ARN-509 | Aurora kinase B

Management of non-metastatic castrate-resistant prostate cancer: a systematic review

Yohann Loriot, Stéphane Supiot, Jean-Baptiste Beauval, Friederike Schlürmann-Constans, Gilles Pasticier, Paul Sargos, Philippe Barthélémy, Géraldine Pignot, Denis Maillet, Sébastien Vincendeau, Emmanuel Gross, Guillaume Ploussard, Marc-Olivier Timsit, Delphine Borchiellini

Abstract

Management of non metastatic castrate resistant prostate cancer is challenging for clinicians due to the heterogeneity of the disease and to the scarce clinical data available in this setting. Recent results obtained with the new generation hormone therapies (NGHT) apalutamide and enzalutamide bring a new perspective for the treatment strategy. The authors present here a systematic review of the treatment options.

Keywords: nmCRPC, non-metastatic, castration-resistant, prostate cancer, hormone therapies

Highlights

• nmCRPC is a heterogeneous stage of prostate cancer for which the challenge is to delay the onset of metastasis
• Until recently, few evidences were available to orient clinicians in the choice of treatment modalities
• Recent results obtained with next generation antiandrogen therapy demonstrate for the first time a survival benefit in this setting and will modify the management of nmCRPC
• New imaging technics will help improving diagnosis of prostate cancer and thus aid in determining the best treatment option

1. Introduction

Epidemiology

Prostate cancer (PC) is the second most frequent cancer and the fifth cause of cancer-related death in men worldwide [1]. Even though the incidence rate decreased significantly between 2010 and 2014 (-10.1 average annual percent change), the estimated number of new cases was 1.1 million worldwide in 2012 and 164,690 in the USA in 2017 while the estimated number of deaths was 307,000 worldwide in 2012 and 29,430 in the USA in 2017 [1, 2]. Most patients present with localized disease at diagnosis (up to more than 80% in the US) [3] and most patients who die from metastatic disease presented with high-risk localized disease at diagnosis [4]. Prostate-specific antigen (PSA) concentration is a predictor of disease progression and outcomes [5]. Therefore, PC screening programs using PSA testing have been introduced the last two decades [6]. This resulted in an increase in the number of men with early stage PCa diagnosis who received local treatment such as surgery or radiation therapy. However, 20–40% of patients undergoing radical prostatectomy (RP) [7, 8] and 30–50% of patients undergoing radiation therapy (RT) will experience biochemical recurrence within 10 years [9]. PC that has recurred after local therapy or has disseminated distantly usually respond to androgen deprivation therapy (ADT). Most patients with biochemically recurrent PC initially respond to ADT, however the vast majority will develop progressive disease within approximately 5 years of diagnosis, which is known as castration resistant prostate cancer (CRPC) [10, 11].

Non-metastatic castrate-resistant prostate cancer

Although CRPC can be defined as biochemical (rising PSA levels), radiological, or clinical progression in a low testosterone environment (<50 ng/dL or 1.7 nmol/L), most CRPC cases are declared based on an isolated PSA progression in the absence of any detectable metastasis [12]. Several definitions of biochemical progression in the context of CRPC are used in the literature [13, #113, 14-17]. The epidemiology of this stage is not well known due to the heterogeneity of the disease [6]. Nevertheless, non-metastatic CRPC (nmCRPC) prevalence has been estimated to 7% of prostate cancer in the EU [18-20]. In these patients, micro-metastases might exist but are usually undetectable by conventional imaging techniques such as CT scan and bone scan [21]. New imaging techniques (Choline-, Fluciclovine-, PSMA-PET scan) will however probably change the landscape of this disease in the near future. nmCRPC is a health state where most patients are usually asymptomatic, with the exception of side-effects due to ADT therapy. As such, in a denosumab prevention trial, serious adverse events in the placebo arm were rare [15]. Therefore, it has become a major challenge to prolong as long as possible this stage by delaying the disease progression marked by onset of the first metastasis. The identification of risk factors of metastasis remains the major challenge as well as the determination of the optimal treatment for a given patient [12]. Patients with nmCRPC have a metastasis-free survival of approximately 25-30 months and 33% of these patients will develop metastases within 2 years [17, 22]. Nonetheless, the guidelines for the management of nmCRPC from the National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO) and European Association of Urology (EAU) only recommend maintaining ADT and enrolment in a clinical trial [23-26].

Prognostic factors

PSA kinetics is an indicator of aggressiveness in this population and can be used to trigger imaging investigation and enrolment in clinical trials [12]. Baseline PSA and PSA doubling time (PSAdt) may predict time to first bone metastases, overall survival (OS) and metastasis-free survival (MFS). In the study by Smith et al. [17], a PSA level >10 ng/mL and a PSAdt <6-8 months were associated with poorer OS and MFS than lower PSA and longer PSAdt. In addition, risk of bone metastasis or death has been shown to increase when PSAdt decreases below 8 months [17, 27].
The 2015 St Gallen advanced prostate cancer consensus conference have addressed the question of nmCRPC management and pointed out the lack of information and clinical needs in this realm [28, 29]. Here we propose an updated review of available clinical data in the nmCRPC setting including the latest findings.

