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Combination radium-223 therapies in patients with bone metastases from castration-resistant prostate cancer: A review
Journal Pre-proof Combination radium-223 therapies in patients with bone metastases from castration-resistant prostate cancer: a review M.C. Cursano, M. Iuliani, C. Casadei, M. Stellato, G. Tonini, G. Paganelli, D. Santini, U. De Giorgi
PII:
S1040-8428(20)30002-0
DOI:
https://doi.org/10.1016/j.critrevonc.2020.102864
Reference:
ONCH 102864
To appear in:
Critical Reviews in Oncology / Hematology
Received Date:
13 October 2019
Revised Date:
27 December 2019
Accepted Date:
4 January 2020
Please cite this article as: Cursano MC, Iuliani M, Casadei C, Stellato M, Tonini G, Paganelli G, Santini D, De Giorgi U, Combination radium-223 therapies in patients with bone metastases from castration-resistant prostate cancer: a review, Critical Reviews in Oncology / Hematology (2020), doi: https://doi.org/10.1016/j.critrevonc.2020.102864
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.
Combination radium-223 therapies in patients with bone metastases from castration-resistant prostate cancer: a review
M.C. Cursano1, MD; M. Iuliani1, BS, PhD; C. Casadei2, MD; M. Stellato1, MD; G. Tonini1,MD, PhD; G. Paganelli3, MD, PhD; D. Santini1§, MD, PhD & U. De Giorgi2§, MD, PhD 1
Department of Medical Oncology, Campus Bio-Medico University of Rome, 00128 Rome, Italy
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Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy 3
Department of Nuclear Medicine Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy §
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co-last authors
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*Corresponding author: Maria Concetta Cursano, MD, Department of Medical Oncology, Campus Bio-Medico University of Rome, via Alvaro del Portillo, 200 00128 Rome, Italy. Email: [email protected]
Highlights
In bone mCRPC, each treatment has an effect on PCa cells and bone microenvironment.
Clinical trials have been performed to evaluate radium 223-based combination therapies.
Pretreated and un-pretreated patients have different morbidity and clinical outcomes.
Different bone metabolic status could justify the different clinical outcomes.
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Associating bone protecting agents reduce treatment-related morbidity.
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Abstract Chemotherapeutic agents (docetaxel, cabazitaxel), hormonal therapies (abiraterone, enzalutamide) and radium-223 improve survival in patients with bone metastatic castration-resistant prostate cancer (mCRPC). Combinations of radium-223 with these agents or novel drugs have been investigated in order to improve survival and decrease bone-related morbidity. In mCRPC, clinical and preclinical data indicate that radium223, abiraterone and enzalutamide have a direct effect on prostate cancer cells and bone microenvironment when administered as single agents. Initial results from studies of radium-223 and abiraterone, enzalutamide or docetaxel demonstrated efficacy without any safety concern in pre-treated mCRPC; however, this safety
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profile changed when radium-based combination therapies were administered in un-pretreated mCRPC. This review underline the biological rationale for combining radium strategies, investigating their effects on bone in terms of control of skeletal-related events and bone disease progression. The aim is to understand the
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possible reasons why different radium-based combination treatments can led to different clinical outcomes.
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Keywords: Castration-resistant prostate cancer; bone metastases; Skeletal-related events; radium-223; enzalutamide; abiraterone; docetaxel; bone protecting agents.
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INTRODUCTION Bone is the most preferential target site for prostate cancer (PCa) metastases with an incidence of nearly 75% [[1],[2]]. “Skeletal-related events” (SREs) represent the most common clinical complication related to PCa bone metastases [[3],[4]]. SREs include pathologic bone fractures, hypercalcaemia, spinal cord compression, surgery to bone, and radiotherapy to bone [[5],[6]]. In the last years, several new drugs including chemotherapy (docetaxel, cabazitaxel), new hormonal therapies (abiraterone, enzalutamide) and radium-223 demonstrated overall survival (OS) benefit and improvements in bone health in mCRPC patients [[7],[8],[9],[10],[11],[12]].
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On the contrary, androgen deprivation therapy (ADT) increases bone turnover and decreases bone mineral density [[13]] due to the inhibition of androgens and estrogens function that preserve bone trabecular structure [[14]]. Therefore, the alteration of bone homeostasis in PCa patients is a multifactorial process, resulting from
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the disease and its treatments.
The receptor-activator of nuclear-factor-k-B (RANK) ligand inhibitor denosumab and bisphosphonates are the
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bone target therapies approved for the prevention of SREs in adults with bone metastases [[15],[16],[17],[18],[19]]. Contrary to denosumab and bisphosphonates, radium-223 is the first bone target
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therapy that provides OS benefit for mCRPC with bone metastasis [[12]]. Recently, several studies try to identify the optimal combination therapy to improve survival and decrease patient bone-related morbidity.
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These investigations showed that combinations of radium-223 and abiraterone, enzalutamide, or docetaxel are associated with unexpected and sometimes discordant results. This review underline the biological rationale
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for combining radium strategies, investigating their biological effects on bone microenvironment and their clinical effect in terms of control of skeletal-related events and bone disease progression.
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PHYSIOPATHOLOGY OF BONE METASTASIS IN PCa Bone metastasis are the result of a series of complex interactions between tumour cells, bone marrow cells, and resident bone cells, which led to the disruption of normal bone homeostasis (Figure 1) [[20]]. Physiological bone remodelling process occurs at specialized skeleton sites, the “bone remodeling units”, in which functions of osteoclasts and osteoblasts are tightly regulated to maintain the balance between bone formation and degradation and preserve skeletal integrity [[21]]. In bone metastatic process, tumour cells are attracted to
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skeletal tissue by the same chemotactic cytokines that regulate the migration of Hematopoietic Stem Cells (HSCs) into the hematopoietic stem cell niche. Osteoblastic-induced stromal-derived factor-1 (SDF-1 or CXCL12) binds CXCR4 receptor expressed both by HSCs and PCa cells [[22],[23],[24],[25],[26]]. SDF1/CXCR4 interaction causes a competition between HSCs and PCa cells, leading to the formation of the “onconiche”, in which tumor cells may be quiescent or active [[20],[22],[23]]. PCa cells migrated in these niches, secrete several paracrine factors such as transforming growth factor β1 (TGF β1), parathyroid-hormone-related peptide (PTHrP) and interleukin 6 (IL-6), that interfere with normal osteoclastic and osteoblastic activity damaging physiological bone remodelling process [[27]]. The result is an abnormal stimulation of bone
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resorption, mediated by an aberrant activation of the RANK/RANK ligand (RANKL) pathway [[20],[22]]. In PCa bone metastasis, a first enhanced osteolysis is followed by a strong osteoblastic stimulation resulting in an excessive abnormal bone apposition. Furthermore, the enhanced osteoclastic activity causes the so-called
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“bone hunger syndrome”, a hyperparathyroidism condition due to calcium entrapment in skeletal tissue and serum calcium deficiency [[20],[28],[29]]. The compensatory hyperparathyroidism leads to osteoclasts
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activation not only at metastatic sites but also at distant sites causing a generalised state of osteoclastogenesis.
