal duration of ADT and identify biomarkers predicting response to SBRT alone. Italian Association of Cancer Research.

ProBio is the first outcome-adaptive platform trial in prostate cancer utilizing a Bayesian framework to evaluate efficacy within predefined biomarker signatures across systemic treatments. Prospective circulating tumor DNA and germline DNA analysis was performed in patients with metastatic castration-resistant prostate cancer before randomization to androgen receptor pathway inhibitors (ARPIs), taxanes or a physician’s choice control arm. The primary endpoint was the time to no longer clinically benefitting (NLCB). Secondary endpoints included overall survival and (serious) adverse events. Upon reaching the time to NLCB, patients could be re-randomized. The primary endpoint was met after 218 randomizations. ARPIs demonstrated ~50% longer time to NLCB compared to taxanes (median, 11.1 versus 6.9 months) and the physician’s choice arm (median, 11.1 versus 7.4 months) in the biomarker-unselected or ‘all’ patient population. ARPIs demonstrated longer overall survival (median, 38.7 versus 21.7 and 21.8 months for taxanes and physician’s choice, respectively). Biomarker signature findings suggest that the largest increase in time to NLCB was observed in AR (single-nucleotide variant/genomic structural rearrangement)-negative and TP53 wild-type patients and TMPRSS2–ERG fusion-positive patients, whereas no difference between ARPIs and taxanes was observed in TP53 -altered patients. In summary, ARPIs outperform taxanes and physician’s choice treatment in patients with metastatic castration-resistant prostate cancer with detectable circulating tumor DNA. ClinicalTrials.gov registration: NCT03903835 . In a biomarker-driven, outcome-adaptive platform trial for patients with metastatic castration-resistant prostate cancer, androgen receptor pathway inhibitors showed longer survival with respect to taxanes and physician’s choice treatment.

In the ProtecT trial, over 1600 men with PSA-detected localized prostate cancer were assigned to active monitoring, prostatectomy, or radiotherapy. Although more patients assigned to active monitoring had disease progression, overall survival was similar in the three groups. The management of clinically localized prostate cancer that is detected on the basis of prostate-specific antigen (PSA) levels remains controversial. In the United States alone, an estimated 180,890 cases will be diagnosed in 2016, and 26,120 men will die from the disease. 1 The widespread use of PSA testing has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer, but many men do not benefit from intervention because the disease is either indolent or disseminated at diagnosis. Prostate cancer often progresses slowly, and many men die of competing causes. In addition, interventions for prostate cancer can have . . .

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. 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. 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. 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. Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

The addition of abiraterone and prednisolone to standard androgen-deprivation therapy as the first treatment for patients with locally advanced or metastatic prostate cancer improved overall and failure-free survival, with a small increase in high-grade toxic effects.

The choice of treatment for PSA-detected, localized prostate cancer is influenced by effects of the interventions on quality of life. In the ProtecT trial, patterns of side-effect severity, improvement, and decline in urinary, sexual, and bowel function differed among the treatments. As reported in a companion article in the Journal, the U.K. National Institute for Health Research–supported Prostate Testing for Cancer and Treatment (ProtecT) trial has shown no significant difference in prostate-cancer–specific mortality or all-cause mortality among men with prostate cancer detected by prostate-specific antigen (PSA) testing who were randomly assigned to radical prostatectomy, active monitoring (a surveillance strategy), or radical conformal radiotherapy with neoadjuvant hormonal therapy, at a median of 10 years of follow-up; however, the ProtecT trial has shown higher rates of metastases and disease progression among men in the active-monitoring group than among men in the radical-treatment groups. . . .

Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy. We did a randomised controlled phase 3 trial at 117 hospitals in Switzerland and the UK. Eligible patients had newly diagnosed metastatic prostate cancer. We randomly allocated patients open-label in a 1:1 ratio to standard of care (control group) or standard of care and radiotherapy (radiotherapy group). Randomisation was stratified by hospital, age at randomisation, nodal involvement, WHO performance status, planned androgen deprivation therapy, planned docetaxel use (from December, 2015), and regular aspirin or non-steroidal anti-inflammatory drug use. Standard of care was lifelong androgen deprivation therapy, with up-front docetaxel permitted from December, 2015. Men allocated radiotherapy received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) schedule that was nominated before randomisation. The primary outcome was overall survival, measured as the number of deaths; this analysis had 90% power with a one-sided α of 2·5% for a hazard ratio (HR) of 0·75. Secondary outcomes were failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival, and symptomatic local event-free survival. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. The primary outcome analysis was by intention to treat. Two prespecified subgroup analyses tested the effects of prostate radiotherapy by baseline metastatic burden and radiotherapy schedule. This trial is registered with ClinicalTrials.gov, number NCT00268476. Between Jan 22, 2013, and Sept 2, 2016, 2061 men underwent randomisation, 1029 were allocated the control and 1032 radiotherapy. Allocated groups were balanced, with a median age of 68 years (IQR 63–73) and median amount of prostate-specific antigen of 97 ng/mL (33–315). 367 (18%) patients received early docetaxel. 1082 (52%) participants nominated the daily radiotherapy schedule before randomisation and 979 (48%) the weekly schedule. 819 (40%) men had a low metastatic burden, 1120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0·76, 95% CI 0·68–0·84; p<0·0001) but not overall survival (0·92, 0·80–1·06; p=0·266). Radiotherapy was well tolerated, with 48 (5%) adverse events (Radiation Therapy Oncology Group grade 3–4) reported during radiotherapy and 37 (4%) after radiotherapy. The proportion reporting at least one severe adverse event (Common Terminology Criteria for Adverse Events grade 3 or worse) was similar by treatment group in the safety population (398 [38%] with control and 380 [39%] with radiotherapy). Radiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer. Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis.

The addition of abiraterone, a drug that blocks endogenous androgen synthesis, to standard androgen-deprivation therapy in patients with newly diagnosed, metastatic prostate cancer significantly increased overall survival, with a low rate of adverse effects.

With a median follow-up of 13 years, a randomized comparison of radiotherapy with or without antiandrogen therapy in patients with a rising PSA level after prostatectomy showed that 2 years of antiandrogen therapy resulted in a significantly higher overall survival rate. Patients with localized prostatic cancer are often treated with radical prostatectomy. More than 30% of such patients will subsequently have recurrence. This recurrence manifests first as a rising serum level of prostate-specific antigen (PSA), 1 – 3 termed biochemical recurrence. Large, retrospective studies suggest that salvage radiation therapy after biochemical recurrence may be associated with long-term freedom from cancer recurrence. 4 , 5 However, 50% of the patients who are treated with salvage radiation therapy will have further disease progression, particularly when there are aggressive disease features. 4 – 7 The combination of radiation therapy and either androgen-deprivation therapy or antiandrogen therapy prolongs survival among some . . .