According to a presentation from the ERA 223 trial atthe 2018 ESMO Congress, no improvements in survival endpoints were seen with the addition of radium-223 dichloride to abiraterone acetate and prednisone in patients with metastatic castration-resistant prostate cancer.
Matthew R. Smith, MD, PhD
According to a presentation from the ERA 223 trial (NCT02043678) at the 2018 ESMO Congress, no improvements in survival endpoints were seen with the addition of radium-223 dichloride (Xofigo) to abiraterone acetate (Zytiga) and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC).
The primary endpoint of the trial was symptomatic skeletal event-free survival (SSE-FS), defined as use of external beam radiation therapy to relieve skeletal symptoms, new symptomatic pathologic bone fracture, spinal cord compression, and/or tumor-related orthopedic surgical intervention. SSE-FS in the radium-223 combination arm was 22.3 months (95% CI, 20.4-24.8) versus 26 months (95% CI, 21.8-28.3) in the abiraterone/prednisone plus placebo group (HR, 1.122; 95% CI, 0.917- 1.374;P= .2636).
The secondary endpoint of overall survival (OS) with the addition of radium-223 was 30.7 months (95% CI, 25.8-NE) versus 33.3 months (95% CI, 30.2-41.1) in the placebo group (HR, 1.195; 95% CI, 0.950-1.505;P= .1280). Of 401 patients who received radium-223 with abiraterone/prednisone, 155 (39%) died, compared with 141 of 405 (35%) patients in the placebo arm.
"Concurrent treatment with abiraterone and radium-223-223 did not improve SSE-FS or OS compared with abiraterone plus placebo in men with mCRPC and bone metastases," said Matthew R. Smith, MD, PhD, director of the Genitourinary Malignancies Program at the Massachusetts General Hospital Cancer Center. "OS was not significantly different between the groups."
In the radium-223 arm, 196 patients died or had ≥1 SSE, compared with 190 patients in the control arm. The number of patients who died prior to SSE was 74 and 73, respectively.
Other secondary endpoints included radiological progression-free survival (rPFS), time to cytotoxic chemotherapy, and time to opiate use for cancer pain. For patients who received radium-223, rPFS was 11.2 months (95% CI, 9.1-11.8) versus 12.4 months (95% CI, 10.8 -14.5) with placebo (HR, 1.152; 95% CI, 0.960-1.383). Time to cytotoxic chemotherapy was 29.5 months (95% CI, 26.5-35.7) versus 28.5 months (95% CI, 23.7-NE; HR, 1.033; 95% CI, 0 .816-1.308), and time to opiate use for cancer pain was 19 months (95% CI, 14.4- 23.2) versus 22.6 months (95% CI, 18-25.7; HR, 1.126; 95% CI, 0.921 -1 .378), respectively.
"There was also no significant difference in time to PSA progression or time to deterioration in health-related quality of life," Smith added. "There were no differences between the groups in any treatment-emergent adverse event (TEAE), grade 3 to 5 TEAEs, or any serious TEAEs. There was also no difference between the groups in TEAEs leading to discontinuation of study-specified treatments."
Safety was evaluated in 392 patients in the radium-223 arm and 394 patients in the control arm. In the experimental arm, 97% of patients experienced a TEAE versus 98% in the placebo arm. The rates of grade 3 to 5 TEAEs were 63% versus 57%, respectively. Smith noted that fracture was the most common serious TEAE, and was experienced by 103 (26%) patients who received radium-223 and 38 (10%) patients in the control arm.
Additionally, all-grade back pain (34% vs 31%), fatigue (23% vs 20%), arthralgia (20% vs 19%), hypertension (15% vs 20%), constipation (14% vs 18%), diarrhea (17% vs 15%), nausea (17% vs 15%), peripheral edema (13% vs 16%), ALT increased (18% vs 15%), and AST increased (16% vs 14%) were observed in the radium-223 and placebo groups, receptively.
"Of interest, baseline bone health agent use was associated with lower fracture rates in both treatment groups," noted Smith.
Between March 30, 2014, and August 12, 2016, 806 patients were enrolled with median age of 71 in both arms. This study was unblinded prematurely in November 2017, due to more fractures and deaths with the radium-223 group. All patients had completed radium-223 or placebo treatment prior to unblinding, and study procedures and treatment continued per protocol after unblinding, Smith reported.
Smith MR, et al. A phase 3 trial of radium-223 (Ra-223) in combination with abiraterone acetate and prednisone/prednisolone for the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve patients (pts) with bone-predominant metastatic castration-resistant prostate cancer (mCRPC). In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA30.
Based on the data from this study, the use of radium-223 in combination with abiraterone for mCRPC is not recommended, concluded Smith.