Drugs (2014) 74:579–586 DOI 10.1007/s40265-014-0198-4

ADIS DRUG EVALUATION

Radium-223 Dichloride: A Review of Its Use in Patients with Castration-Resistant Prostate Cancer with Symptomatic Bone Metastases Matt Shirley • Paul L. McCormack

Published online: 8 March 2014 Ó Springer International Publishing Switzerland 2014

Abstract Radium-223 dichloride (XofigoÒ; formerly AlpharadinTM) [hereafter referred to as radium-223] is a first-in-class alpha particle-emitting radiopharmaceutical that has recently been approved for the treatment of patients with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease. Radium-223 is a calcium mimetic, which targets bone, delivering cytotoxic radiation to the sites of bone metastases. In the recently reported AlpharadinTM in Symptomatic Prostate Cancer (ALSYMPCA) phase III study, radium-223 was associated with significantly improved overall survival compared with placebo, making it the first bone-targeted CRPC therapy for which an overall survival benefit has been demonstrated. The ALSYMPCA study also demonstrated the beneficial effects of radium-223 on disease-related symptomatic skeletal events, pain and health-related quality of life. Radium-223 was generally well tolerated, being associated with low rates of myelosuppression and generally mild gastrointestinal adverse events. Thus, radium-223 is a valuable addition to the treatment options for this poor-prognosis population.

The manuscript was reviewed by: J.B. Aragon-Ching, Department of Medicine, Division of Hematology/Oncology, George Washington University Medical Center, Washington, DC, USA; J. Carles, Department of Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Spain; L. Costa, Hospital de Santa Maria and Instituto de Medicina Molecular, Lisbon, Portugal; D. Mukherji, Department of Internal Medicine, Division of Hematology/Oncology, American University of Beirut Medical Center, Beirut, Lebanon. M. Shirley (&)
P. L. McCormack Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, 0754 Auckland, New Zealand e-mail: [email protected]

Radium-223 dichloride in castration-resistant prostate cancer with symptomatic bone metastases: a summary A first-in-class alpha particle-emitting radiopharmaceutical The first bone-targeted castration-resistant prostate cancer therapy demonstrating an overall survival benefit Delays occurrence of symptomatic skeletal events, and has a positive effect on pain and health-related quality of life A favourable safety and tolerability profile

1 Introduction Worldwide, prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancerrelated death among men [1]. In approximately 10–20 % of prostate cancer patients, the disease will progress (despite androgen depletion therapy) to so-called castration-resistant prostate cancer (CRPC) within around 5 years of follow-up [2]. Until recently, following progression to CRPC, the median survival time has been in the range of 9–30 months, reducing to 9–13 months for those with metastases [2]. However, the development of therapy options continues to advance [3–9], and median survival times are improving [10]. Current treatment options for CRPC include cytotoxic chemotherapy agents, inhibitors of androgen biosynthesis and signalling, immunotherapies and bone-targeted therapies.

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Despite the advances in treatment options, CRPC continues to be associated with significant morbidity and mortality, commonly due to bone metastases [11, 12]. The vast majority of patients with advanced CRPC will develop bone metastases over the course of their disease [12, 13]. Besides contributing towards cancer-related mortality, bone metastases are associated with serious complications, including pathological fractures, spinal cord compression and severe pain [4, 11]. Bone-targeted therapies for CRPC include bisphosphonates, receptor activator of nuclear factor kappa B ligand (RANK-L) inhibitors and bone-targeting radionuclides [4, 6, 8]. Radionuclides, which act by delivering cytotoxic radiation to the sites of bone metastases, include beta particle-emitters (such as strontium-89 and samarium-153 ethylenediaminetetramethylene phosphonate) as well as the recently approved alpha particleemitter, radium-223 dichloride (XofigoÒ; formerly known as AlpharadinTM) [hereafter referred to as radium-223] [14–17]. Radium-223 is a first-in-class alpha particle-emitting radiopharmaceutical, which has recently been approved as an intravenously administered treatment for patients with CRPC with symptomatic bone metastases and no known visceral metastases [16, 17]. This article reviews the therapeutic efficacy of radium-223 in the approved treatment population and details its pharmacological properties and tolerability profile.

