P4-16-04: An Open-Label, Phase IIa, Non-Randomized Study of Radium-223 in Breast Cancer Patients with Bone Dominant Disease No Longer Considered Suitable for Endocrine Therapy.
Authors: Coleman R , Flamen P , Naume B , Jerusalem G , Garcia C , Piccart M , OBryan-Tear CG , Aksnes A-K 
Published: June 2012

Abstract
Background
Radium-223 (Alpharadin™) is a 1st-in-class alpha-pharmaceutical. It targets bone metastases (mets) with high-energy alpha-radiation of extremely short range that spares bone marrow. These characteristics generate highly localized radiation zones that may inhibit tumor progression and induce pain relief. Radium-223 has a profound effect on markers of bone metabolism and has shown a survival advantage over standard of care in pts with castration-resistant prostate cancer. The study's main objective was to investigate whether multiple IV injections (inj) of radium-223 have any clinically relevant effect on bone markers in metastatic breast cancer (MBC) pts with bone dominant disease (BDD).
Methods: Study included MBC pts with BDD who had progressed (based on imaging or other clinically relevant information) on endocrine therapy and were no longer considered suitable for endocrine therapy. In this open-label, multicenter, single-arm, phase IIa study (EudraCT #2009-012189-30), 23 pts were scheduled to receive 4 IV inj of radium-223 50 kBq/kg every 4 wk. Bone markers were assessed at baseline, prior to every treatment, and thereafter at each follow-up visit. Primary efficacy endpoint was change in urine levels of NTX (uNTX) and bALP at 16 wk. Functional imaging with FDG-PET was performed in 20 pts at baseline and wk 8 and 16. Symptomatic response was assessed using validated questionnaires.
Results: Histologic types were ductal carcinoma (n=12), lobular carcinoma (n=7), and others (n=2). Median interval from diagnosis of breast cancer to 1st relapse was 3 (1, 11) years. All except 1 pt received endocrine therapies, and adjuvant chemotherapy was given to approximately 60%. 21 of 23 pts were treated concurrently with bisphosphonates. 15 of 23 pts received all 4 inj of radium-223; 4/23 received 3 inj; and 4/23 received 2 inj. Pts who received &lt;4 inj had disease progression (bone and visceral mets [n=3], visceral mets [n=3]) or withdrawn consent (n=1) and were not eligible to continue radium-223. One pt died before 4th inj due to atrial fibrillation. Median age was 58 (41, 83) years. Median uNTX levels were reduced by 20% (from 36 to 29 ***nmo1BCE/mmo1 creatinine; P=0.03) and 5% (from 36 to 23 ***nmo1BCE/mmo1 creatinine; P=NS) at wk 8 and 16 respectively; 17/23 and 9/13 pts (for whom data were available) had a decrease in uNTX at wk 8 and 16 respectively. Median bALP levels were reduced by 33% (from 22.1 to 12.1 ng/mL; P=0.0001) at wk 8 and 33% (from 22.1 to 10.4 ng/mL; P=0.04) at wk 16. Bone-ALP levels were reduced in 20/22 pts at wk 8 and in 10/12 pts (for whom data were available) at wk 16. Radium-223 was found to be safe and well tolerated. 3 pts had serious AEs, none related to study drug; 1 of them died due to disease progression. Functional imaging results, additional bone marker data, and pt-reported outcomes are being analyzed.
Conclusions: Radium-223 consistently reduced uNTX and bALP during the 16-wk treatment period, results observed in addition to bisphosphonate use. Results show radium-223 targets the areas of increased bone metabolism caused by bone mets. Radium-223 found to be safe and well tolerated, confirming highly tolerable SE profile seen in other studies.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-16-04.