Abiraterone acetate received licencing for use in only “high-risk” metastatic hormone-naïve prostate cancer (mHNPC) following the LATITUDE trial findings. However, a “risk”-related effect was not seen in the STAMPEDE trial. There remains uncertainty as to whether men with LATITUDE “low-risk” M1 disease benefit from androgen deprivation therapy (ADT) combined with abiraterone acetate and prednisolone (AAP).
Objective
Evaluation of heterogeneity of effect between LATITUDE high- and low-risk M1 prostate cancer patients receiving ADT + AAP in the STAMPEDE trial.
Design, setting, and participants
A post hoc subgroup analysis of the 2017 STAMPEDE “abiraterone comparison”. Staging scans for M1 patients contemporaneously randomised to ADT or ADT + AAP within the STAMPEDE trial were evaluated centrally and blind to treatment assignment. Stratification was by risk according to the criteria set out in the LATITUDE trial. Exploratory subgroup stratification incorporated the CHAARTED criteria.
Outcome measurements and statistical analysis
The primary outcome measure was overall survival (OS) and the secondary outcome measure was failure-free survival (FFS). Further exploratory analysis evaluated clinical skeletal-related events, progression-free survival (PFS), and prostate cancer-specific death. Standard Cox-regression and Kaplan-Meier survival estimates were employed for analysis.
Results and limitations
A total of 901 M1 STAMPEDE patients were evaluated after exclusions. Of the patients, 428 (48%) were identified as having a low risk and 473 (52%) a high risk. Patients receiving ADT + AAP had significantly improved OS (low-risk hazard ratio [HR]: 0.66, 95% confidence interval or CI [0.44–0.98]) and FFS (low-risk HR: 0.24, 95% CI [0.17–0.33]) compared with ADT alone. Heterogeneity of effect was not seen between low- and high-risk groups for OS or FFS. For OS benefit in low risk, the number needed to treat was four times greater than that for high risk. However, this was not observed for the other measured endpoints.
Conclusions
Men with mHNPC gain treatment benefit from ADT + AAP irrespective of risk stratification for “risk” or “volume”.
Patient summary
Coadministration of abiraterone acetate and prednisolone with androgen deprivation therapy (ADT) is associated with prolonged overall survival and disease control, compared with ADT alone, in all men with metastatic disease starting hormone therapy for the first time.
Introduction
Two randomised controlled trials have reported survival gains for men with metastatic hormone-naïve prostate cancer (mHNPC) treated with androgen deprivation therapy (ADT) plus abiraterone acetate and prednisolone/prednisone (AAP) compared with ADT alone [1], [2]. These results have established ADT + AAP as an alternative standard of care to ADT + docetaxel in the treatment of men with mHNPC. However, there are important differences in the design of the two trials regarding inclusion of patients based on their disease burden: LATITUDE recruited only newly diagnosed metastatic (M1) patients with “high-risk” disease starting long-term ADT for the first time, whereas STAMPEDE recruited nonmetastatic (M0) and M1 patients without risk stratification. The LATITUDE trial defined high-risk disease according to a combination of poor prognostic radiological and/or pathological features. In 2018, the European Medicines Agency and the Food and Drug Administration licensed AAP for the treatment of M1 patients with “high-risk” disease only [3], [4]. Uncertainty now exists regarding the treatment benefit for patients with “low-risk” M1 disease. To address this, patients in the “abiraterone comparison” of STAMPEDE underwent image-based post hoc subset analysis, stratified retrospectively by baseline staging risk to assess whether ADT + AAP is effective in low- as well as high-risk M1 disease.
Section snippets
Trial design
STAMPEDE uses a multiarm multistage platform [5] design to test multiple treatment approaches against control [6], [7], [8], [9]. All patients relevant to this comparison were randomised to ADT + AAP (trial arm G) or ADT alone (trial arm A). Patients underwent baseline imaging prior to randomisation, including computed tomography (CT) or magnetic resonance imaging (MRI) of the pelvis/abdomen, and a technetium-99 bone scan before 1:1 randomisation to ADT + AAP or ADT alone.
Cohort selection and imaging review
Patients from the
Study cohort
Between 15 November 2011 and 17 January 2014, 990 mHNPC M1 patients were randomised to receive ADT alone or with AAP. Patients with incomplete information precluding radiological risk-based classification were excluded as follows: absent Gleason score (n = 34), unobtainable bone scintigraphy (n = 41), and bone metastases diagnosed using nonconventional imaging (n = 14). A total of 901 mHNPC patients underwent stratification using the LATITUDE risk criteria (Fig. 1) and, thereafter, the CHAARTED
Discussion
The results from this STAMPEDE analysis support the use of ADT + AAP in men with mHNPC irrespective of “risk” or “volume” stratifications. The ADT + AAP benefit extended throughout all measured efficacy endpoints with a clear survival advantage in the de novo metastatic setting (HR: 0.59, 95% CI [0.47–0.74]). The survival benefit with ADT + AAP extends to the entire M1 cohort, irrespective of subgroup classification as defined by the LATITUDE or CHAARTED criteria, on each of the efficacy
Conclusions
Men with mHNPC benefit from ADT + AAP irrespective of whether they have LATITUDE low/high-risk or CHAARTED low/high-volume categorisation. The license indications for the use of this combination treatment irrespective of “risk” or “volume” classification should now be reconsidered.
Author contributions: Noel W. Clarke had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer
N Engl J Med
(2017)
N.D. James et al.