2 Pharmacological Properties This section discusses the pharmacological properties of radium-223, as assessed in in vitro studies [18], animal studies [19] and phase I and II clinical trials [20–24] (including some data published as abstracts [18, 22, 23]). Supplementary information has been included from the US FDA prescribing information [16] and the EU summary of product characteristics [17]. 2.1 Pharmacodynamic Properties 2.1.1 Mechanism of Action Radium-223 is an alpha particle-emitting radioisotope that acts by delivering damaging radiation to sites of bone metastases [16, 17]. As a calcium mimetic, radium targets bone, forming complexes with the bone mineral hydroxyapatite [16, 17]. Moreover, it preferentially targets areas of high bone turnover, as is present in bone metastases [20]. Radium-223, with a half-life of 11.4 days, decays to radon219, which subsequently (over five more stages) decays to lead-207 [25]. Over the six-stage decay process, for each atom of 223Ra, four alpha particles (each composed of two

M. Shirley, P. L. McCormack

protons and two neutrons) are released, representing approximately 95 % of the total radiation energy emitted [16, 25, 26]. The alpha particles have a high linear energy transfer (that is, the energy imparted per distance travelled) and are believed to exert their cytotoxic action by inducing damaging double-stranded breaks in the DNA of adjacent cells [16, 17, 26, 27]. Following the generation of DNA breaks, cell death can be initiated via numerous mechanisms or cellular pathways [28]. The cytocidal activity of radium-223 alpha radiation appears to be largely independent of dose rate, oxygen levels and cell cycle status [18, 26, 28]. Besides DNA breaks, supplementary cytotoxicity mechanisms have been proposed, including the potential involvement of reactive oxygen species [28]. Although alpha particles have high energies, their penetration in biological tissue is very short (\100 lm), corresponding to around two to ten cell diameters. Thus, the cytotoxic effects of radium-223 are limited to a very short range, potentially minimising adverse effects, particularly those affecting bone marrow cell populations. Indeed, animal studies have shown the potential for radium-223 to deliver a therapeutically effective radiation dose to bone surfaces while minimising the dose of radiation absorbed by bone marrow (see Sect. 2.2) [19]. 2.1.2 Effects on Markers of Bone Metabolism Consistent with the mechanism of action at sites of bone activity, data from a randomized, placebo-controlled, phase II clinical trial in patients with CRPC with symptomatic bone metastases (n = 64) showed that radium-223 (four 4-weekly intravenous injections of 50 kBq/kg) was associated with significantly greater median relative changes (improvements) from baseline, compared with placebo, in serum markers of bone turnover, including total alkaline phosphatase (ALP; -46 vs. ?31 %; p \ 0.0001), bone ALP (-66 vs. ?9 %; p \ 0.0001), procollagen I N propeptide (PINP; -63 vs. ?38 %; p \ 0.0001), C-terminal crosslinking telopeptide of type I collagen (CTX-I; -31 vs. ?32 %; p = 0.002) and type I collagen crosslinked C-telopeptide (ICTP; ?15 vs. ?43 %; p = 0.011) [21]. An effect of radium-223 on total ALP levels was also demonstrated in the phase III AlpharadinTM in Symptomatic Prostate Cancer (ALSYMPCA) clinical trial (see Sect. 3). 2.2 Pharmacokinetic Properties Over the radiation dose range of 46–250 kBq/kg, radium223 demonstrated linear pharmacokinetics in blood in terms of time independence and dose proportionality [16, 17]. Following intravenous injection, radium-223 is rapidly cleared from the blood [16, 17, 24]. Within 15 min post-