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RATIONALE FOR RADIUM-223 COMBINATION THERAPY
Radium-223, as a cationic calcium-mimic, is absorbed and concentrated in the bone and binds to hydroxyapatite. Radium-223 deposits mostly in active bone remodelling areas such as osteoblastic bone
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metastasis and emits α-particles (with locally high energy but limited tissue penetrance), inducing DNA double-strand breaks and complex chromosomal rearrangements leading to cell death [[12],Error! Reference
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source not found.]. Preclinical studies have been designed to investigate if radium-223 beneficial clinical effects in mCRPC are solely due to its effect on osteoblasts and/or osteoclasts or also to a direct effect on PCa
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cells. Suominen et al demonstrated that radium-223 therapy had a dual mode of-action: localized cytotoxic effects on PCa cells and bone integrity preservation. Using two different prostate cancer xenograft models LNCaP (with osteoblastic or mixed metastases) and LuCaP 58 PDX (with osteoblastic metastases), the authors proved that radium-223 inhibited tumor-induced osteoblastic activity, safeguarded normal bone architecture and contrasted prostate cancer growth in bone. Treatment with radium-223 was associated with the reduction of bone formation marker N-terminal propeptide of type I procollagen (PINP) and overall tumour burden as
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measured by prostate specific antigen (PSA) [[31]]. Furthermore, previous studies showed similar results in a murine model of osteolytic breast cancer bone metastasis treated with radium-223, suggesting that it potentially acts regardless of primary origin or nature of bone alterations (osteolytic or osteoblastic) [[31]]. Abou D.S. et al confirmed these data demonstrating that radium-223 localizes in active bone remodelling areas of healthy mice, as well as of osteoblastic (LNCaP) and osteolytic (PC3) PCa mice [[33]]. Recently, radium-223 showed an immunomodulation activity by inducing T cell-mediated cell death in human prostate, breast, and lung cancers;[34] several studies of concomitant radium-223 with immunotherapy are ongoing and could give the clinical validation of this preclinical data. Furthermore, since the evidence of somatic DNA repair gene defects
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(DRD) in nearly 20% of PCa, other studies are evaluating combination strategies of inhibitors of the enzyme poly ADP ribose polymerase (PARP), as olaparib and niraparib, with radium-223 [[35]].
Abiraterone inhibits androgen biosynthesis through irreversibly blocking Cyp17 [[36],[37]]. Abiraterone
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significantly improves OS, radiological skeletal progression and time to SREs in both pre-docetaxel and post-docetaxel mCRPC setting [[38],[39]]. Iuliani et al, have previously demonstrated that abiraterone
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exerted a direct effect on bone microenvironment inhibiting osteoclast function and promoting osteoblast activity. Abiraterone induced inhibitory effect on osteoclastic differentiation, down-modulating osteoclastic
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marker genes TRAP, cathepsin K and metalloproteinase-9 and decreasing serum levels of C-terminal type I collagen (CTX). Furthermore, abiraterone promoted osteoblastic differentiation and bone matrix deposition
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up-regulating osteoblastic specific genes, osteocalcin and serum value of alkaline phosphatase (ALP). These data suggested an anabolic and anti-resorpive effect of abiraterone in addition to its well-known antitumoral
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effect [[40]]. Enzalutamide is an oral androgen receptor (AR) inhibitor, which significantly improves OS in both chemotherapy-naïve and post-chemotherapy mCRPC patients. Additional benefits included an increase
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in radiographic PFS (rPFS), a significant delay in time to first SREs and an improvement in several measures of pain and health-related quality of life (QoL) [[10],[11]]. Preclinical data demonstrated that enzalutamide was associated with higher bone turnover: both serum levels of C-terminal type I collagen (CTX, marker of bone resorption) and OCN (marker of bone formation) were increased in mice treated with enzalutamide. In the same mice, there was an increased number of osteoblasts and osteoclasts per bone perimeter in the trabecular bone of L4 vertebrae but not in the trabecular bone of tibia after 21 days of treatment with
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enzalutamide [[41]]. It is well-known that ADT sensitizes radiotherapy-induced cell death in PCa by inhibiting DNA repair mechanisms and blocking the radiotherapy-induced upregulation of AR [[42]]. Basing on the synergistic effect of ADT and radiotherapy and the preclinical evidences of the effects of the new anti-androgen agents on both tumour cells and bone microenvironment, several clinical trials have been performed to evaluate radium 223-based combination therapies. The aim is to study if concomitant treatments can increase the effectiveness of each treatment through a synergic interaction. RADIUM-223-BASED COMBINATION THERAPY
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New clinical trials evaluating radium-223 combination therapies mainly focused on five combination treatment strategies: radium-223 and abiraterone, radium-223 and enzalutamide, radium-223 and docetaxel, radium-223 and immunotherapy and radium-223 and PARP inhibitors (Table 1). The aim of these studies was to improve
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efficacy of each treatment, without enhancing the toxic effects. Radium-223 and abiraterone
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In an international, early access, single-arm phase 3b study, enrolling symptomatic or asymptomatic mCRPC with bone metastases and no visceral disease, patients were stratified to receive concomitant radium-223 and other
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therapies versus radium-223 alone. The majority of patients enrolled (97% of the entire population) received a previous treatment with abiraterone plus prednisone, enzalutamide or docetaxel; 12% of patients received a previous
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treatment with denosumab or zoledronic acid. The results were encouraging: there was OS advantage in the subgroup of patients (154 patients) who received concomitant radium-223 and abiraterone acetate plus prednisone
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[[43]]. This finding was confirmed by the results of the expanded access program (EAP) providing early-access
radium-223 with or without concomitant other life-prolonging therapies. Concurrent radium-223 and
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abiraterone was administered to 14% of patients, maintaining efficacy without any new safety concerns [[44]]. The phase II eRADicAte trial was the first single arm prospective study evaluating the combination of radium223 and abiraterone acetate plus prednisone in patients with symptomatic bone metastatic mCRPC. In this small trial, the 31 patients enrolled experienced benefit both in bone pain and in QoL patient measures [[45]]. Moreover, there was a significant reduction of the mean number of bone scan lesions (from 11.6±2.8 at baseline to 5.6±2.4 at the end of treatment) [[45]]. Recently, Smith and colleagues published the results of the phase III
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study ERA 223 in which abiraterone plus prednisone were combined with radium-223 or placebo in asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients with bone metastases. Differently from the previous studies, concomitant radium-223 and abiraterone did not improve OS or skeletal event-free survival and was associated to higher risk of fractures. Fractures of any grade occurred in 112 (29%) of 392 patients in the radium-223 group and 45 (11%) of 394 patients in the placebo group. Fractures were localized at no-metastatic skeletal site and mainly were osteoporotic fractures. Forty percent of patients received bone protective agents before their enrolment and continued treatment during the study; the post hoc analysis revealed that bone protective agents significantly reduced risk of fractures in both arms. In fact, fractures occurred in 24 (15%) of 157 patients
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(experimental group) and in 11 (7%) of 169 patients (control arm) after treatment with bone health agents [[46]]. Based on these results, the trial was unblended and stopped prematurely and FDA and EMA changed the prescribing recommendations for radium-223.
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Radium-223 and enzalutamide
In the above mentioned single-arm phase 3b trial published by Saad and colleagues, the subgroup of patients
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(n=50) treated with concomitant enzalutamide and radium-223 showed a survival benefit without presenting additional adverse events (AEs) [[43]]. In the EAP program, concomitant radium-223 and enzalutamide
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treatment confirmed its efficacy and safety profile [[44]]. Safety and tolerability of the association between radium-223 and enzalutamide was assessed in a phase II single arm study (NCT02225704) enrolling 45
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patients with mCRPC and bone metastases. A retrospective analysis of this population reported an incidence of asymptomatic osteoporotic fracture of 24.4%; in particular, asymptomatic osteoporotic fractures related to
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insufficiency and trauma occurred in 11 (24.4%) and 4 (9%) patients enrolled, respectively [[47]]. Recently, the results of the safety analysis of the phase 3 PEACE III trial of concomitant treatment of enzalutamide with
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radium-223 versus enzalutamide alone in asymptomatic or mildly symptomatic mCRPC patients with bone metastasis were presented. After the results of the ERA-223 trial, the Internal Displacement Monitoring Centre (IDMC) issued an urgent safety letter for mandatory use of bone-protecting agents in both arms of the trial and for delayed initiation of radium-223 for new randomized patients (at least six weeks between the start of the bone healthy agent and start date of radium-223). After urgent safety letter, the proportion of patients treated with bone protecting agents changed from 40% to 55% in both treatment arms. In patients not exposed to bone protecting agents, the cumulative incidence of bone fracture at 12 months was 12.4% with enzalutamide and 7
37.4% with radium and enzalutamide. No patients treated with bone protecting agents experienced bone fractures in both treatment arms [[47]]. Radium-223 and docetaxel Docetaxel is the first chemotherapy agents able to increase overall survival in mCRPC by inhibiting tumour grow through interfering with microtubules dynamics [[49]]. The efficacy and safety of combining radium223 with docetaxel was examined in a Phase I/II trial (NCT01106352). In this study, PSA decline >50% occurred in 61% of patients in the combination arm (versus 54% in the docetaxel arm) with a median PFS of
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12 months in the combination arm (versus 9.3 months in the docetaxel arm). In patients treated with the concomitant docetaxel and radium-223, bone marker levels indicated a greater suppression of osteoblastic activity. In fact, serum level of PINP showed a decline trend in favour of the combination arm, whereas CTX, markers of osteoclastic activity, showed similar trend in the two arms [[50],[49]]. These findings are currently
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under evaluation in the ongoing phase 3 DORA trial (NCT03574571), randomizing mCRPC patients to
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receive docetaxel and radium-223 versus docetaxel alone, in which OS is the primary end point [[51]]. Radium-223 and immunotherapy or PARP inhibitors
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To date, there are three clinical trials evaluating the association of radium-223 with pembrolizumab (phase 2,
NCT03093428), atezolizumab (phase 1, NCT02814669), sipuleucel (phase 2, NCT02463799) [[52];[53];[54]].
