Adding abiraterone to androgen deprivation therapy plus docetaxel improves outcomes in men with metastatic castration-sensitive prostate cancer
The treatment landscape for metastatic castration-sensitive prostate cancer (mCSPC) has rapidly evolved over the past 5 years. Although androgen-deprivation therapy (ADT) is still the backbone of treatment, the addition of docetaxel or abiraterone acetate has improved outcomes for patients with mCSPC and become standard of care. During ESMO 2021, results of the phase III PEACE-1 trial suggest that a triplet combination of abiraterone acetate, ADT and docetaxel may provide further benefit to patients with mCSPC.
Since 2015, combining androgen deprivation therapy (ADT) with either docetaxel, androgen signalling inhibitors, or radiotherapy to the primary tumour (RXT) (for low metastatic burden) was shown to improve overall survival (OS) and has thus become the new standard of care (SOC) in men with metastatic castration-sensitive prostate cancer (mCSPC). It is unknown whether combining those treatments on top of ADT could further improve outcomes. PEACE-1 is a phase III trial with a 2x2 factorial design of abiraterone acetate plus prednisone (abiraterone) and/or local radiotherapy. First results demonstrated that adding abiraterone to ADT plus docetaxel significantly improves the radiographic progression-free survival (rPFS) in men with mCSPC (HR: 0.50 (0.40-0.62), p< 0.0001).
PEACE-1 study design
In total, 1,173 men with de novo mCSPC were randomised (1:1:1:1) to SOC, SOC+abiraterone, SOC+RXT or SOC+abiraterone+RXT. All patients had distant metastatic disease by at least one lesion on bone and/or CT scan and an ECOG performance status of 0-2. Patients were allowed to have received ADT for up to three months before randomisation. Standard treatments included continuous ADT (LHRH agonist/antagonist or bilateral orchiectomy), with or without docetaxel at 75 mg/m2 every three weeks for six cycles. Abiraterone treatment consisted of 1000 mg/day with prednisone 5 mg twice per day until disease progression or intolerance and was administered concomitant with docetaxel for patients who underwent chemotherapy. Radiotherapy to the prostate was delivered in 37 fractions to a cumulative dose of 74 Gy after patients completed docetaxel if receiving chemotherapy. Median age of patients in the ADT+docetaxel population was 66 year and 64% of patients had high disease burden. Co-primary endpoints of PEACE-1 are rPFS and overall survival (OS).
Results
In the ADT+docetaxel with or without RXT population, abiraterone reduced the risk of radiographic progression or death by half (HR[95%CI]: 0.50[0.40-0.62], p< 0.0001). This benefit was seen regardless of metastatic burden. Of note, in men with high volume disease, median rPFS was improved from 1.6 years with SOC to 4.1 years when abiraterone was added.
The effect of abiraterone on OS did not interact with the one of RXT (p= 0.82), allowing to pool the two abiraterone arms together for comparison. OS was improved by abiraterone both in the overall population (HR[95%CI]: 0.82[0.69-0.98], p= 0.030; medians: 5.7 vs. 4.7 years) and in the ADT+docetaxel population (HR[95%CI]: 0.75[0.59-0.95], p= 0.017; medians: not reached vs. 4.4 years). The OS benefit of adding abiraterone to ADT + docetaxel was consistent across subgroups, including the use of radiotherapy, performance status of the patient, type of castration and metastatic burden. In men with high-volume disease, adding abiraterone to ADT + docetaxel reduced the risk of death by 28%, with a median OS of 3.5 years in the control arm and 5.1 years in the abiraterone arm. On the other hand, OS data are less mature for low-volume patients and median OS has not yet been reached in either arm.
Among the ADT+docetaxel patients who developed castration-resistant prostate cancer (CRPC, N= 263), 84% received at least one life-prolonging therapy and 81% at least one next generation hormonal agent (mostly abiraterone or enzalutamide) in the control arm, compared to 74% and 46% in the abiraterone arm, respectively. Grade 3-5 toxicity on study treatments reported in >5% of men in the ADT+docetaxel population included febrile neutropenia (5% vs. 5%), neutropenia (10% vs. 9%), liver toxicity (6% vs. 1%) and hypertension (22% vs. 13%) in the abiraterone and control arms, respectively.
Conclusion
Adding abiraterone to ADT plus docetaxel significantly improves median rPFS by 2.5 years in men with de novo metastatic prostate cancer. The addition of abiraterone also led to a 25% reduction in the risk of death, even when 84% of mCRPC men in the control group receive at least one life-prolonging treatment. This benefit translated in a median lifetime gain of more than 1.5 year for men with high-volume metastases. Toxicity was as expected, with no apparent synergistic side effects from this combination. Therefore, at least de novo high-volume mCSPC men should be offered ADT plus docetaxel plus abiraterone.
Reference
Fizazi K, Galceran JC, Foulon S, et al. A phase 3 trial with a 2x2 factorial design in men with de novo metastatic castration-sensitive prostate cancer: overall survival with abiraterone acetate plus prednisone in PEACE-1. Presented at ESMO 2021; Abstract LBA5_PR.