Radium-223 Dichloride: A Review

injection, approximately 80 % of the radioactivity is removed; 4 h post-injection, approximately 2–4 % remains in the blood and, by 24 h, \1 % of injected radioactivity remains in the blood [16, 17, 24]. From the blood, radium223 is primarily transferred to the bone or excreted into the intestine [16, 17, 23], with radioactivity present at these sites within 10 min post-injection [17, 24]. The highest absorbed radiation doses are to osteogenic cells, red bone marrow and the intestinal wall [16, 17, 22, 23], with an approximate tenfold higher dose absorbed at the bone surface compared with the red bone marrow [26]. Due to the short penetration distance of alpha particles, it is assumed that the majority of the radioactivity in the gut will be absorbed by the gut content [20] and, secondly, that most of the radiation reaching the intestinal walls will be from beta radiation (from radium-223 daughter nuclides and representing 4 % of the total radiation energy emitted during radium-223 decay) [29]. No significant radiation uptake is observed in other organs such as the kidneys, liver or bladder [16, 17, 22, 24]. At 4 h post-injection, approximately 60 % of the injected radioactivity is present in bone [16, 22, 23], and it is well-retained at this site [19, 24]. Radium-223 is not metabolized by the body [16, 17]. However, it does undergo radioactive decay, in six stages, to stable lead-207 [25]. The daughter nuclides produced during the decay are short-lived (with half-lives ranging between 1.8 ms and 36.1 min) [25], and their retention in bone is similar to that of radium-223 itself [19]. Excretion of radium-223 occurs primarily via the faecal route [20, 22, 24]; 48 h post-injection, the cumulative urinary excretion was \5 %, and hepato-biliary excretion was not observed [16, 22–24]. Approximately 63–76 % of injected radioactivity was eliminated from the body within 7 days (after correcting for decay) [16, 17, 24].

3 Therapeutic Efficacy The efficacy of radium-223 in the treatment of patients with CRPC with symptomatic bone metastases has been evaluated in the ALSYMPCA study, a large (n = 921), randomized, double-blind, placebo-controlled, multicentre, phase III clinical trial [30]. The primary endpoint of the ALSYMPCA study was overall survival in the intention-totreat population. Key secondary endpoints focused on symptomatic skeletal events and changes in the levels of the disease biomarkers prostate-specific antigen (PSA) and ALP (see Table 1). In the study, patients were randomized in a 2:1 ratio to receive six 4-weekly intravenous injections of radium-223 (50 kBq per kg of bodyweight) or placebo. In addition to the injections, all patients received the best

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standard of care, defined as the routine care provided at each centre, which included the possible use of ketoconazole, glucocorticoids, antiandrogens, oestrogens or local external-beam radiation therapy (EBRT); the use of chemotherapy, hemibody radiotherapy or other radionuclides was not permitted. Prior to randomization, patients were stratified according to baseline ALP level (\220 vs. C220 U/L), current or non-use of a bisphosphonate, and previous or non-use of docetaxel. Patients were eligible to participate if they had symptomatic, histologically-confirmed CRPC with (C2) bone metastases and no known visceral metastases [30]. Additional eligibility criteria included a baseline PSA level C5 ng/mL (with increasing PSA values), an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0–2 [31], adequate haematological function and a life expectancy of C6 months [30]. Besides the presence of visceral metastases, key exclusion criteria included a malignant lymphadenopathy[3 cm in diameter, chemotherapy within the previous 4 weeks, systemic radiotherapy within the previous 24 weeks and the presence of established or imminent spinal cord compression [30]. The two arms of the study were well balanced in terms of demographics and baseline characteristics; the median age was 71 years for both groups [30]. At baseline, the proportions of patients receiving bisphosphonates were similar in the radium-223 and placebo groups (40 vs. 41 %) [30]. During the ALSYMPCA study, a prespecified interim analysis (published as an abstract) was performed when 314 patients had died [32]. Based on this analysis (showing an overall survival benefit with radium-223), an independent committee recommended early termination of the study, with patients in the placebo arm of the study to be offered treatment with radium-223 [30]. This section focuses on the findings of an updated analysis from the ALSYMPCA study that was performed when 528 patients had died, before the crossover from placebo to radium-223 occurred [30]. At that time, 63 % of the radium-223 group and 47 % of the placebo group had received all six injections. 3.1 Effects on Overall Survival The ALSYMPCA study found that radium-223 significantly improved the median overall survival (primary endpoint) of CRPC patients with symptomatic bone metastases compared with placebo [30]. Patients who received radium-223 had a median overall survival of 14.9 months, compared with a median survival of 11.3 months for patients who received placebo (hazard ratio [HR] 0.70; 95 % CI 0.58–0.83; p \ 0.001). A significant survival benefit with radium-223 compared with

