In an open-label, randomized, controlled, phase 3 PEACE-1 study (NCT01957436) with a 2×2 factorial design, conducted at 77 hospitals across Europe, radiotherapy significantly improved radiographic progression-free survival (rPFS). However, the researchers did not observed effect on overall survival (OS) in patients diagnosed with de novo metastatic castration-sensitive prostate cancer presenting with low-volume metastatic disease.
The study team also found that radiotherapy delayed the occurrence of castration-resistant prostate cancer, regardless of disease burden.
Prevalence of serious genitourinary events
In this study, the researchers, for the first time, were able to show that the prevalence of serious genitourinary events was reduced by radiotherapy, both in patients with low-volume metastatic disease and in the overall study population. Time to the occurrence of castration-resistant prostate cancer events typically preceded rPFS events.
The findings of the study, funded by Janssen-Cilag, Ipsen, Sanofi, and Institut National du Cancer, were published by Alberto Bossi, MD, of the Department of Radiotherapy, Institut Gustave Roussy in Villejuif, France and colleagues on November 23, 2024 in The Lancet. [1]
The authors wrote in the background that STOPCAP meta-analysis reported that adding prostate radiotherapy to androgen deprivation therapy (ADT) in patients diagnosed with de novo metastatic castration-sensitive prostate cancer did not increase OS. However, in individuals presenting with up to four bone metastases, this therapy translated into an improvement in absolute OS of 7% at 3 years. The active control arms of the STAMPEDE trial (NCT00268476) and HORRAD study selected in the meta-analysis consisted of ADT, with only 184 of 1029 patients (18%) in the STAMPEDE trial also receiving docetaxel in addition to ADT.
Interplay
PEACE-1 is the only randomized study to date to investigate the interplay between an intensified systemic therapy consisting of ADT, docetaxel, and abiraterone plus prednisone, in addition to radiotherapy in patients diagnosed with de novo metastatic castration-sensitive prostate cancer.
A previous analysis of the results from the PEACE-1 study showed that ADT, docetaxel, and abiraterone plus prednisone administered as a triple systemic therapy improved both rPFS and OS in this patient group. In the latest article published in The Lancet, the study investigators aimed to examine the efficacy and safety of adding radiotherapy to this intensified systemic treatment in patients with de novo metastatic castration-sensitive prostate cancer.
In this ongoing study, eligible participants were male patients (aged ≥18 years) with de novo metastatic castration-sensitive prostate cancer confirmed by bone scan, CT, or MRI, and an ECOG performance status of 0–1 (or 2 in the case of bone pain). Patients were randomly assigned (1:1:1:1) to standard-of-care (SOC, either ADT alone or six cycles of intravenous docetaxel 75 mg/m² every 3 weeks), SOC plus abiraterone (oral 1000 mg abiraterone once daily plus oral 5 mg prednisone twice daily), SOC plus radiotherapy (74 Gy in 37 fractions to the prostate), or SOC plus radiotherapy and abiraterone. Participants and investigators were not masked to treatment allocation. The coprimary endpoints were rPFS and OS, analysed by intention-to-treat in patients with low-volume metastatic disease and in the overall study population.
Between 27 November 2013 and 20 December 2018, a total of 1173 patients were enrolled and 1172 were randomly assigned to receive SOC (25.3%), SOC plus abiraterone (24.9%), SOC plus radiotherapy (25.0%), and SOC plus abiraterone and radiotherapy (24.8%). Median follow-up was 6.0 years (interquartile range, 5.1–7.0) at the time of rPFS and OS analysis. A qualitative interaction between radiotherapy and abiraterone for rPFS in the population of patients with low-volume disease prevented the pooling of intervention groups for analysis (p = 0.026).
Adding radiotherapy to SOC improved rPFS in patients with low-volume disease treated with abiraterone, median 4.4 years (99.9% confidence interval [CI] 2.5–7.3) in the SOC plus abiraterone group versus 7.5 years (4.0–not reached) in the SOC plus abiraterone and radiotherapy group with adjusted hazard ratio (HR) of 0.65 (99.9% CI 0.36–1.19; p = 0.019), but not in patients not treated with abiraterone, median 3.0 years (99.9% CI 2.3–4.8] in the SOC group versus 2.6 years (1.7–4.6] in the SOC plus radiotherapy group (HR 1.08, 0.65–1.80; p = 0.61).
For OS, the predefined threshold for a statistical interaction was not reached (p = 0.12); therefore, the two intervention groups receiving radiotherapy were pooled together for analysis. In patients with low-volume disease, the OS was not influenced by radiotherapy, median 6.9 years (95.1% CI 5.9–7.5] for SOC with or without abiraterone versus 7.5 years (6.0–not reached) for SOC plus radiotherapy with or without abiraterone (HR 0.98, 95.1% CI 0.74–1.28; p = 0.86).