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Pembrolizumab and atezolizumab are two immunotherapy drugs, which block the Programmed Death-1 (PD-1) pathway [[55]]. EMA and FDA have not approved Pembrolizumab and atezolizumab for mCRCP treatment.
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Sipuleucel is the first therapeutic vaccine approved by EMA and FDA for mCRPC [[56]]. In PCa, PARP inhibitors have shown significant response rates up to 88% for PCa patients having DRD [[35]].
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Clinical trials are evaluating the combination of Radium-223 and olaparib (NCT03317392)[57] or niraparib (NCT03076203)[[58]]. The above-mentioned studies are ongoing and there are not published data of safety and tolerability to date.
ADVERSE EVENTS CONSIDERATIONS In the early access phase 3b trial and in the phase 2 EAP, the association of radium-223 with abiraterone or enzalutamide was safe, without warning for SREs in the subgroup of patients treated with concomitant radium8
223 and enzalutamide or abiraterone [[43],[44]]. In these studies, population was quite different from ERA 223 trial; in fact, the majority of patients (97 % the early access phase 3b trial and 99% in the phase 2 EAP) were previously treated with at least one systemic therapy for mCRPC, mainly docetaxel. Therefore, EAP program was not a randomized trial and follow up time was too short to detect long acting treatment related AEs [[43],[44]]. The first randomized phase II eRADicAte trial confirmed safety profile of the association of radium-223 and abiraterone. Patients reported diarrhoea (17%), nausea (17%), and fatigue (14%) similarly to those observed in previously reported trials [[45]]. Contrary to all predictions, the phase III ERA 223 trial did not report the same safety data [[46]]. Dalla Volta et al hypothesized that prednisone, administered in
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combination with abiraterone, could be the possible cause of increased bone fragility and increased incidence of osteoporotic fractures, because the combination of glucocorticoid and radium-223 induced a synergic inhibition of osteoblast differentiation, maturation, and activity and caused an increased bone fragility [[58],[60]]. Similarly, Daniel Spratt defined the increased fracture risk as the results of the multifactorial insult
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to bone from chronic androgenic deprivation, prednisone, low use of bone health agents in ERA 223 and
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unknown use of preventive fracture measures [[61]]. In this scenario, they supposed that radium-223 was the final additional factor to enhance fracture risk of this population [[61]]. However, fractures were an acute
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toxicity, occurring in the first six months as the result of the interaction of abiraterone and radium-223 with bone microenvironment, whereas glucocordicoid-induced bone mineral density reduction is a long-term bone
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metabolic effect [[62]]. Recently, Attard et al published the results of the phase 2 study evaluating the safety of abiraterone with 4 different glucocorticoid regimens (dexamethasone 0.5 mg once daily, prednisone 5 mg once daily, prednisone 5 mg twice daily and prednisone 2.5 mg twice daily). They demonstrated that
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abiraterone with prednisone 5 mg twice daily or dexamethasone 0.5 mg once daily were not associated to
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mineralcorticoid excess. A reduction of bone mineral density was observed from baseline to the end of the main study in dexamethasone group but in prednisone group, independently of schedule and dose of administration [[56]]. Results from preclinical trials provide other possible additional explanations for
the explanation about the increased bone fragility with radium-223 concomitant treatments. It has been demonstrated that abiraterone has an inhibitory effect on osteoclasts and promoted osteoblasts differentiation and bone matrix deposition [[40]]. Radium-223 deposits mostly in active bone remodelling areas such as osteoblastic bone metastasis, which are a result of stimulation of osteoblasts, inhibition of 9
osteoclasts or both, by cancer cells (Figure 2) [[12]]. If abiraterone produces an anabolic effect by promoting osteoblastic activity in healthy and metastatic bone, the combination of abiraterone and radium-223 may result in the accumulation of radium-223 not only at the metastatic site level (notoriously an area of increased bone turnover and osteoblastic activation) but even at healthy bone. Consequently, the greater deposit of radium223 in healthy bone and the subsequent emission of α-particles could result in cell and tissue damage with loss of bone matrix and osteoporosis. Enzalutamide did not demonstrate the same anabolic and anti-resorpive effect of abiraterone. In fact, preclinical evidence suggests that enzalutamide- mediated AR inhibition is associated with enhanced bone turnover and increased vertebral fracture risk [[41]]. Probably, it could be the reason why
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concomitant use of bone protecting agents abolishes the risk of bone fractures in PEACE III trial and reduces, even not eliminating, that risk in ERA 223 patients. Concomitant use of docetaxel and radium-223 was associated with more diarrhea and back pain, whereas less hematological toxicity, nausea, arthralgia and fatigue was seen in the combination arm [[50]]. In the phase 1/2a trial of radium-223 in combination with
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docetaxel vs docetaxel alone, no data about SREs are reported [[50]]
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CONCLUSIONS
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Drug treatment combinations have not always a synergistic action. Probably, the conflicting results of the phase III ERA 223 and PEACE III trials compared with the prior studies combining radium-223 with abiraterone or enzalutamide could be attributed to the different enrolled population. In fact, ERA 223 and
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PEACE III trials only enrolled patients who were naive to any treatment for mCRPC, whereas the others studies included patients in later stages of the disease. Bone pretreated with LH-RH analogs only showed a
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more intense anabolic response to abiraterone, with greater accumulation of radium and bone fragility even in non-metastatic sites. Contrary to abiraterone, enzalutamide has not the same bone anabolic effect and does not
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require association with steroid therapy, contributing to lower fracture risk. This could be a plausible reason why bone-protecting agents abolish fracture risk in PEACE III trial and reduce, without eliminating, that risk in ERA 223 trial. However, corticosteroids seem to have a marginal role in the increase of bone fragility of these patients. In fact, bone fragility fracture occurred as an acute toxicity in ERA 223 trial, whereas corticosteroids-induced bone mineral density reduction is a long-term effect, mainly associated to dexamethasone than to prednisone. Moreover, the association between docetaxel and radium-223 did not result
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in an increase in SREs in spite of the use of corticosteroids as well as with abiraterone. No data are still available regarding the association of radium-223 and immunotherapy or PARP inhibitors on bone metabolism. When addressing effect of drug combinations on bone health, the setting of disease needs to be considered, results in far advanced disease cannot be shifted to early stages, where the bone could have a different metabolic status. Preclinical studies and/or proof-of concept translational studies could help to provide
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information useful to design large phase 3 trials on bone health in specific settings of disease.
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Author Contributions: All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: All authors. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: All authors. Critical revision of the manuscript for important intellectual content: All authors. Administrative, technical, or material support: All authors.
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Supervision: All authors.
