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ASCO 2019 Annual Meeting

ASCO 2019: Concurrent or Layered Treatment with Radium-223 and Enzalutamide or Abiraterone plus Prednisone/Prednisolone: A Retrospective Study of Real-World Clinical Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer

Chicago, IL (UroToday.com) Bone metastases are present in approximately 90% of patients with metastatic castration-resistant prostate cancer (mCRPC). These are associated with an increased rate of fractures, spinal cord compression, bone surgery, and external beam radiotherapy (EBRT).1, 2

Radium-223 is a targeted alpha therapy that accumulates in areas of increased bone turnover located near and around metastatic lesions. It has been shown to prolong the overall survival (OS) of mCRPC patients.3–6 Data from prospective, randomized clinical trial regarding treatment options and sequences of mCRPC patients are still limited.

The phase 3 ERA 223 study assessed the efficacy and safety of radium-223 in combination with abiraterone plus prednisone or prednisolone in patients with CRPC and bone metastases. This study demonstrated an increased frequency of bone fractures with the combination of radium-223, abiraterone, and prednisone/prednisolone when compared to placebo plus abiraterone and prednisone/prednisolone.7

In this presented retrospective study, real-world experience of radium-223 combined with abiraterone + prednisone or enzalutamide use was examined.

The authors used the Flatiron Health database, which is a longitudinal, demographically, and geographically diverse database derived from de-identified electronic health record data, curated via technology-enabled abstraction. This database includes de-identified data from over 280 cancer clinics (~800 sites of care) representing over 2.2 million US patients with cancer available for analysis.

In this study, patients who had received radium-223 for mCRPC between 2013 and 2017 were included. Patients who received radium-223 in combination with abiraterone/prednisone or enzalutamide in a concurrent fashion (given within 30 days of each other) or layered fashion (one treatment starting ≥ 30 days after the other) were analyzed. Follow-up was until patient death or last data entry.

The study’s primary objective was to assess symptomatic skeletal event (SSE) rates following treatment (stratified by bone health agent use; denosumab or bisphosphonates). SSE was defined as either:
  1. Spinal cord compression
  2. Pathologic fracture
  3. EBRT to the site of bone metastasis
  4. Surgery to bone
Additionally, secondary objectives included OS from radium-223 initiation and CRPC diagnosis. The baseline was defined as the date of the first dose of radium-223.

A total of 625 patients were treated with radium-223, and 303 (49%) received combination therapy with abiraterone/prednisone or enzalutamide. Of these patients, 220 (73%) received this treatment combination in a layered fashion. A large proportion of patients received prior therapies (Table 1). The median time from CRPC diagnosis to radium-223 initiation varied between the sub-cohorts, as can be seen in Table 1. Lastly, most patients received prior bone health agents.

Table 1 – Baseline characteristics:
ASCO2019_Baselinecharacteristics_Abstract5026.png
The median follow-up time was nine months in the main cohort (Table 2). The median OS from mCRPC diagnosis was 28.3 months (95% CI: 18.4–not reached) and 34.5 months (95% CI: 25.9–50.9) in patients who received concurrent and layered radium-223 + abiraterone/prednisone, respectively. In those who received concurrent and layered radium-223 + enzalutamide, the median OS was 28.1 months (95% CI: 16.7–not reached) and 26.9 months (95% CI: 25.0–34.4), respectively, as shown in Table 2 and Figure 1.

Table 2 – Summary of clinical outcomes:
ASCO2019_Table2_Abstract5026.png
The rate of SSEs is shown in Table 3, while the incidence rates of SSE are shown in Figure 2A. Concomitant use of any bone health agent had occurred in most patients (Table 3). SSE and pathologic fracture incidence rates stratified by concomitant bone health agent use are shown in Figures 2B and 2C.

Figure 1 – Overall survival from mCRPC diagnosis:
ASCO2019_Figure1_Abstract5026.png

Table 3 – Summary of symptomatic skeletal events and bone health agent use:
ASCO2019_table3_abstract5026.png

Figure 2 – Symptomatic skeletal event incidence from Radium 223 initiation:
ASCO2019_figure2_Abstract5026.pngASCO2019_figure2partc_abstract5026.png

The authors summarized their results stating that during the study period, the use of the combination of radium-223 with either abiraterone/prednisone or enzalutamide was common in the US, occurring in approximately 50% of mCRPC patients who received radium-223. Approximately half (55%) of all patients received a concomitant bone health agent. The incidence of SSEs ranged from a fifth to over a third of patients across the sub-cohorts.

Looking at the tables, it seems that patients who received concomitant bone health agents had a lower incidence rate of pathologic bone fractures compared with patients who did not. 

The limitations of this study include its retrospective, non-randomized nature, with the associated potential for selection bias or misclassifications, and varying follow-up time.

There is currently an ongoing phase 3 trial (PEACE III; NCT02194842) examining the combination of radium-223 and enzalutamide in first-line, asymptomatic, chemotherapy-naive mCRPC patients. This study aims to assess the efficacy and safety of this combination, administered concurrently.

Another planned phase 3 trial (ESCALATE) aims to explore the layered combination of radium-223 and enzalutamide, with the first patient expected to be enrolled in late 2019.

Presented by: Neal D. Shore, FACS, MD, Carolina Urologic Research Center, Myrtle Beach, SC

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, @GoldbergHanan at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA

References
  1. Tannock IF, et al. Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer. NEJM 2004;351(15):1502–12.
  2. Whitney CA, et al. In Men with Castration-Resistant Prostate Cancer, Visceral Metastases Predict Shorter Overall Survival: What Predicts Visceral Metastases? Results from the SEARCH Database. Eur Urol Focus 2017;3(4–5):480–6.
  3. Bruland OS, et al. High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Cancer Res.2006;12(20 Pt 2):6250s–7s.
  4. Nilsson S, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8(7):587–94.
  5. Nilsson S, et al. Clin Gen. Cancer. 2013;11(1):20–6.
  6. Parker C, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. NEJM. 2013;369(3):213–23.
  7. Smith M, 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 randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol.2019;20(3):408–19.