New data just presented on the treatment of men with de novo metastatic castration-sensitive prostate cancer (mCSPC) are “practice changing,” say experts.
“If one thing comes across, no matter what you do as of tomorrow, don’t go for androgen-deprivation therapy [ADT] alone for these patients,” commented Eleni Efstathiou, MD, PhD, from Houston Methodist Cancer Center, in Houston, Texas.
She was reacting to new results from the PEACE-1 trial, which show that regardless of the standard-of-care regimen used, the addition of abiraterone (Zytiga) has a “clinically meaningful impact on survival.”
Efstathiou was invited discussant for the trial after long-term results were presented at the annual meeting of the European Society for Medical Oncology.
Adding abiraterone to ADT plus docetaxel resulted in significant improvements in both radiographic progression-free survival (rPFS) and overall survival (OS) compared with the standard of care.
The outcomes, including a median 2.5-year improvement in rPFS and a 25% reduction in risk for death with abiraterone, were significant despite the fact that a high proportion of patients in the standard-of-care control arm crossed over to receive abiraterone during the course of the study, noted lead author Karim Fizazi, MD, PhD, from Institut Gustave Roussy and the University of Paris-Saclay, in Villejuif, France.
“We believe the data are practice changing. At least men with de novo high-volume metastatic prostate cancer should be offered ADT plus docetaxel plus abiraterone, based on evidence that this triplet combination will provide 2.5 years of additional time without radiographic progression or death and 1.5 additional years of survival,” he said.
“It is a practice-changing trial,” Efstathiou agreed. “The positive outcomes are surely meaningful when it comes to rPFS and OS, with the exception of low-volume disease.”
PEACE-1 Rationale and Design
Since 2015, the standard of care for men with mCSPC has been ADT combined with either docetaxel, androgen signaling inhibitors, such as abiraterone and enzalutamide (Xtandi), or radiotherapy to the primary tumor for men with low metastatic burden.
Until these new results from the PEACE-1 trial, it was unclear whether ADT plus a combination of other therapies could further improve outcomes, Fizazi said.
The phase 3 trial had a 2 x 2 factorial design. Men with de novo mCSPC and an Eastern Cooperative Oncology Group Performance Status score of 0-2 who were receiving continuous ADT were stratified by performance status, metastatic sites (lymph nodes, bones, or viscera), type of castration (orchiectomy vs luteinizing hormone-releasing hormone agonist or antagonist) and docetaxol use and were then randomly assigned on an equal basis to one of four study arms.
All participants received standard of care, which was ADT with or without docetaxel.
The study arms were standard of care alone (296 patients), standard of care with abiraterone (292 patients), standard of care with radiotherapy (293 patients), and standard of care with radiotherapy plus abiraterone.
Progression Risk Halved
For the patients who received abiraterone with ADT plus docetaxel, with or without radiotherapy, the median rPFS was 4.5 years, compared with 2.0 years for patients who received the standard of care alone. This translated into a hazard ratio (HR) for progression with abiraterone of 0.50 (P < .0001).
For men with high metastatic burden, the median rPFS was 4.1 years with abiraterone, compared with 1.6 years with standard of care only (HR, 0.47; P < .0001) .
The benefit was less pronounced for men with low-volume metastases, however, because among these patients there were relatively fewer cases of progression or deaths. The median rPFS among men in this group who received abiraterone plus standard of care was not reached; it was 2.7 years for men treated with standard of care alone (HR, 0.58; P = .006; the trial design required a P value <.001 for statistical significance of rPFS).
In the overall study population, the median OS was 5.7 years for patients who received the standard of care plus abiraterone, vs 4.7 years for those who received standard of care alone. The HR for death with abiraterone was 0.82 (P = .030).
Among patients who received ADT plus docetaxel with or without radiotherapy, the median OS was not reached at the time of data cutoff in June 2021; it was 4.4 years for patients treated with the standard of care alone (HR, 0.75; P = .017).
The overall survival benefit of abiraterone among patients who also received ADT plus docetaxel occurred almost exclusively among patients with high metastatic burden. The median OS was 5.1 years, vs 3.5 years with the standard of care, which translated into an HR for death with abiraterone of 0.72 (P = .019).
In contrast, among men with low-volume disease, the median OS was not reached in either comparison arm. There were 29 deaths among 131 patients who received abiraterone and 31 among 123 patients who received standard of care only. The HR of 0.83 favoring abiraterone was not statistically significant.
Among patients who were treated with ADT plus docetaxel as the standard of care alone (with or without radiotherapy), 84% received additional life-prolonging treatments after progression, and 81% received next-generation hormonal therapies. In contrast, among patients who also received abiraterone, the respective percentages were 74% and 46%.
There were seven deaths among 346 patients who received abiraterone. There were three deaths among patients treated with the standard of care alone. Adverse events that occurred more frequently with abiraterone were liver toxicities, hypertension, and hypokalemia.
Efstathiou said that the strengths of the PEACE-1 study include the combinatorial strategy, which helps to address previously unanswered questions; a study design that compared an experimental arm to standard practice; and the use of treatments that are accessible to community practices.
Still uncertain, however, is how the combination of ADT, docetaxel, and abiraterone compares with ADT plus abiraterone only.
Summuning up, she said that these latest data from PEACE-1 and from other trials with docetaxel and androgen signaling inhibitors suggest that monotherapy with ADT is no longer acceptable for treatment of men with mCSPC.
Potential treatment options include doublets consisting of ADT plus abiraterone, enzalutamide, or apalutamide, or ADT plus docetaxel; and a triplet combination of ADT plus docetaxel and abiraterone, especially for patients with high-volume disease.
She said that more data are needed regarding the potential combination of ADT plus docetaxel and either apalutamide or enzalutamide.
PEACE-1 is supported by Janssen, Ipsen, Sanofi and EORTC. Fizazi has received consulting or advisory fees from Janssen, Sanofi, and others. Efstathiou has received research support or consultant/advisory fees from Janssen-Cilag, Sanofi, and others.
European Society for Medical Oncology (ESMO) Annual Meeting 2021: Abstract LBA5_PR. Presented September 19, 2021.
Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.
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