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Figure 1. Title: Bone metastatic process phases: expansion, homing, dormancy and onco-niche formation
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and colonization.
Figure 1. Legend: Bone metastatic process involves endothelial cells, osteocytes, stromal cells, osteoclasts,
na
osteoblasts and the chemical structure of the bone. After the escape from the primary tumor into systemic circulation, prostate cancer (PCa) cells are attracted to skeletal tissue by the same chemotactic cytokines involved in Hematopoietic Stem Cells (HSCs) homing to the bone marrow. The CXCL12-CXC-chemokine
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receptor 4 (CXCR4) axis is one of the signalling pathways involved in the “onco-niche” generation.
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Endothelial cells contribute to the bone metastatic process by expressing P-selectin, E-selectin and vascular adhesion molecule 1 which are responsible of tumor cells adhesion. Moreover, endothelial cells promote PCa cell dormancy and neovascularization for metastatic growth. Tumor cells can secrete angiogenetic factors such as vascular endothelial growth factor (VEGF) and IL-8, which increase PCa cells survival and tumor neovascularization. In the onco-niche, PCa cells interfere with normal osteoclastic and osteoblastic activity leading to an abnormal stimulation of bone resorption (mediated by an aberrant activation of the
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RANK/RANK ligand) as well as an abnormal osteoblastic stimulation resulting in an excessive abnormal bone apposition.
Figure 2. Title: The interaction of abiraterone, enzalutamide and radium-223 with bone
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microenvironment and prostate cancer cells.
Figure 2. Legend: Osteoclasts are monocyte-macrophage derived multinuclear cells that are initially
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inactive. Osteoclasts generally are positioned in resorption areas and when activated secrete cathepsin K. Osteoclast activation is controlled by parathryroid hormone, 1,25-dihydroxyvitamin D3, and prostaglandins
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which cause upregulation of receptor activator of nuclear factor-κB ligand (RANKL). RANKL activates osteoclasts by signaling though its receptor, RANK. Locally, stromal cells and osteoblasts also activate osteoclasts by production of macrophage colony stimulating factor (M-CSF). Osteoblasts originate from mesenchymal stem cells and are responsible for synthesizing new bone. After differentiation, osteoblasts secrete osteocalcin and calcified matrix, eventually becoming osteocytes as they are encapsulated within the bone. Osteocytes osteocytes are surrounded by the bone matrix and regulate osteoclast activation through 21
expression of: RANKL, macrophage colony stimulating factor (M-CSF) and osteoprotegerin (OPG). Hydroxyapatite, the mineral structure of the bone, may liberate growth factors (such as insulin like growth factors I and II, platelet-derived growth factor, transforming growth factor-beta and fibroblast growth factor) which could cause a proliferative effects on tumor cells. Radium-223, as a cationic calcium-mimic, is absorbed and concentrated in the bone and binds to hydroxyapatite. Radium-223 deposits mostly in active bone remodelling and emits α-particles inducing tissue damage. Abiraterone inhibits androgen biosynthesis through irreversibly blocking Cyp17. Abiraterone has an anabolic and anti-resorpive effect by inhibiting osteoclastic differentiation (down-modulation of osteoclastic marker genes TRAP, cathepsin K and
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metalloproteinase-9 and decreased serum levels of C-terminal type I collagen (CTX)). Furthermore,
abiraterone promoted osteoblastic differentiation and bone matrix deposition up-regulating osteoblastic
specific genes, osteocalcin (OCN) and serum value of alkaline phosphatase (ALP). Enzalutamide is an oral
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androgen receptor (AR) inhibitor. Enzalutamide has not an anabolic effect on bone, although it could
enhances bone turnover (both serum levels of CTX, marker of bone resorption and OCN marker of bone
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formation are increased after enzalutamide in a preclinical model).
22
NCT02043678 Phase 3
NCT02225704 Phase 2
Adverse events
safety and OS
OS advantage for concomitant Ra-223 and AAP, ENZA or denosumab
G3-4: anemia 5% Thrombocytopenia 2% Neutropenia 1%: 40% of any G AEs
Radium223safety,efficacy, and concurrent use with AAP or ENZA: first u.s. experience from an expanded access program
acute and long-term safety
Ra-223 was safe regardless of concurrent abiraterone or enzalutamide
G3-4: anemia (AAP 16% vs ENZA 13%) thrombocytopenia (AAP 4% vs ENZA0%) back pain (AAP 0% vs ENZA 13%)
eRADicAte: A prospective evaluation combining ra-223 dichloride and AAP in patients with mCRPC
QoL and pain, radiographic response, safety
Improvement in all primary and secondary endpoints
17% nausea, 17% diarrhea, fatigue 14%
SREs- free survival: 22.3 mo in Ra-223 group and 26·0 mo in placebo group
Fractures in 29% of pts RA-223 group vs 11% in pbo group
13% of SREs
24% of osteoporotic asymptomatic fracture
No data still posted
Without BPA: fractures in 37.4% of pts RA-223 group vs 12.4% in pbo. With BPA fracture 0% in both arms
Addition of ra-223 to AAP in patients with mCRPC (ERA 223): a randomised, doubleblind, placebocontrolled, phase 3 trial A phase 2, interventational trial to determine safety and tolerability of Ra-223 administered in combination with ENZA in progressive mCRPC
A randomized, multicenter phase 3 trial comparing enzalutamide vs a combination of Ra223 and ENZA in asymptomatic or mildly symptomatic CRPC with bone metastasis
11%
No data
SREs-free survival
Safety (SREs)
Radiologic PFS
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12%
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Ra-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial
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NCT0219484 Phase 3
Results
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NCT02097303 Phase 2
Concomitant/prior denosumab or zoledronic acid
39% of pts in Ra-223 group
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NCT01516762 Phase 2
Primary/Secondary Endpoints
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NCT01618370 Phase 3b
Trial design
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Trial/Phase
1%
55%
Ra-223 + D Ra-223+D greater % 60mg/mq less Phase 1/2a trial of of Assessment of doseNCT01106352 decline in hematologic radium-223 with limiting toxicities and No data Phase 1/2a bone toxicity than RaDocetaxel safety formation 223+D 75mg/mq markers Table 1 Clinical trials of Radium-223 combined with other agents. Abbreviations: AAP: abiraterone acetate and prendisone; ENZA; enzalutamide; Ra-223: radium-223; D: docetaxel; BPA: bone protecting agents; ORR: overall response rate; OS: overall survival; PFS: progression free survival; AEs: adverse events; SREs: Skeletal related events
23
Trial design
Primary/Secondary Endpoints
Concomitant/prior denosumab or zoledronic acid
Results
Adverse events
NCT03574571 Phase 3
Open-labeled, randomized, phase III study of docetaxel versus docetaxel in combination with radium-223 in subjects with mCRPC
OS
Recruiting, no data still posted
Recruiting, no data still posted
Recruiting, no data still posted
NCT03093428 Phase 2
A randomized, phase II study evaluating the addition of pembrolizumab (MK-3475) to Ra-223 in (mCRPC)
Extent Of Immune Cell Infiltration, PFS, OS, AEs
Recruiting, no data still posted
Recruiting, no data still posted
Recruiting, no data still posted
NCT02814669 Phase 1
Safety and tolerability of atezolizumab in combination with Ra-223 and D in mCRPC progressed following treatment with an androgen pathway inhibitor
Dose-Limiting Toxicities, AEs, ORR
no data still posted
no data still posted
no data still posted
A Phase 2 study of sipuleucel-t with or without Ra-223 in men with asymptomatic or minimally symptomatic bone mCRPC
Immune responses to sipuleucel-T +/Ra-223 measured by peripheral PA2024 T-cell proliferation
no data still posted
NCT02463799 Phase 2
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Trial/Phase
no data still posted
no data still posted
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Table 1 Clinical trials of Radium-223 combined with other agents. Abbreviations: AAP: abiraterone acetate and prendisone;
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ENZA; enzalutamide; Ra-223: radium-223; D: docetaxel; ORR: overall response rate; OS: overall survival; PFS: progression free survival; AEs: adverse events; SREs: Skeletal related events
24
PII:
S1040-8428(20)30002-0
DOI:
https://doi.org/10.1016/j.critrevonc.2020.102864
Reference:
ONCH 102864
To appear in:
Critical Reviews in Oncology / Hematology
Received Date:
13 October 2019
Revised Date:
27 December 2019
Accepted Date:
4 January 2020
Please cite this article as: Cursano MC, Iuliani M, Casadei C, Stellato M, Tonini G, Paganelli G, Santini D, De Giorgi U, Combination radium-223 therapies in patients with bone metastases from castration-resistant prostate cancer: a review, Critical Reviews in Oncology / Hematology (2020), doi: https://doi.org/10.1016/j.critrevonc.2020.102864
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.
