Background
Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population.
Methods
These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8–10, and prostate-specific antigen [PSA] concentration ≥40 ng/mL) or relapsing with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse) non-metastatic prostate cancer, and a WHO performance status of 0–2. Local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. In both trials, patients were randomly assigned (1:1), by use of a computerised algorithm, to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate (1000 mg daily) and oral prednisolone (5 mg daily; combination-therapy group). In the second trial with no overlapping controls, the combination-therapy group also received enzalutamide (160 mg daily orally). ADT was given for 3 years and combination therapy for 2 years, except if local radiotherapy was omitted when treatment could be delivered until progression. In this primary analysis, we used meta-analysis methods to pool events from both trials. The primary endpoint of this meta-analysis was metastasis-free survival. Secondary endpoints were overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival, and toxicity and adverse events. For 90% power and a one-sided type 1 error rate set to 1·25% to detect a target hazard ratio for improvement in metastasis-free survival of 0·75, approximately 315 metastasis-free survival events in the control groups was required. Efficacy was assessed in the intention-to-treat population and safety according to the treatment started within randomised allocation. STAMPEDE is registered with ClinicalTrials.gov, NCT00268476, and with the ISRCTN registry, ISRCTN78818544.
Findings
Between Nov 15, 2011, and March 31, 2016, 1974 patients were randomly assigned to treatment. The first trial allocated 455 to the control group and 459 to combination therapy, and the second trial, which included enzalutamide, allocated 533 to the control group and 527 to combination therapy. Median age across all groups was 68 years (IQR 63–73) and median PSA 34 ng/ml (14·7–47); 774 (39%) of 1974 patients were node positive, and 1684 (85%) were planned to receive radiotherapy. With median follow-up of 72 months (60–84), there were 180 metastasis-free survival events in the combination-therapy groups and 306 in the control groups. Metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR not evaluable [NE]–NE) than in the control groups (not reached, 97–NE; hazard ratio [HR] 0·53, 95% CI 0·44–0·64, p<0·0001). 6-year metastasis-free survival was 82% (95% CI 79–85) in the combination-therapy group and 69% (66–72) in the control group. There was no evidence of a difference in metatasis-free survival when enzalutamide and abiraterone acetate were administered concurrently compared with abiraterone acetate alone (interaction HR 1·02, 0·70–1·50, p=0·91) and no evidence of between-trial heterogeneity (I2 p=0·90). Overall survival (median not reached [IQR NE–NE] in the combination-therapy groups vs not reached [103–NE] in the control groups; HR 0·60, 95% CI 0·48–0·73, p<0·0001), prostate cancer-specific survival (not reached [NE–NE] vs not reached [NE–NE]; 0·49, 0·37–0·65, p<0·0001), biochemical failure-free-survival (not reached [NE–NE] vs 86 months [83–NE]; 0·39, 0·33–0·47, p<0·0001), and progression-free-survival (not reached [NE–NE] vs not reached [103–NE]; 0·44, 0·36–0·54, p<0·0001) were also significantly longer in the combination-therapy groups than in the control groups. Adverse events grade 3 or higher during the first 24 months were, respectively, reported in 169 (37%) of 451 patients and 130 (29%) of 455 patients in the combination-therapy and control groups of the abiraterone trial, respectively, and 298 (58%) of 513 patients and 172 (32%) of 533 patients of the combination-therapy and control groups of the abiraterone and enzalutamide trial, respectively. The two most common events more frequent in the combination-therapy groups were hypertension (abiraterone trial: 23 (5%) in the combination-therapy group and six (1%) in control group; abiraterone and enzalutamide trial: 73 (14%) and eight (2%), respectively) and alanine transaminitis (abiraterone trial: 25 (6%) in the combination-therapy group and one (<1%) in control group; abiraterone and enzalutamide trial: 69 (13%) and four (1%), respectively). Seven grade 5 adverse events were reported: none in the control groups, three in the abiraterone acetate and prednisolone group (one event each of rectal adenocarcinoma, pulmonary haemorrhage, and a respiratory disorder), and four in the abiraterone acetate and prednisolone with enzalutamide group (two events each of septic shock and sudden death).
Interpretation
Among men with high-risk non-metastatic prostate cancer, combination therapy is associated with significantly higher rates of metastasis-free survival compared with ADT alone. Abiraterone acetate with prednisolone should be considered a new standard treatment for this population.
Funding
Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.
By Dr. Constance Thibault
In the last decade, the outcome of metastatic prostate cancer has been improved by new hormonal therapies (abiraterone, enzalutamide, apalutamide, darolutamide), but none of these drugs has demonstrated an improvement in the survival of patients with non-metastatic prostate cancer. Recently, a meta-analysis has been conducted on 2 randomized controlled phase III trials included in the STAMPEDE platform to evaluate the efficacy of ADT + abiraterone +/- enzalutamide in non-metastatic prostate cancer patients.
To be enrolled, patients had to have a high-risk non-metastatic prostate cancer (defined as having at least two of the following: T3-T4, Gleason 8–10, and PSA ≥40 ng/mL) or to be N+ or to have a relapsing prostate cancer with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL). The standard treatment consisted of 3 years of ADT. Prostate radiotherapy was mandatory for N0 patients and suggested for N+ patients and encompassed 74 Gy in 37 fractions to the prostate and seminal vesicles. The experimental treatment consisted of 2 years of abiraterone in the first trial, and 2 years of abiraterone + enzalutamide in the second trial. As no benefit was observed when combining abiraterone and enzalutamide in metastatic disease, the authors decided to pool events from both trials to evaluate the benefit of adding abiraterone to standard treatment. The primary endpoint was metastasis-free survival. Secondary endpoints included: overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival and safety.
A total of 1974 patients were enrolled and randomized between 2011 and 2016. The median age was 68 years and the median PSA 34 ng/ml (14.7–47). The majority of the patients were de novo non-metastatic disease (only 3% of relapsing patients after previous treatment) and node negative (61%). Almost all of them were planned to received radiotherapy (85%). After a median follow-up of 72 months (60-84) in abiraterone trial and 60 months (59-71) in abiraterone + enzalutamide trial, the MFS was significantly longer in the experimental arms (ADT + abiraterone +/- enzalutamide) compared to standard treatment with a 6-years-MFS of 82% vs 69% (median not reached, HR=0.53, 95%CI 0.44–0.64, p<0.0001). All other secondary endpoints were also in favor of abiraterone +/- enzalutamide, including overall survival (median not reached in both arms; HR=0.60, 95% CI 0.48–0.73, p<0.0001). Regarding tolerance, they were no new adverse events. The safety profile with abiraterone was similar to the one observed in metastatic disease.
By Dr. Constance Thibault
Once again, STAMPEDE reports practice changing results. Indeed, treatment intensification by adding 2 years of abiraterone to the standard treatment (3 years of ADT + RT) for high-risk non-metastatic prostate cancer improved both metastasis-free and overall survival with an acceptable safety profile. This treatment option is now strongly recommended by the EAU guidelines in patients treated with ADT + radiotherapy for a non-metastatic prostate cancer cN1 or ≥ 2 high-risk factors (cT3–4, Gleason ≥ 8 or PSA ≥ 40 ng/mL). Of note, as patients with a non-metastatic relapse prostate cancer after local treatment represented only 3% of the population enrolled in the study, there is no place for abiraterone in this setting.