Editor’s Note: During a recent major international oncology congress, Professor Karim Fizazi from the University of Paris-Saclay (Gustave Roussy) presented the first results of the Phase III PEACE-2 trial. This study evaluated whether the addition of cabazitaxel and/or pelvic radiotherapy to the standard of care—androgen deprivation therapy (ADT) combined with prostate radiation—improves outcomes in patients with very high-risk localized prostate cancer.01 Research Background: Clinical Challenges in Very High-Risk Localized Disease
The definition of “very high-risk localized prostate cancer” was established in 2012, referring to patients with non-metastatic (M0) and node-negative (N0) disease who possess at least two of the following three risk factors: T3/T4 stage, a Gleason score of 8–10, and a PSA > 20 ng/mL.
The current standard of care (SOC) remains prostate radiotherapy combined with long-term ADT. However, the role of taxane-based chemotherapy in this population has been a subject of debate following conflicting results from the GETUG-12 and STAMPEDE trials. Furthermore, the benefit of elective pelvic radiotherapy remains unproven in this specific setting. The PEACE-2 trial was designed to address these therapeutic uncertainties.
02 PEACE-2 Trial Design: A 2×2 Factorial Phase III Investigation
PEACE-2 is an international, multicenter, randomized Phase III trial utilizing a 2×2 factorial design. Between 2013 and 2021, patients meeting the very high-risk criteria were enrolled across France, Spain, Belgium, and Italy.
All participants received 3 years of ADT (LHRH agonist or antagonist) plus prostate radiotherapy (74–78 Gy in 2 Gy fractions, IMRT mandatory, starting 3 months after ADT initiation). Patients were randomized to:
- Pelvic RT Randomization: Pelvic radiotherapy (46–50 Gy) vs. No pelvic radiotherapy.
- Cabazitaxel Randomization: Cabazitaxel (20–25 mg/m² every 3 weeks for 4 cycles, with mandatory G-CSF support) vs. No cabazitaxel.
The primary endpoint was clinical progression-free survival (cPFS), defined as the time to death, distant metastasis, or proven local relapse. Secondary endpoints included biochemical progression-free survival (bPFS), metastasis-free survival (MFS), and prostate cancer-specific survival (PCSS).
03 Efficacy Outcomes: Cabazitaxel Fails to Meet Primary Endpoint
With a median follow-up of over 7 years, the study analyzed a highly representative cohort: a median age of 67, 90% with T3/T4 disease, and 80% with a Gleason score of 8–10. Approximately 80% of patients had two risk factors, while 20% had all three.
No statistical interaction was found between the cabazitaxel and pelvic RT arms. Key findings regarding the cabazitaxel randomization include:
- Primary Endpoint (cPFS): No detectable difference was observed between the cabazitaxel and control arms. At the 7-year mark, approximately one-third of patients in both groups had experienced a clinical progression event.
- Secondary Endpoints: MFS showed no significant difference between arms. For bPFS, the median was approximately 9 years in the non-cabazitaxel group versus 10 years in the cabazitaxel group.
- Specific Survival: Notably, the cohort demonstrated an excellent long-term prognosis, with a 9-year prostate cancer-specific survival (PCSS) rate of 90%.
04 Safety Profile: Consistent with Known Taxane Toxicity
The safety profile of cabazitaxel was consistent with previous clinical experience. In the cabazitaxel arm, Grade 3/4 neutropenia occurred in 20% of patients, and Grade 3/4 diarrhea was reported in approximately 4%. No new or unexpected safety signals were identified.
Conclusion and Outlook
Professor Fizazi concluded that the addition of cabazitaxel does not improve clinical outcomes for men with very high-risk localized prostate cancer. While data regarding the pelvic radiotherapy randomization will be presented at a later date, the current results prompt a critical re-evaluation of the disease definition itself.
Professor Fizazi noted that since only 1 in 10 patients died of prostate cancer over nearly a decade of follow-up, the 2012 definition of “very high risk” may be too aggressive for patients confirmed as N0 by modern imaging. In the era of PSMA PET, patients identified as truly node-negative (N0) have an excellent prognosis with ADT and radiotherapy alone, suggesting that chemotherapy intensification is likely unnecessary for this specific subgroup.