Combination radium-223 therapies in patients with bone metastases from castration-resistant prostate cancer: a review
M.C. Cursano1, MD; M. Iuliani1, BS, PhD; C. Casadei2, MD; M. Stellato1, MD; G. Tonini1,MD, PhD; G. Paganelli3, MD, PhD; D. Santini1§, MD, PhD & U. De Giorgi2§, MD, PhD 1
Department of Medical Oncology, Campus Bio-Medico University of Rome, 00128 Rome, Italy
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Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy 3
Department of Nuclear Medicine Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy §
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co-last authors
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*Corresponding author: Maria Concetta Cursano, MD, Department of Medical Oncology, Campus Bio-Medico University of Rome, via Alvaro del Portillo, 200 00128 Rome, Italy. Email: [email protected]
Highlights
In bone mCRPC, each treatment has an effect on PCa cells and bone microenvironment.
Clinical trials have been performed to evaluate radium 223-based combination therapies.
Pretreated and un-pretreated patients have different morbidity and clinical outcomes.
Different bone metabolic status could justify the different clinical outcomes.
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Associating bone protecting agents reduce treatment-related morbidity.
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Abstract Chemotherapeutic agents (docetaxel, cabazitaxel), hormonal therapies (abiraterone, enzalutamide) and radium-223 improve survival in patients with bone metastatic castration-resistant prostate cancer (mCRPC). Combinations of radium-223 with these agents or novel drugs have been investigated in order to improve survival and decrease bone-related morbidity. In mCRPC, clinical and preclinical data indicate that radium223, abiraterone and enzalutamide have a direct effect on prostate cancer cells and bone microenvironment when administered as single agents. Initial results from studies of radium-223 and abiraterone, enzalutamide or docetaxel demonstrated efficacy without any safety concern in pre-treated mCRPC; however, this safety
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profile changed when radium-based combination therapies were administered in un-pretreated mCRPC. This review underline the biological rationale for combining radium strategies, investigating their effects on bone in terms of control of skeletal-related events and bone disease progression. The aim is to understand the
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possible reasons why different radium-based combination treatments can led to different clinical outcomes.
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Keywords: Castration-resistant prostate cancer; bone metastases; Skeletal-related events; radium-223; enzalutamide; abiraterone; docetaxel; bone protecting agents.
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INTRODUCTION Bone is the most preferential target site for prostate cancer (PCa) metastases with an incidence of nearly 75% [[1],[2]]. “Skeletal-related events” (SREs) represent the most common clinical complication related to PCa bone metastases [[3],[4]]. SREs include pathologic bone fractures, hypercalcaemia, spinal cord compression, surgery to bone, and radiotherapy to bone [[5],[6]]. In the last years, several new drugs including chemotherapy (docetaxel, cabazitaxel), new hormonal therapies (abiraterone, enzalutamide) and radium-223 demonstrated overall survival (OS) benefit and improvements in bone health in mCRPC patients [[7],[8],[9],[10],[11],[12]].
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On the contrary, androgen deprivation therapy (ADT) increases bone turnover and decreases bone mineral density [[13]] due to the inhibition of androgens and estrogens function that preserve bone trabecular structure [[14]]. Therefore, the alteration of bone homeostasis in PCa patients is a multifactorial process, resulting from
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the disease and its treatments.
The receptor-activator of nuclear-factor-k-B (RANK) ligand inhibitor denosumab and bisphosphonates are the
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bone target therapies approved for the prevention of SREs in adults with bone metastases [[15],[16],[17],[18],[19]]. Contrary to denosumab and bisphosphonates, radium-223 is the first bone target
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therapy that provides OS benefit for mCRPC with bone metastasis [[12]]. Recently, several studies try to identify the optimal combination therapy to improve survival and decrease patient bone-related morbidity.
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These investigations showed that combinations of radium-223 and abiraterone, enzalutamide, or docetaxel are associated with unexpected and sometimes discordant results. This review underline the biological rationale
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for combining radium strategies, investigating their biological effects on bone microenvironment and their clinical effect in terms of control of skeletal-related events and bone disease progression.
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PHYSIOPATHOLOGY OF BONE METASTASIS IN PCa Bone metastasis are the result of a series of complex interactions between tumour cells, bone marrow cells, and resident bone cells, which led to the disruption of normal bone homeostasis (Figure 1) [[20]]. Physiological bone remodelling process occurs at specialized skeleton sites, the “bone remodeling units”, in which functions of osteoclasts and osteoblasts are tightly regulated to maintain the balance between bone formation and degradation and preserve skeletal integrity [[21]]. In bone metastatic process, tumour cells are attracted to
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skeletal tissue by the same chemotactic cytokines that regulate the migration of Hematopoietic Stem Cells (HSCs) into the hematopoietic stem cell niche. Osteoblastic-induced stromal-derived factor-1 (SDF-1 or CXCL12) binds CXCR4 receptor expressed both by HSCs and PCa cells [[22],[23],[24],[25],[26]]. SDF1/CXCR4 interaction causes a competition between HSCs and PCa cells, leading to the formation of the “onconiche”, in which tumor cells may be quiescent or active [[20],[22],[23]]. PCa cells migrated in these niches, secrete several paracrine factors such as transforming growth factor β1 (TGF β1), parathyroid-hormone-related peptide (PTHrP) and interleukin 6 (IL-6), that interfere with normal osteoclastic and osteoblastic activity damaging physiological bone remodelling process [[27]]. The result is an abnormal stimulation of bone
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resorption, mediated by an aberrant activation of the RANK/RANK ligand (RANKL) pathway [[20],[22]]. In PCa bone metastasis, a first enhanced osteolysis is followed by a strong osteoblastic stimulation resulting in an excessive abnormal bone apposition. Furthermore, the enhanced osteoclastic activity causes the so-called
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“bone hunger syndrome”, a hyperparathyroidism condition due to calcium entrapment in skeletal tissue and serum calcium deficiency [[20],[28],[29]]. The compensatory hyperparathyroidism leads to osteoclasts
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activation not only at metastatic sites but also at distant sites causing a generalised state of osteoclastogenesis.