Abiraterone for prostate cancer not previously treated with hormone therapy
N Engl J Med
(2017)
EMA
Zytiga (abiraterone acetate) licencing
FDA
FDAC for DER. Zytiga (abiraterone acetate) plus prednisone approved for treatment of patients with metastatic high-risk castrate sensitive metastatic prostate cancer
(2018)
P. Royston et al.
Designs for clinical trials with time-to-event outcomes based on stopping guidelines for lack of benefit
Trials
(2011)
M.R. Sydes et al.
Flexible trial design in practice—stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial
Trials
(2012)
M.R. Sydes et al.
Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial
The utility of prostate radiotherapy (RT) is unclear in men with metastatic hormone-sensitive prostate cancer (mHSPC) receiving intensified systemic therapy with androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs). We performed a network meta-analysis of randomized controlled trials (RCTs) to investigate the role of prostate RT in low-volume mHSPC.
Bibliographic databases and conference proceedings were searched through July 2023 for RCTs evaluating the addition of ARPIs or prostate RT to standard of care (SOC) systemic therapy, defined as ADT or ADT plus docetaxel, for the initial treatment of mHSPC. We focused exclusively on aggregate data from the low-volume mHSPC subpopulation in these trials. We pooled the treatment arms into four groups: SOC, SOC plus ARPI, SOC plus RT, and SOC plus ARPI plus RT. The primary outcome was overall survival (OS). To compare treatment strategies, a fixed-effects Bayesian network meta-analysis was undertaken, while a Bayesian network meta-regression was performed to account for across-trial differences in docetaxel use as part of SOC and in proportions of patients with de novo presentation.
Ten RCTs comprising 4423 patients were eligible. The Surface Under the Cumulative Ranking Curve scores were 0.0006, 0.45, 0.62, and 0.94 for SOC, SOC plus RT, SOC plus ARPI, and SOC plus ARPI plus RT, respectively. On a meta-regression, in a population with de novo mHSPC and no docetaxel use, we did not find sufficient evidence of a difference in OS between SOC plus ARPI plus RT versus SOC plus ARPI (hazard ratio [HR]: 0.76; 95% credible interval: 0.51–1.16) and SOC plus RT versus SOC plus ARPI (HR: 1.10; 95% credible interval: 0.92–1.42).
There was some evidence that SOC plus ARPI plus RT reduced mortality compared with the next best strategy of SOC plus ARPI in patients with low-volume de novo mHSPC. A meta-analysis with individual patient data or an RCT is needed to confirm these findings.
Two randomized controlled trials recently demonstrated an overall survival benefit with triplet therapy (androgen receptor axis–targeted agent [ARAT] + docetaxel + androgen deprivation therapy [ADT]) over doublet therapy (docetaxel + ADT) in metastatic hormone-sensitive prostate cancer (mHSPC), broadening the treatment options. In our previous systematic review and network meta-analysis on the role of triplet versus doublet therapy, we focused on ARAT + ADT, as this is the actual standard of care in many countries for mHSPC. However, survival data by disease volume were only available for one triplet therapy regimen (PEACE-1). Survival data stratified by disease volume for a second triplet regimen (ARASENS) are now available, hence we updated our meta-analysis for low- and high-volume mHSPC. Consistent with previous findings, ADT alone no longer represents a valid treatment option for mHSPC. Similar considerations apply to doublet therapy with docetaxel + ADT. For low-volume mHSPC, in comparison to ADT, the benefit of combination therapies other than ARAT + ADT was not substantial. For high-volume mHSPC, darolutamide + docetaxel + ADT ranked first (P score 0.92), followed by abiraterone + docetaxel + ADT (P score 0.85) and then ARAT + ADT combination therapies. In high-volume mHSPC, only darolutamide + docetaxel + ADT demonstrated superior overall survival (hazard ratio 0.76, 95% confidence interval 0.59–0.97) versus (pooled) ARAT + ADT, confirming the importance of triplet therapy in (high-volume) mHSPC.
We performed an updated comparison of double and triple therapy options for metastatic prostate cancer that still responds to hormone treatment. For patients with low-volume cancer, there was no significant survival benefit from addition of a third drug. For patients with high-volume cancer, the best survival was obtained with darolutamide + docetaxel + androgen deprivation therapy.
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.
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).
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).
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.
Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.
2023, Urologic Oncology: Seminars and Original Investigations
There have been a growing number of treatment options available for men with metastatic castration-sensitive prostate cancer. Not only have newer agents entered the clinical landscape, there is a trend toward treatment intensification by combining multiple agents simultaneously. We aim to assess the best contemporary treatment option for men with mCSPC.
We perform an updated systematic review and network meta-analysis of randomized control trials that evaluated systemic therapies in men with castration-sensitive prostate cancer. We searched multiple databases up to April 2022. We included all randomized trials assessing the effect of systemic agents. We performed subgroup analyses based on disease volume and timing of presentation. Statistical analysis was performed with Bayesian methods.
We found 10 eligible trials with 10,065 patients who were included in this analysis. Triplet therapy with darolutamide or abiraterone with docetaxel and ADT improved overall survival. In the sensitivity analysis, the respective hazard ratios for triplet therapy was HR 0.70 (95%CI 0.61–0.80) compared to docetaxel+ADT and 0.77 (95%CI 0.65–0.91) compared to androgen receptor pathway inhibitors+ADT combinations. It was estimated that there was 96% chance that one of the triplet therapy combinations were the best treatment option from an OS perspective. Triplet therapy also improved progression-free survival. These benefits were pronounced in men with high-volume disease burden and those with de novo metastatic disease.
The finding suggest that triplet therapy is likely the most efficacious available option in men with metastatic, castration-sensitive prostate cancer, especially in those with high-volume disease burden.