In the overall safety population, 339 of 604 patients (56.1%) who did not receive radiotherapy and 329 of 560 patients (58.8%) who received radiotherapy developed at least one severe adverse event (grade ≥3), the most common being hypertension (18.2% patients in the SOC with or without abiraterone group and 22.7% in the SOC plus radiotherapy with or without abiraterone group) and neutropenia (6.6% and 5.2%).
Study amendments
The authors commented that rapidly evolving landscape of treatment options for patients with metastatic castration-sensitive prostate cancer prompted the adoption of two major amendments during the accrual period. Consequently, the statistical plan had to be reviewed to implement docetaxel, making SOC more heterogeneous.
Additionally, during the inclusion period of PEACE-1, hypofractionated radiotherapy became progressively more commonly used for the management of patients with prostate cancer; however, this therapy was not permitted in this trial. Furthermore, PEACE-1 established that a triplet systemic therapy (ADT plus docetaxel and abiraterone) improved OS compared with a doublet therapy (ADT plus docetaxel). Nevertheless, PEACE-1 was not designed to address treatment outcomes with a SOC consisting of dual hormone therapy (e.g. ADT plus contemporary androgen receptor signaling inhibitors).
The authors concluded that prostate radiotherapy combined with an intensified systemic treatment based on abiraterone (with or without docetaxel) showed an improvement in rPFS, prevented the emergence of severe genitourinary events, and delayed the time to onset of castration-resistant prostate cancer, regardless of metastatic burden and without increasing the overall toxicity in patients with de novo metastatic castration-sensitive prostate cancer.
Commentary
In an accompanied comment, Cristian Udovicich, MD, and Andrew Loblaw, MD, of the Odette Cancer Centre, Sunnybrook Health Sciences Centre and Department of Radiation Oncology, University of Toronto, both in Toronto, ON, Canada wrote that although comparative statistics were not presented in the study, a shortened course of radiotherapy was associated with reduced toxicity and clear advantages to both the patient (e.g. convenience and decreased financial burden) and to the healthcare system (e.g. reduced costs and increased treatment capacity), and could be reasonably considered as an alternative to the conventional radiotherapy given in PEACE-1.
Given that metastasis-to-metastasis seeding can also occur, there might be a role for total consolidative therapy with stereotactic body radiotherapy to all sites or [177Lu]-PSMA-617 radioligand therapy in patients with low-volume metastatic disease. These therapies are being investigated by the STAMPEDE2 (NCT06320067) the Canadian Cancer Trials Group(CCTG) PR.20/PLATON (NCT03784755), and the UpFrontPSMA (NCT04343885) trials.
Definitive Answers and more Questions
According to commentators, the PEACE-1 provides some definitive answers, but also raises other questions. Reported improved outcomes are important for patients. However, the finding of no benefit to OS could be explained by several potential reasons and be further elucidated by an individual-level meta-analysis of the STAMPEDE, HORRAD, and PEACE-1 trials. They concluded that prostate radiotherapy is an important component of effective therapies in the management of patients with metastatic prostate cancer and should be offered to all men with synchronous metastatic disease.
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Clinical trials
A Phase III Study for Patients With Metastatic Hormone-naïve Prostate Cancer (PEACE1)
ClinicalTrials.gov ID NCT01957436
Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) ClinicalTrials.gov ID NCT00268476
A Randomised Controlled Platform Trial Testing Treatments in Metastatic Hormone Sensitive Prostate Cancer (STAMPEDE2) – ClinicalTrials.gov ID NCT06320067
In Men With Metastatic Prostate Cancer, What is the Safety and Benefit of Lutetium-177 PSMA Radionuclide Treatment in Addition to Chemotherapy (UpFrontPSMA) – ClinicalTrials.gov ID NCT04343885
Local Ablative Therapy For Hormone Sensitive Oligometastatic Prostate Cancer (PLATON) – ClinicalTrials.gov ID NCT03784755
References
[1] Bossi A, Foulon S, Maldonado X, Sargos P, MacDermott R, Kelly P, Fléchon A, Tombal B, Supiot S, Berthold D, Ronchin P, Kacso G, Salem N, Calabro F, Berdah JF, Hasbini A, Silva M, Boustani J, Ribault H, Fizazi K; PEACE-1 investigators. Efficacy and safety of prostate radiotherapy in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet. 2024 Nov 23;404(10467):2065-2076. doi: 10.1016/S0140-6736(24)01865-8. PMID: 39580202. [Abstract]
[2] Udovicich C, Loblaw A. Prostate radiotherapy in the era of intensified systemic treatment of metastatic prostate cancer. Lancet. 2024 Nov 23;404(10467):2023-2026. doi: 10.1016/S0140-6736(24)01967-6. PMID: 39580189. [Abstract]
Featured image: Prostate Cancer. Photo courtesy: © 2016 – 2024 Fotolia/Adobe. Used with permission.
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