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RATIONALE FOR RADIUM-223 COMBINATION THERAPY
Radium-223, as a cationic calcium-mimic, is absorbed and concentrated in the bone and binds to hydroxyapatite. Radium-223 deposits mostly in active bone remodelling areas such as osteoblastic bone
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metastasis and emits α-particles (with locally high energy but limited tissue penetrance), inducing DNA double-strand breaks and complex chromosomal rearrangements leading to cell death [[12],Error! Reference
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source not found.]. Preclinical studies have been designed to investigate if radium-223 beneficial clinical effects in mCRPC are solely due to its effect on osteoblasts and/or osteoclasts or also to a direct effect on PCa
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cells. Suominen et al demonstrated that radium-223 therapy had a dual mode of-action: localized cytotoxic effects on PCa cells and bone integrity preservation. Using two different prostate cancer xenograft models LNCaP (with osteoblastic or mixed metastases) and LuCaP 58 PDX (with osteoblastic metastases), the authors proved that radium-223 inhibited tumor-induced osteoblastic activity, safeguarded normal bone architecture and contrasted prostate cancer growth in bone. Treatment with radium-223 was associated with the reduction of bone formation marker N-terminal propeptide of type I procollagen (PINP) and overall tumour burden as
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measured by prostate specific antigen (PSA) [[31]]. Furthermore, previous studies showed similar results in a murine model of osteolytic breast cancer bone metastasis treated with radium-223, suggesting that it potentially acts regardless of primary origin or nature of bone alterations (osteolytic or osteoblastic) [[31]]. Abou D.S. et al confirmed these data demonstrating that radium-223 localizes in active bone remodelling areas of healthy mice, as well as of osteoblastic (LNCaP) and osteolytic (PC3) PCa mice [[33]]. Recently, radium-223 showed an immunomodulation activity by inducing T cell-mediated cell death in human prostate, breast, and lung cancers;[34] several studies of concomitant radium-223 with immunotherapy are ongoing and could give the clinical validation of this preclinical data. Furthermore, since the evidence of somatic DNA repair gene defects
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(DRD) in nearly 20% of PCa, other studies are evaluating combination strategies of inhibitors of the enzyme poly ADP ribose polymerase (PARP), as olaparib and niraparib, with radium-223 [[35]].
Abiraterone inhibits androgen biosynthesis through irreversibly blocking Cyp17 [[36],[37]]. Abiraterone
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significantly improves OS, radiological skeletal progression and time to SREs in both pre-docetaxel and post-docetaxel mCRPC setting [[38],[39]]. Iuliani et al, have previously demonstrated that abiraterone
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exerted a direct effect on bone microenvironment inhibiting osteoclast function and promoting osteoblast activity. Abiraterone induced inhibitory effect on osteoclastic differentiation, down-modulating osteoclastic
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marker genes TRAP, cathepsin K and metalloproteinase-9 and decreasing serum levels of C-terminal type I collagen (CTX). Furthermore, abiraterone promoted osteoblastic differentiation and bone matrix deposition
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up-regulating osteoblastic specific genes, osteocalcin and serum value of alkaline phosphatase (ALP). These data suggested an anabolic and anti-resorpive effect of abiraterone in addition to its well-known antitumoral
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effect [[40]]. Enzalutamide is an oral androgen receptor (AR) inhibitor, which significantly improves OS in both chemotherapy-naïve and post-chemotherapy mCRPC patients. Additional benefits included an increase
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in radiographic PFS (rPFS), a significant delay in time to first SREs and an improvement in several measures of pain and health-related quality of life (QoL) [[10],[11]]. Preclinical data demonstrated that enzalutamide was associated with higher bone turnover: both serum levels of C-terminal type I collagen (CTX, marker of bone resorption) and OCN (marker of bone formation) were increased in mice treated with enzalutamide. In the same mice, there was an increased number of osteoblasts and osteoclasts per bone perimeter in the trabecular bone of L4 vertebrae but not in the trabecular bone of tibia after 21 days of treatment with
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enzalutamide [[41]]. It is well-known that ADT sensitizes radiotherapy-induced cell death in PCa by inhibiting DNA repair mechanisms and blocking the radiotherapy-induced upregulation of AR [[42]]. Basing on the synergistic effect of ADT and radiotherapy and the preclinical evidences of the effects of the new anti-androgen agents on both tumour cells and bone microenvironment, several clinical trials have been performed to evaluate radium 223-based combination therapies. The aim is to study if concomitant treatments can increase the effectiveness of each treatment through a synergic interaction. RADIUM-223-BASED COMBINATION THERAPY
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New clinical trials evaluating radium-223 combination therapies mainly focused on five combination treatment strategies: radium-223 and abiraterone, radium-223 and enzalutamide, radium-223 and docetaxel, radium-223 and immunotherapy and radium-223 and PARP inhibitors (Table 1). The aim of these studies was to improve
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efficacy of each treatment, without enhancing the toxic effects. Radium-223 and abiraterone
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In an international, early access, single-arm phase 3b study, enrolling symptomatic or asymptomatic mCRPC with bone metastases and no visceral disease, patients were stratified to receive concomitant radium-223 and other
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therapies versus radium-223 alone. The majority of patients enrolled (97% of the entire population) received a previous treatment with abiraterone plus prednisone, enzalutamide or docetaxel; 12% of patients received a previous
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treatment with denosumab or zoledronic acid. The results were encouraging: there was OS advantage in the subgroup of patients (154 patients) who received concomitant radium-223 and abiraterone acetate plus prednisone
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[[43]]. This finding was confirmed by the results of the expanded access program (EAP) providing early-access
radium-223 with or without concomitant other life-prolonging therapies. Concurrent radium-223 and
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abiraterone was administered to 14% of patients, maintaining efficacy without any new safety concerns [[44]]. The phase II eRADicAte trial was the first single arm prospective study evaluating the combination of radium223 and abiraterone acetate plus prednisone in patients with symptomatic bone metastatic mCRPC. In this small trial, the 31 patients enrolled experienced benefit both in bone pain and in QoL patient measures [[45]]. Moreover, there was a significant reduction of the mean number of bone scan lesions (from 11.6±2.8 at baseline to 5.6±2.4 at the end of treatment) [[45]]. Recently, Smith and colleagues published the results of the phase III
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study ERA 223 in which abiraterone plus prednisone were combined with radium-223 or placebo in asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients with bone metastases. Differently from the previous studies, concomitant radium-223 and abiraterone did not improve OS or skeletal event-free survival and was associated to higher risk of fractures. Fractures of any grade occurred in 112 (29%) of 392 patients in the radium-223 group and 45 (11%) of 394 patients in the placebo group. Fractures were localized at no-metastatic skeletal site and mainly were osteoporotic fractures. Forty percent of patients received bone protective agents before their enrolment and continued treatment during the study; the post hoc analysis revealed that bone protective agents significantly reduced risk of fractures in both arms. In fact, fractures occurred in 24 (15%) of 157 patients
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(experimental group) and in 11 (7%) of 169 patients (control arm) after treatment with bone health agents [[46]]. Based on these results, the trial was unblended and stopped prematurely and FDA and EMA changed the prescribing recommendations for radium-223.
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Radium-223 and enzalutamide
In the above mentioned single-arm phase 3b trial published by Saad and colleagues, the subgroup of patients
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(n=50) treated with concomitant enzalutamide and radium-223 showed a survival benefit without presenting additional adverse events (AEs) [[43]]. In the EAP program, concomitant radium-223 and enzalutamide
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treatment confirmed its efficacy and safety profile [[44]]. Safety and tolerability of the association between radium-223 and enzalutamide was assessed in a phase II single arm study (NCT02225704) enrolling 45
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patients with mCRPC and bone metastases. A retrospective analysis of this population reported an incidence of asymptomatic osteoporotic fracture of 24.4%; in particular, asymptomatic osteoporotic fractures related to
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insufficiency and trauma occurred in 11 (24.4%) and 4 (9%) patients enrolled, respectively [[47]]. Recently, the results of the safety analysis of the phase 3 PEACE III trial of concomitant treatment of enzalutamide with
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radium-223 versus enzalutamide alone in asymptomatic or mildly symptomatic mCRPC patients with bone metastasis were presented. After the results of the ERA-223 trial, the Internal Displacement Monitoring Centre (IDMC) issued an urgent safety letter for mandatory use of bone-protecting agents in both arms of the trial and for delayed initiation of radium-223 for new randomized patients (at least six weeks between the start of the bone healthy agent and start date of radium-223). After urgent safety letter, the proportion of patients treated with bone protecting agents changed from 40% to 55% in both treatment arms. In patients not exposed to bone protecting agents, the cumulative incidence of bone fracture at 12 months was 12.4% with enzalutamide and 7
37.4% with radium and enzalutamide. No patients treated with bone protecting agents experienced bone fractures in both treatment arms [[47]]. Radium-223 and docetaxel Docetaxel is the first chemotherapy agents able to increase overall survival in mCRPC by inhibiting tumour grow through interfering with microtubules dynamics [[49]]. The efficacy and safety of combining radium223 with docetaxel was examined in a Phase I/II trial (NCT01106352). In this study, PSA decline >50% occurred in 61% of patients in the combination arm (versus 54% in the docetaxel arm) with a median PFS of
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12 months in the combination arm (versus 9.3 months in the docetaxel arm). In patients treated with the concomitant docetaxel and radium-223, bone marker levels indicated a greater suppression of osteoblastic activity. In fact, serum level of PINP showed a decline trend in favour of the combination arm, whereas CTX, markers of osteoclastic activity, showed similar trend in the two arms [[50],[49]]. These findings are currently
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under evaluation in the ongoing phase 3 DORA trial (NCT03574571), randomizing mCRPC patients to
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receive docetaxel and radium-223 versus docetaxel alone, in which OS is the primary end point [[51]]. Radium-223 and immunotherapy or PARP inhibitors
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To date, there are three clinical trials evaluating the association of radium-223 with pembrolizumab (phase 2,
NCT03093428), atezolizumab (phase 1, NCT02814669), sipuleucel (phase 2, NCT02463799) [[52];[53];[54]].