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placebo was observed across all stratification subgroups (with HRs ranging from 0.62 to 0.74) except for low (\220 U/L) total ALP level at baseline where the survival benefit with radium-223 was not significant (HR 0.82; 95 % CI 0.64–1.07) (Fig. 1). Ad hoc analyses of other subgroups, based on ECOG scores (\2 or C2), disease extent (\6, 6–20 or [20 metastases, or superscan) and opioid or no opioid use at baseline, also favoured radium223 over placebo, with HRs ranging from 0.64 to 0.95, significant for all except ECOG score C2, \6 metastases and superscan [30]. The lack of significance displayed for these three subgroups could be related to the smaller numbers of patients (n B 138).

3.2 Effects on Symptomatic Skeletal Events Radium-223 was associated with a significant delay in the median time to the first symptomatic skeletal event compared with placebo (15.6 vs. 9.8 months; HR 0.66; 95 % CI 0.52–0.83; p \ 0.001) [30]. Radium-223 also significantly delayed the time to the first event for two of the four components comprising symptomatic skeletal events (see Table 1): spinal cord compression and the use of EBRT for relief of skeletal symptoms, with reductions in risk of 48 % (HR 0.52; 95 % CI 0.29–0.93; p = 0.025) and 33 % (HR 0.67; 95 % CI 0.53–0.85; p = 0.001), respectively (data published in an abstract and poster) [33].

Table 1 Key endpoints of the ALSYMPCA study [30] Endpoint

Definition

Primary endpoint Overall survival

Time from randomization to date of death

Key secondary endpoints Time to first symptomatic skeletal event

Time to (i) the first use of EBRT for relief of skeletal symptoms, (ii) new symptomatic pathological bone fractures, (iii) spinal cord compression, or (iv) orthopaedic surgical intervention

Time to an increase in PSA level

Time to a relative increase of C25 % from baseline level with an absolute increase of C2 ng/mL at C12 weeks or, for patients with an initial decrease from baseline, a relative increase of C25 % with an absolute increase of C2 ng/mL above the nadir, confirmed C3 weeks later

A PSA response

A reduction of C30 % from baseline level

Time to an increase in total ALP level

Time to an increase of C25 % from baseline level at C12 weeks or, for patients with an initial decrease from baseline, an increase of C25 % from the nadir, confirmed C3 weeks later

Normalization of total ALP level

Among patients with an above normal total ALP level at baseline, a return to within normal range at 12 weeks, confirmed by two consecutive measurements C2 weeks apart

A total ALP response

A reduction of C30 % from baseline level, confirmed C4 weeks later

PSA prostate-specific antigen, ALP alkaline phosphatase, EBRT external-beam radiation therapy

Rad-223

18

Median overall survival (mo)

Fig. 1 Median overall survival of patients participating in the ALSYMPCA study (updated analysis), including subgroups stratified by total alkaline phosphatase level at baseline, use of bisphosphonates at baseline, and any previous use of docetaxel [30]. The numbers above the columns are hazard ratios (95 % CIs). Rad-223 radium-223 dichloride, ALP alkaline phosphatase

0.70 (0.58-0.83)

0.82 (0.64-1.07)

0.70 (0.52-0.93)

Placebo 0.74 (0.56-0.99)

0.74 (0.59-0.92)

0.71 (0.56-0.89)

No

Yes

16 0.62 (0.49-0.79)

14 12 10 8 6 4 2 0