Background
Current standard of care for metastatic castration-sensitive prostate cancer supplements androgen deprivation therapy with either docetaxel, second-generation hormonal therapy, or radiotherapy. We aimed to evaluate the efficacy and safety of abiraterone plus prednisone, with or without radiotherapy, in addition to standard of care.
Methods
We conducted an open-label, randomised, phase 3 study with a 2 × 2 factorial design (PEACE-1) at 77 hospitals across Belgium, France, Ireland, Italy, Romania, Spain, and Switzerland. Eligible patients were male, aged 18 years or older, with histologically confirmed or cytologically confirmed de novo metastatic prostate adenocarcinoma, and an Eastern Cooperative Oncology Group performance status of 0–1 (or 2 due to bone pain). Participants were randomly assigned (1:1:1:1) to standard of care (androgen deprivation therapy alone or with intravenous docetaxel 75 mg/m2 once every 3 weeks), standard of care plus radiotherapy, standard of care plus abiraterone (oral 1000 mg abiraterone once daily plus oral 5 mg prednisone twice daily), or standard of care plus radiotherapy plus abiraterone. Neither the investigators nor the patients were masked to treatment allocation. The coprimary endpoints were radiographic progression-free survival and overall survival. Abiraterone efficacy was first assessed in the overall population and then in the population who received androgen deprivation therapy with docetaxel as standard of care (population of interest). This study is ongoing and is registered with ClinicalTrials.gov, NCT01957436.
Findings
Between Nov 27, 2013, and Dec 20, 2018, 1173 patients were enrolled (one patient subsequently withdrew consent for analysis of his data) and assigned to receive standard of care (n=296), standard of care plus radiotherapy (n=293), standard of care plus abiraterone (n=292), or standard of care plus radiotherapy plus abiraterone (n=291). Median follow-up was 3·5 years (IQR 2·8–4·6) for radiographic progression-free survival and 4·4 years (3·5–5·4) for overall survival. Adjusted Cox regression modelling revealed no interaction between abiraterone and radiotherapy, enabling the pooled analysis of abiraterone efficacy. In the overall population, patients assigned to receive abiraterone (n=583) had longer radiographic progression-free survival (hazard ratio [HR] 0·54, 99·9% CI 0·41–0·71; p<0·0001) and overall survival (0·82, 95·1% CI 0·69–0·98; p=0·030) than patients who did not receive abiraterone (n=589). In the androgen deprivation therapy with docetaxel population (n=355 in both with abiraterone and without abiraterone groups), the HRs were consistent (radiographic progression-free survival 0·50, 99·9% CI 0·34–0·71; p<0·0001; overall survival 0·75, 95·1% CI 0·59–0·95; p=0·017). In the androgen deprivation therapy with docetaxel population, grade 3 or worse adverse events occurred in 217 (63%) of 347 patients who received abiraterone and 181 (52%) of 350 who did not; hypertension had the largest difference in occurrence (76 [22%] patients and 45 [13%], respectively). Addition of abiraterone to androgen deprivation therapy plus docetaxel did not increase the rates of neutropenia, febrile neutropenia, fatigue, or neuropathy compared with androgen deprivation therapy plus docetaxel alone.
Interpretation
Combining androgen deprivation therapy, docetaxel, and abiraterone in de novo metastatic castration-sensitive prostate cancer improved overall survival and radiographic progression-free survival with a modest increase in toxicity, mostly hypertension. This triplet therapy could become a standard of care for these patients.
Funding
Janssen-Cilag, Ipsen, Sanofi, and the French Government.
In the last decade, assessment of the upfront combinatory treatment encompassing androgen deprivation therapy (ADT) supplemented by either docetaxel or androgen receptor targeting agents (ARTAs), has yielded evidence for this strategy being strikingly efficacious for survival extension in males with metastatic hormone-sensitive prostate cancer (mHSPC).
Meanwhile, enzalutamide, apalutamide and abiraterone acetate (AA; the latter only for high-risk tumours) have been registered for use as a doublet therapy with concurrent ADT in this condition, whereas docetaxel is being utilised strictly speaking “off-label”. Apart from the value of local treatment on the primary, the current focus of clinical trials in mHSPC has been shifted towards further intensification of the upfront systemic disease management by contemporaneously combining more than two agents. Most recently, first results of the ARASENS trial showed a significant survival prolongation when adding darolutamide to ADT+docetaxel as compared to ADT+docetaxel only.
PEACE-1 is another study evaluating inter alia the activity of a triple drug combination by adding AA to ADT+docetaxel in men with mHSPC. Fizazi and co-authors performed this open-label, randomised, phase 3 study in a 2×2 factorial design, while 1,173 men with de novo mHSPC were enrolled and assigned to standard of care (SOC), SOC+AA, SOC+radiotherapy (RT) or SOC+RT+AA. Co-primary endpoints were radiographic progression-free (rPFS) as well as overall survival (OS) assessed in overall and in docetaxel-treated population. SOC was ADT at the beginning of the study and was changed first to facultative and later mandatory ADT+docetaxel following emerging evidence for the benefit of the upfront chemohormonal treatment.
While no interaction was found between RT and AA, the pooled assessment of AA efficacy including patients of all four arms could be exerted (overall:1,172 and docetaxel-treated: 710 patients, respectively) balancing the effect of RT in the comparison between men with and without AA therapy. The rate of high-volume disease (CHAARTED definition) was ca. 60% in the docetaxel-treated population, which represents the cohort of interest in this trial. Adding AA to SOC (with docetaxel) led to a risk reduction of event occurrence in rPFS and OS by 50% and 25%, respectively. Moreover, rPFS was significantly extended both in low- and high-volume disease by ADT+docetaxel+AA as compared to ADT+docetaxel only. At the same time, OS was prolonged in men with a high-volume disease, while it was immature in those with a low-burden mHSPC. Prostate-cancer-specific and castration-resistant-prostate-cancer-free survival was significantly extended by the triplet as well. Grade≥3 toxicity was higher in patients with ADT+docetaxel+AA compared to males with ADT+docetaxel in the docetaxel-treated cohort (63% vs. 52%, respectively) mostly due to a higher rate of hypertension. There were no safety signals concerning a possible exposure prolongation by pharmacodynamic interaction between both agents.
This trial demonstrates a meaningful survival advantage for men with mHSPC treated with upfront ADT+docetaxel+AA compared to the ones who received ADT+docetaxel, even if approx. 80% of the latter ones were treated with an ARTA upon castration-resistance. Taken together, upfront treatment intensification appears to outperform compound sequencing in metastatic prostate cancer delaying emergence of acquired drug resistance.
Nonetheless, several aspects still remain to be elucidated. Since PEACE-1 enrolled only males with de novo mHSPC, it remains unclear whether or not men with recurrent mHSPC, which is mainly associated with a more favourable course of disease, should also be treated with an intensified regimen. Since OS results are still immature for men with a low burden mHSPC, the question for the optimal management of this population is still open. Last but not least, it remains to be investigated if ADT+docetaxel+AA would outperform a doublet treatment with ADT combined with an ARTA instead of docetaxel.