In De-Novo mCSPC, The Addition of Prednisone to Standard of Care May Be Practice-Changing

For the treatment of de novo metastatic castration-sensitive prostate cancer (mCSPC) improved radiographic progression-free survival (rPFS) and overall survival (OS) was seen with the addition of prednisone (abiraterone) to androgen-deprivation therapy (ADT) plus docetaxel (Docefrez), as shown by data from the PEACE-1 trial presented at the 2021 ESMO Annual Congress.

“We believe [these] data [are] practice-changing,” said Karim Fizazi, MD, PhD, medical oncologist at Gustave Roussy and professor of Oncology at the University of Paris-Saclay in Villejuif, France, during a presentation of the findings. “At least, men with de novo high volume metastatic prostate cancer should be offered ADT plus docetaxel plus abiraterone based on evidence that this treatment combination will provide 2.5 years additional time without radiographic progression or death, and 1.5 additional years of survival.”

In the phase III trial (NCT01957436), researchers randomized 1173 men with de novo mCSPC (57% high-volume and 43% low-volume) to receive standard of care (SOC) – which was ADT continuously with or without 75 mg/m2/3w for 6 cycles docetaxel (n = 296), SOC plus 1000 mg per day of abiraterone plus 5 mg twice daily of prednisone (n = 292), SOC plus 74 grades of radiotherapy to the primary tumor (RXT) (n = 293), or SOC plus abiraterone plus RXT (n = 292).

Trial candidates included men with de novo mCSPC who may have received up to 3 months of ADT before randomization for the study. The stratification factors were ECOG performance status (PS) (0 vs 1-2), site of metastasis (lymph node vs bone vs visceral), type of castration (orchidectomy vs LHRH-agonist vs LHRH-antagonist), and the use of docetaxel.

“(Patient characteristics) were well-balanced between arms, as expected in such a large trial,” Fizazi explained. Focusing on the 710 men who received ADT plus docetaxel as their SOC, he added that about two thirds of them had high metastatic burden – with 63% in the SOC +/- RXT + abiraterone arm (n = 355) and 65% in the SOC +/- RXT arm (n = 355).

Other notable characteristics included a median age of 66 in both arms, an ECOG PS score of 0 in most patients (70% and 69%, respectively), and 1-2 in the remaining (30% and 31%, respectively). Median time from diagnosis was 2.2 (IQR, 1.6-3.0) in the SOC +/- RXT + abiraterone arm and 2.2 (IQR, 1.4-2.9) in the SOC +/- RXT arm. Most patients in both arms had metastasis in the bone without visceral – 81% in the SOC +/- RXT + abiraterone arm and 79% in the SOC +/- RXT arm – while 8% of both arms had it in the lymph nodes, and 12% and 13%, respectively, had visceral metastasis.

The co-primary endpoints were rPFS and OS, and “PEACE-1 used a factorial design, … answering 2 questions: the role of abiraterone and that of radiotherapy on top of SOC. The number of events for the abiraterone analysis has been reached, while a longer follow-up is needed to assess the role of radiotherapy,” Fizazi said.

The co-primary endpoint of rPFS was reached in the ADT plus docetaxel (+/- RXT) population (HR: 0.50, 95% CI, 0.40-0.62; p<0.0001). It reduced the risk of radiographic progression or death by a median of 4.5 years with abiraterone, compared with 2 years without. Men with low- (HR: 0.58, 95% CI, 0.39-0.87; p<0.006) and high-volume (HR: 0.47, 95% CI, 0.36-0.60; p<0.0001) disease alike saw benefit with abiraterone.

Median follow-up in the overall population was 4.4 years, 5.7 in the ADT alone +/- RXT arm, and 3.8 in the ADT + docetaxel +/- RXT arm. OS was improved with abiraterone in the overall population (HR: 0.83, 95% CI, 0.69-0.99, p=0.034) as well as in the ADT + docetaxel population (HR: 0.75, 95% CI, 0.59-0.96, p=0.021).

For patients with high metastatic burden, adding abiraterone to ADT plus docetaxel reduced the risk of death by 28%. However, for men with low-volume disease, the medians have not yet been reached in either arm.

“Reporting data about treatments use beyond progression is important,” Fizazi said, explaining that in the control arm, 84% of men who experienced cancer progression received at least 1 life prolonging therapy, and 81% received at least 1 next generation hormonal agent, mostly abiraterone or enzalutamide. “This clearly suggests that early use of these agents is better than deferred use.”

In terms of adverse events – which were generally balanced between arms – there were grade 3-5 events in more than 5% of patients in the ADT plus docetaxel population. These included neutropenic fever (5% vs 5%), neutropenia (10% vs 9%), liver toxicity (6% vs 1%), and hypertension (21% vs 13%) in the abiraterone and control arms, respectively.

“We showed today that using … a treatment combination of ADT, docetazel, and abiraterone further prolongs survival, with medians now reaching more than five years,” Fizazi said.

Determining the best way to combine systemic treatments with local radiotherapy, particularly in patients with oligo-metastatic disease, requires longer follow-up of PEACE-1.

_Reference

_{Fiazi K, Charles Galceran J, Foulon S, et al. A phase III trial with a 2x2 factorial design in men with de novel metastatic castration-sensitive prostate cancer: overall survival with abiraterone acetate plus prednisone in PEACE-1. Presented at: 2021 ESMO Annual Congress. September 16-21, 2021.}