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Pembrolizumab and atezolizumab are two immunotherapy drugs, which block the Programmed Death-1 (PD-1) pathway [[55]]. EMA and FDA have not approved Pembrolizumab and atezolizumab for mCRCP treatment.
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Sipuleucel is the first therapeutic vaccine approved by EMA and FDA for mCRPC [[56]]. In PCa, PARP inhibitors have shown significant response rates up to 88% for PCa patients having DRD [[35]].
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Clinical trials are evaluating the combination of Radium-223 and olaparib (NCT03317392)[57] or niraparib (NCT03076203)[[58]]. The above-mentioned studies are ongoing and there are not published data of safety and tolerability to date.
ADVERSE EVENTS CONSIDERATIONS In the early access phase 3b trial and in the phase 2 EAP, the association of radium-223 with abiraterone or enzalutamide was safe, without warning for SREs in the subgroup of patients treated with concomitant radium8
223 and enzalutamide or abiraterone [[43],[44]]. In these studies, population was quite different from ERA 223 trial; in fact, the majority of patients (97 % the early access phase 3b trial and 99% in the phase 2 EAP) were previously treated with at least one systemic therapy for mCRPC, mainly docetaxel. Therefore, EAP program was not a randomized trial and follow up time was too short to detect long acting treatment related AEs [[43],[44]]. The first randomized phase II eRADicAte trial confirmed safety profile of the association of radium-223 and abiraterone. Patients reported diarrhoea (17%), nausea (17%), and fatigue (14%) similarly to those observed in previously reported trials [[45]]. Contrary to all predictions, the phase III ERA 223 trial did not report the same safety data [[46]]. Dalla Volta et al hypothesized that prednisone, administered in
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combination with abiraterone, could be the possible cause of increased bone fragility and increased incidence of osteoporotic fractures, because the combination of glucocorticoid and radium-223 induced a synergic inhibition of osteoblast differentiation, maturation, and activity and caused an increased bone fragility [[58],[60]]. Similarly, Daniel Spratt defined the increased fracture risk as the results of the multifactorial insult
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to bone from chronic androgenic deprivation, prednisone, low use of bone health agents in ERA 223 and
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unknown use of preventive fracture measures [[61]]. In this scenario, they supposed that radium-223 was the final additional factor to enhance fracture risk of this population [[61]]. However, fractures were an acute
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toxicity, occurring in the first six months as the result of the interaction of abiraterone and radium-223 with bone microenvironment, whereas glucocordicoid-induced bone mineral density reduction is a long-term bone
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metabolic effect [[62]]. Recently, Attard et al published the results of the phase 2 study evaluating the safety of abiraterone with 4 different glucocorticoid regimens (dexamethasone 0.5 mg once daily, prednisone 5 mg once daily, prednisone 5 mg twice daily and prednisone 2.5 mg twice daily). They demonstrated that
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abiraterone with prednisone 5 mg twice daily or dexamethasone 0.5 mg once daily were not associated to
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mineralcorticoid excess. A reduction of bone mineral density was observed from baseline to the end of the main study in dexamethasone group but in prednisone group, independently of schedule and dose of administration [[56]]. Results from preclinical trials provide other possible additional explanations for
the explanation about the increased bone fragility with radium-223 concomitant treatments. It has been demonstrated that abiraterone has an inhibitory effect on osteoclasts and promoted osteoblasts differentiation and bone matrix deposition [[40]]. Radium-223 deposits mostly in active bone remodelling areas such as osteoblastic bone metastasis, which are a result of stimulation of osteoblasts, inhibition of 9
osteoclasts or both, by cancer cells (Figure 2) [[12]]. If abiraterone produces an anabolic effect by promoting osteoblastic activity in healthy and metastatic bone, the combination of abiraterone and radium-223 may result in the accumulation of radium-223 not only at the metastatic site level (notoriously an area of increased bone turnover and osteoblastic activation) but even at healthy bone. Consequently, the greater deposit of radium223 in healthy bone and the subsequent emission of α-particles could result in cell and tissue damage with loss of bone matrix and osteoporosis. Enzalutamide did not demonstrate the same anabolic and anti-resorpive effect of abiraterone. In fact, preclinical evidence suggests that enzalutamide- mediated AR inhibition is associated with enhanced bone turnover and increased vertebral fracture risk [[41]]. Probably, it could be the reason why
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concomitant use of bone protecting agents abolishes the risk of bone fractures in PEACE III trial and reduces, even not eliminating, that risk in ERA 223 patients. Concomitant use of docetaxel and radium-223 was associated with more diarrhea and back pain, whereas less hematological toxicity, nausea, arthralgia and fatigue was seen in the combination arm [[50]]. In the phase 1/2a trial of radium-223 in combination with
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docetaxel vs docetaxel alone, no data about SREs are reported [[50]]
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CONCLUSIONS
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Drug treatment combinations have not always a synergistic action. Probably, the conflicting results of the phase III ERA 223 and PEACE III trials compared with the prior studies combining radium-223 with abiraterone or enzalutamide could be attributed to the different enrolled population. In fact, ERA 223 and
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PEACE III trials only enrolled patients who were naive to any treatment for mCRPC, whereas the others studies included patients in later stages of the disease. Bone pretreated with LH-RH analogs only showed a
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more intense anabolic response to abiraterone, with greater accumulation of radium and bone fragility even in non-metastatic sites. Contrary to abiraterone, enzalutamide has not the same bone anabolic effect and does not
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require association with steroid therapy, contributing to lower fracture risk. This could be a plausible reason why bone-protecting agents abolish fracture risk in PEACE III trial and reduce, without eliminating, that risk in ERA 223 trial. However, corticosteroids seem to have a marginal role in the increase of bone fragility of these patients. In fact, bone fragility fracture occurred as an acute toxicity in ERA 223 trial, whereas corticosteroids-induced bone mineral density reduction is a long-term effect, mainly associated to dexamethasone than to prednisone. Moreover, the association between docetaxel and radium-223 did not result
10
in an increase in SREs in spite of the use of corticosteroids as well as with abiraterone. No data are still available regarding the association of radium-223 and immunotherapy or PARP inhibitors on bone metabolism. When addressing effect of drug combinations on bone health, the setting of disease needs to be considered, results in far advanced disease cannot be shifted to early stages, where the bone could have a different metabolic status. Preclinical studies and/or proof-of concept translational studies could help to provide
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information useful to design large phase 3 trials on bone health in specific settings of disease.
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Author Contributions: All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: All authors. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: All authors. Critical revision of the manuscript for important intellectual content: All authors. Administrative, technical, or material support: All authors.
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Supervision: All authors.
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Figure 1. Title: Bone metastatic process phases: expansion, homing, dormancy and onco-niche formation
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and colonization.
