The use of bone-protecting agents (BPAs) during treatment with radium-223 (Xofigo) plus enzalutamide (Xtandi) controls the risk of fractures in men with metastatic prostate cancer resistant to Asymptomatic or mildly symptomatic castration (mCRPC), according to an updated safety analysis presented at the 2021 American Society of Clinical Oncology (ASCO) annual meeting.1
“This safety analysis confirms the importance of donating a bone protective agent when treating patients with CRPC and bone metastases,” said Silke Gillessen, MD, Institute of Oncology of Southern Switzerland, in a presentation. presentation of the security analysis.
In the phase 3 randomized trial EORTC-1333-GUCG / Peace-3 (NCT02194842), investigators randomized patients 1: 1 to receive either enzalutamide 160 mg per day plus radium-223 at 55 kBq / kg every 4 weeks for 6 cycles, or enzalutamide alone.
The study population included patients with predominantly bone-based mCRPC (≥2 bone metastases); asymptomatic or slightly asymptomatic disease; a WHO performance score of 0 or 1; no previous treatment with inhibitors of cyp17, enzalutamide, other radionucleotides or hemibody radiotherapy; and no known cerebral or visceral metastasis.
Radiographic progression-free survival was used as the primary endpoint.
Following the results of fractures that occurred in the ERA223 trial (NCT02043678),2 the investigators of the EORTC-1333-GUCG / PEACE-3 trial have decided to send an urgent security letter. “In this context, it was made mandatory to use a bone protective agent in all patients for at least 6 weeks before starting radium-223. In April 2018, an IDMC analysis was performed and the recommendation was to continue the trial, but to use a bone protection agent in all patients on both arms, ”explained Gillessen. “The IDMC regularly monitors the trial and, following the review in December of last year, recommended presenting the updated bone fracture figures to the scientific community.”
In his presentation at the ASCO 2021 annual meeting, Gillessen presented the updated safety analysis results of the trial, highlighting the impact of BPAs on fracture rates.
As of the April 2021 deadline, of the 267 patients randomized to the two treatment arms, 74 in each had received BPA.
Before the safety letter was administered, 45.2% of patients had not received BPA, compared with only 3% who had not received it after the letter was sent.
The cumulative incidence of fractures at 1 year was 37.1% (95% CI, 21.3% to 53.0%) in the combination arm and 15.6% (95% CI, 5.6 % to 30.3%) in the enzalutamide alone arm. In men who received BPA, the incidence of fractures at 1 year was reduced to 2.7% (95% CI, 0.5% -8.5%) and 2.6% (95% CI , 0.5% to 8.3%), respectively.
At 18 months, the cumulative incidence was 45.9% (95% CI, 28.6% -61.6%) in the combination arm and 21.9% (95% CI, 9.5% at 37.5%) in the enzalutamide alone arm, without BPA. With BPA, the incidence was 4.3% (95% CI, 1.1% -10.9%) and 2.6% (95% CI, 0.5% -8.3%), respectively .
“According to our study, we will continue and want to motivate all researchers to include [bone-protecting agents in the treatment of] the patients. And if all goes well, we can still report efficacy results as well. It is important to note that the IDMC will also continue to closely monitor the study, ”said Gillessen.
Radium-223 is an alpha-emitting radiopharmaceutical that has demonstrated overall survival benefit in males with mCRPC, with the hypothesis that its combination with a novel androgen receptor (AR) pathway inhibitor may improve clinical outcomes. .
In the randomized, double-blind, placebo-controlled trial ERA223, investigators evaluated the use of concomitant treatment with abiraterone acetate (Zytiga; 1000 mg once daily) plus prednisone (5 mg twice daily) or prednisolone (5 mg twice daily) and radium -223 (55 kBq / kg) in 806 patients with mCRPC.2 Symptomatic skeletal event-free survival was used as the primary endpoint.
BPAs were only allowed in the trial if a patient received them initially. Initiation of such agents during the study was prohibited to avoid confounding effects. Therefore, only 60% of patients had not received BPA at entry into the study.
In a post-hoc analysis of the trial, BPAs significantly reduced the fracture rate in both treatment arms.
“To better understand the nature of these fractures, an independent review of fracture events was performed. Interestingly, fracture maturity in both groups occurred at sites with no detectable metastasis and was considered osteoporotic or traumatic, ”explained Gillessen.
“Treatment with [androgen-deprivation therapy (ADT)] can induce bone loss. And we know that bone protection agents can be used in this bone loss and also in osteoporotic fractures in men treated with ADT, ”said Gillessen. “Bone protection agents may also delay the onset of a first skeletal event [SRE] in men with castration-resistant prostate cancer and bone metastases.
Skeletal complications can be common in patients with advanced prostate cancer and result in 2 distinct mechanisms, she added: fragility or osteoporotic fractures are reported in 11% of patients, and SREs occur in as many as 11%. ‘in 40% of people treated with ADT and an inhibitory AR pathway.
“To prevent these SREs, many guidelines recommend using bone protection agents for patients with castration-resistant prostate cancer and bone metastases. The combination of gamma radiation and hormonal manipulation is a well-validated treatment strategy in prostate cancer, ”said Gillessen.
1. Gillessen S, Choudhury A, Rodriguez-Vida A, et al. Decreasing Fracture Rate by Imposing Bone Protective Agents in the EORTC 1333 / PEACEIII Trial Combining Ra223 with Enzalutamide Compared to Enzalutamide Alone: An Updated Safety Analysis. J Clin Oncol. 2021; 39: (suppl 15; abstr 5002). doi: 10.1200 / JCO.2021.39.15_suppl.5002.
2. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomized phase 3 trial , double-blind, placebo-controlled. Lancet Oncol. 2019; 20 (3): 408-419.