The addition of abiraterone acetate plus prednisone on top of androgen-deprivation therapy plus docetaxel improved survival in patients with de novo metastatic castration-sensitive prostate cancer vs androgen-deprivation therapy plus docetaxel alone. These results were from the phase III PEACE-1 trial and were reported during the European Society for Medical Oncology (ESMO) Congress 2021.¹

In patients who received the triplet combination, radiographic progression-free survival was a median of 4.5 years vs 2 years without abiraterone acetate plus prednisone. The addition of abiraterone acetate plus prednisone to androgen-deprivation therapy plus docetaxel improved overall survival by 25% vs androgen-deprivation therapy plus docetaxel alone. Both radiographic progression-free survival and overall survival were more robust with abiraterone acetate plus prednisone in men with high-volume disease.

These data support the growing body of evidence on the earlier use of abiraterone acetate plus prednisone in metastatic prostate cancer.

“We believe these data are practice-changing,” stated lead author Karim Fizazi, MD, PhD, a medical oncologist at the Institute Gustave Roussy and Professor in Oncology at the University of Paris-Saclay, Villejuif, France. “At least, men with de novo high-volume metastatic prostate cancer should be offered androgen-deprivation therapy plus docetaxel plus abiraterone acetate plus prednisone, based on evidence that this triplet combination provided 2.5 years additional time without radiographic disease progression or death and 1.5 years of additional survival.”

Karim Fizazi, MD, PhD

“Overall survival is improved [with the triplet combination], with a 25% reduction in the risk of death, even when 84% of men with metastatic castration-sensitive prostate cancer in the control group received at least one life-prolonging treatment [ie, next-generation androgen signaling inhibitors in 81%],” he noted.

Study Details and Major Results

The PEACE-1 trial had a 2 × 2 factorial design. Patients with de novo metastatic castration-sensitive prostate cancer (n = 1,173) were randomly assigned 1:1:1:1 to receive the standard of care (n = 296); the standard of care plus abiraterone (n = 292); the standard of care plus radiotherapy (n = 293); or the standard of care plus abiraterone plus radiotherapy (n = 292). All patients had continuous androgen-deprivation therapy. Standard treatments were defined as androgen-deprivation therapy with or without docetaxel. Stratification factors included Eastern Cooperative Oncology Group performance status (0 or 1), metastatic sites (lymph node vs bone vs visceral), type of castration (orchiectomy vs androgen-deprivation therapy), and docetaxel (yes or no).

Disease and demographic factors were well balanced at baseline. At baseline, in the population given androgen-deprivation therapy plus docetaxel (accounting for 710 patients), the median age was 66, and about 78% had a Gleason score > 8. About 80% had bone-alone metastasis; 8% had lymph-node–alone metastasis; and about 12% had visceral metastasis. About 36% had low-volume disease, and 64% had high-volume disease.

Co-primary endpoints were radiographic ­progression-free survival and overall survival. Radiographic progression-free survival was significantly improved with the addition of abiraterone acetate plus prednisone to androgen-deprivation therapy plus docetaxel (P < .0001). At a median follow-up of 4.5 years, in patients treated with abiraterone acetate plus prednisone and the standard of care, 139 events were reported; at a median follow-up of 2 years in the standard-of-care-alone arm, there were 211 events.

Looking at radiographic progression-free survival in the population given androgen-deprivation therapy plus docetaxel (with or without radiotherapy), according to disease burden, the addition of abiraterone acetate plus prednisone benefited both groups, but the benefit tended to be greater in the group with high-volume disease. Median radiographic progression-free survival was 4.1 years when abiraterone acetate plus prednisone was added vs 1.6 years for those with high-volume disease who received the standard of care (< .0001), compared with not reached vs a median of 2.7 years in those with low-volume disease (P = .006).

Overall Survival

Follow-up for overall survival was 4.4 years in the overall population; 5.7 years in the control arm of androgen-deprivation therapy alone with or without radiotherapy; and 3.8 years in the control arm of androgen-deprivation therapy plus docetaxel with or without radiotherapy. Overall survival was improved by 25% with the addition of abiraterone acetate plus prednisone to androgen-deprivation therapy plus docetaxel vs the standard of care alone: not reached vs a median of 4.4 years, respectively (P = .017).

A subgroup analysis of overall survival showed a benefit for abiraterone acetate plus prednisone added to androgen-deprivation therapy plus docetaxel in all subgroups, including those stratified by receipt of radiotherapy, performance status, type of castration, and metastatic burden. In patients with high-volume disease, overall survival was improved by 28% with the addition of abiraterone acetate plus prednisone to androgen-deprivation therapy plus docetaxel: median of 5.1 years vs 3.5 years with the standard of care (P = .019). In patients with low-volume disease, overall survival is immature at this point, and medians were not reached in either group.

“The overall survival benefit translates to a median lifetime gain of more than 1.5 years for men with high-volume metastases. Overall survival for men with low-volume disease may be immature,” Dr. Fizazi concluded.

Toxicity and Treatment Beyond Disease Progression

“Toxicity was as expected, with no apparent synergistic side effects from the combination of abiraterone acetate plus prednisone with androgen-deprivation therapy plus docetaxel,” he said.

Adverse events were generally well balanced between the two arms. Grade 3 to 5 toxicity in patients given androgen-deprivation therapy plus docetaxel was similar with or without the addition of abiraterone acetate plus prednisone, except for hypertension: 22% with abiraterone acetate plus prednisone vs 13% without it.

Dr. Fizazi noted that it is important to report data about treatments beyond disease progression. In this study, 84% of men in the control arm who experienced disease progression received at least one life-prolonging therapy, and 81% received at least one next-generation hormonal therapy, mainly abiraterone acetate plus prednisone or enzalutamide.

“This clearly suggests that earlier use of next-generation hormonal therapy is better than deferred use,” he said.

Next Step

Dr. Fizazi noted that PEACE-1 was designed to answer two questions: the role of abiraterone acetate plus prednisone and that of radiotherapy on top of the standard of care. Longer follow-up of PEACE-1 is needed to define the optimal combination of systemic treatments with local radiotherapy in men with metastatic castration-sensitive prostate cancer, especially those with oligometastatic disease (ie, low-volume disease). 

DISCLOSURE: Dr. Fizazi has served as a consultant or advisor to Amgen, Astellas, Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis Oncology, CureVac, ESSA, Janssen Oncology, Orion Pharma GmbH, and Sanofi. 

REFERENCE

1. Fizazi K, Carles-Galceran J, Foulon S, et al: A phase III 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. ESMO Congress 2021. Abstract LBA5–PR. Presented September 19. 2021.