Figure 1. Legend: Bone metastatic process involves endothelial cells, osteocytes, stromal cells, osteoclasts,
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osteoblasts and the chemical structure of the bone. After the escape from the primary tumor into systemic circulation, prostate cancer (PCa) cells are attracted to skeletal tissue by the same chemotactic cytokines involved in Hematopoietic Stem Cells (HSCs) homing to the bone marrow. The CXCL12-CXC-chemokine
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receptor 4 (CXCR4) axis is one of the signalling pathways involved in the “onco-niche” generation.
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Endothelial cells contribute to the bone metastatic process by expressing P-selectin, E-selectin and vascular adhesion molecule 1 which are responsible of tumor cells adhesion. Moreover, endothelial cells promote PCa cell dormancy and neovascularization for metastatic growth. Tumor cells can secrete angiogenetic factors such as vascular endothelial growth factor (VEGF) and IL-8, which increase PCa cells survival and tumor neovascularization. In the onco-niche, PCa cells interfere with normal osteoclastic and osteoblastic activity leading to an abnormal stimulation of bone resorption (mediated by an aberrant activation of the
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RANK/RANK ligand) as well as an abnormal osteoblastic stimulation resulting in an excessive abnormal bone apposition.
Figure 2. Title: The interaction of abiraterone, enzalutamide and radium-223 with bone
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microenvironment and prostate cancer cells.
Figure 2. Legend: Osteoclasts are monocyte-macrophage derived multinuclear cells that are initially
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inactive. Osteoclasts generally are positioned in resorption areas and when activated secrete cathepsin K. Osteoclast activation is controlled by parathryroid hormone, 1,25-dihydroxyvitamin D3, and prostaglandins
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which cause upregulation of receptor activator of nuclear factor-κB ligand (RANKL). RANKL activates osteoclasts by signaling though its receptor, RANK. Locally, stromal cells and osteoblasts also activate osteoclasts by production of macrophage colony stimulating factor (M-CSF). Osteoblasts originate from mesenchymal stem cells and are responsible for synthesizing new bone. After differentiation, osteoblasts secrete osteocalcin and calcified matrix, eventually becoming osteocytes as they are encapsulated within the bone. Osteocytes osteocytes are surrounded by the bone matrix and regulate osteoclast activation through 21
expression of: RANKL, macrophage colony stimulating factor (M-CSF) and osteoprotegerin (OPG). Hydroxyapatite, the mineral structure of the bone, may liberate growth factors (such as insulin like growth factors I and II, platelet-derived growth factor, transforming growth factor-beta and fibroblast growth factor) which could cause a proliferative effects on tumor cells. Radium-223, as a cationic calcium-mimic, is absorbed and concentrated in the bone and binds to hydroxyapatite. Radium-223 deposits mostly in active bone remodelling and emits α-particles inducing tissue damage. Abiraterone inhibits androgen biosynthesis through irreversibly blocking Cyp17. Abiraterone has an anabolic and anti-resorpive effect by inhibiting osteoclastic differentiation (down-modulation of osteoclastic marker genes TRAP, cathepsin K and
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metalloproteinase-9 and decreased serum levels of C-terminal type I collagen (CTX)). Furthermore,
abiraterone promoted osteoblastic differentiation and bone matrix deposition up-regulating osteoblastic
specific genes, osteocalcin (OCN) and serum value of alkaline phosphatase (ALP). Enzalutamide is an oral
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androgen receptor (AR) inhibitor. Enzalutamide has not an anabolic effect on bone, although it could
enhances bone turnover (both serum levels of CTX, marker of bone resorption and OCN marker of bone
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formation are increased after enzalutamide in a preclinical model).
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NCT02043678 Phase 3
NCT02225704 Phase 2
Adverse events
safety and OS
OS advantage for concomitant Ra-223 and AAP, ENZA or denosumab
G3-4: anemia 5% Thrombocytopenia 2% Neutropenia 1%: 40% of any G AEs
Radium223safety,efficacy, and concurrent use with AAP or ENZA: first u.s. experience from an expanded access program
acute and long-term safety
Ra-223 was safe regardless of concurrent abiraterone or enzalutamide
G3-4: anemia (AAP 16% vs ENZA 13%) thrombocytopenia (AAP 4% vs ENZA0%) back pain (AAP 0% vs ENZA 13%)
eRADicAte: A prospective evaluation combining ra-223 dichloride and AAP in patients with mCRPC
QoL and pain, radiographic response, safety
Improvement in all primary and secondary endpoints
17% nausea, 17% diarrhea, fatigue 14%
SREs- free survival: 22.3 mo in Ra-223 group and 26·0 mo in placebo group
Fractures in 29% of pts RA-223 group vs 11% in pbo group
13% of SREs
24% of osteoporotic asymptomatic fracture
No data still posted
Without BPA: fractures in 37.4% of pts RA-223 group vs 12.4% in pbo. With BPA fracture 0% in both arms
Addition of ra-223 to AAP in patients with mCRPC (ERA 223): a randomised, doubleblind, placebocontrolled, phase 3 trial A phase 2, interventational trial to determine safety and tolerability of Ra-223 administered in combination with ENZA in progressive mCRPC
A randomized, multicenter phase 3 trial comparing enzalutamide vs a combination of Ra223 and ENZA in asymptomatic or mildly symptomatic CRPC with bone metastasis
11%
No data
SREs-free survival
Safety (SREs)
Radiologic PFS
ro of
12%
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Ra-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial
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NCT0219484 Phase 3
Results
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NCT02097303 Phase 2
Concomitant/prior denosumab or zoledronic acid
39% of pts in Ra-223 group
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NCT01516762 Phase 2
Primary/Secondary Endpoints
na
NCT01618370 Phase 3b
Trial design
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Trial/Phase
1%
55%
Ra-223 + D Ra-223+D greater % 60mg/mq less Phase 1/2a trial of of Assessment of doseNCT01106352 decline in hematologic radium-223 with limiting toxicities and No data Phase 1/2a bone toxicity than RaDocetaxel safety formation 223+D 75mg/mq markers Table 1 Clinical trials of Radium-223 combined with other agents. Abbreviations: AAP: abiraterone acetate and prendisone; ENZA; enzalutamide; Ra-223: radium-223; D: docetaxel; BPA: bone protecting agents; ORR: overall response rate; OS: overall survival; PFS: progression free survival; AEs: adverse events; SREs: Skeletal related events
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Trial design
Primary/Secondary Endpoints
Concomitant/prior denosumab or zoledronic acid
Results
Adverse events
NCT03574571 Phase 3
Open-labeled, randomized, phase III study of docetaxel versus docetaxel in combination with radium-223 in subjects with mCRPC
OS
Recruiting, no data still posted
Recruiting, no data still posted
Recruiting, no data still posted
NCT03093428 Phase 2
A randomized, phase II study evaluating the addition of pembrolizumab (MK-3475) to Ra-223 in (mCRPC)
Extent Of Immune Cell Infiltration, PFS, OS, AEs
Recruiting, no data still posted
Recruiting, no data still posted
Recruiting, no data still posted
NCT02814669 Phase 1
Safety and tolerability of atezolizumab in combination with Ra-223 and D in mCRPC progressed following treatment with an androgen pathway inhibitor
Dose-Limiting Toxicities, AEs, ORR
no data still posted
no data still posted
no data still posted
A Phase 2 study of sipuleucel-t with or without Ra-223 in men with asymptomatic or minimally symptomatic bone mCRPC
Immune responses to sipuleucel-T +/Ra-223 measured by peripheral PA2024 T-cell proliferation
no data still posted
NCT02463799 Phase 2
ro of
Trial/Phase
no data still posted
no data still posted
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Table 1 Clinical trials of Radium-223 combined with other agents. Abbreviations: AAP: abiraterone acetate and prendisone;
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ENZA; enzalutamide; Ra-223: radium-223; D: docetaxel; ORR: overall response rate; OS: overall survival; PFS: progression free survival; AEs: adverse events; SREs: Skeletal related events
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