2. Material and methods

A review of the literature has been conducted in February 2018 using the PubMed Medline database following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) guidelines. We searched for clinical trial articles with the following keywords: non-metastatic OR non metastatic AND, castrate-resitance ORcastration-resistant OR castration refractory AND prostate cancer. Search results were restricted to English language without a year limit. From this research, 59 articles were identified. Studies were selected based on title and abstract reading by two authors. Then, for relevant articles, the full text was evaluated, discrepancies were resolved via consensus after discussion between 4 authors. Duplicates, studies which did not include nmCRPC patients or did not present clinical outcome measurement, or nmCRPC subgroup analysis or metastatic status were excluded. The search was complemented by additional sources principally the reference lists of included studies and meeting abstracts. A total of 21 articles were selected and are presented by type of treatment. The selection process is presented in Figure 1. Ongoing trials on nonmetastatic castrate-resistant prostate cancer were searched on the clinicaltrials.gov website and are also presented.

3. nmCRPC management strategies

3.1. Local treatment

Following radical prostatectomy, biochemical relapse may occur in up to 40 % of patients [30]. Local salvage radiotherapy (RT) with or without luteinizing hormone-releasing hormone (LHRH) agonist is a standard-of-care in this clinical situation [31, 32], but some patients may only receive androgen ablation. When castration refractory local relapse develop following RP, limited information is available on the best treatment modality. A retrospective study evaluated high-dose palliative RT (total dose of 40 Gy or greater) in 51 nmCRPC patients [33]. Six different regimens were used, but most patients (75%) received 50 Gy in 20 fractions over 4 weeks. The estimated local failure-free survival, cause-specific survival and OS at 5 years were 81%, 65% and 35%, respectively. Grade 3 or worse toxicity was experienced in 8% of patients. Another study by Sanguineti et al. evaluated retrospectively the benefit of RT administered with curative intent after ADT failure in patients with no distant of lymph node metastases [34]. RT was administered to the prostate at a median dose of 70 Gy (range 66-76 Gy). Out of the 29 patients included, 24 (83%) had a biochemical relapse after a median time of 9.2 months from RT, 79% of which developed metastases. The estimate disease-free survival at 5 years was 25  8% and the 5-year OS from the RT was only 28%. The potential benefit of salvage prostate RT after primary androgen ablation was also investigated in a retrospective study including 42 patients with non-metastatic CRPC [35]. External beam RT (EBRT) was administrated to the prostate to a total dose of 78 Gy in conventional fractionation. The 5-years biochemical disease-free survival, distant MFS and cancer-specific survival were 35%, 60% and 65% respectively. In a multivariate analysis, the best predictors of biochemical disease-free survival were Gleason score (GS), nadir PSA and pre-EBRT PSA ≤5 ng/mL T stage, while GS and T stage significantly affected distant metastasis onset. No grade 3 or higher acute/late toxicity was observed. Similar results were achieved in a small series of 27 patients treated with EBRT or brachytherapy in the castration-resistant setting, where median biochemical relapse free survival was also very limited (21 months) [36]. Therefore, EBRT can be considered a therapeutic option for some patients in the nmCRPC setting, but with limited efficacy.
Since the introduction of multi-parametric magnetic resonance imaging (MRI) and novel prostate specific radiotracers such as 11C or 18F-Flurocholine, 68Ga-PSMA or 18F-Fuciclovine, local failure following radical radiotherapy is now detected in 15-20% of patients [37]. Until recently, these patients were routinely treated with androgen deprivation only [38]. During the last decade, several local salvage strategies including salvage prostatectomy, cryotherapy, High-Intensity Focused Ultra Sound (HIFU), Photodynamic therapy, salvage brachytherapy and stereotactic radiotherapy have been developed, mostly in paucicentric retrospective series [39]. Only a limited number of studies specifically addressed the question of salvage local therapy in the castration resistance setting. Salvage prostatectomy and extended lymphadenectomy were evaluated in patients with nmCRPC after primary radiotherapy in a prospective study [40]. Among the 12 patients included, 6 were pN1. A potential positive impact of radical prostatectomy (RP) in some patients was suggested by the initial PSA response in one of two cases and by disease-free status in one of four patients. However, two patients experienced major adverse events (rectal injury and recto-urethral fistula). This phase II study focused on safety outcomes and suggested that RP was feasible in the nmCRPC setting. However, oncologic results (such as PFS and OS) were not well-described and larger cohorts as well as longer follow-up are needed to draw any firm conclusions regarding the benefit of such surgical approach.
High-level prospective evidences are still needed to determine if a local treatment can improve overall or progression-free survival in patients with nmCRPC.

3.2. Systemic treatments

3.2.1. Bone targeted agents

Bone targeted agents have been approved for mCRPC patients with bone metastasis. Zoledronic acid, the third generation nitrogen-containing bisphosphonate and potent inhibitor of osteoclast activity, differentiation, and survival, decreases the risk of skeletal complications in men with metastatic castrationresistant prostate cancer and bone metastases (mCRPC) [41]. Other bisphosphonates, including pamidronate and clodronate, seem to be ineffective in this setting. Zoledonic acid was also evaluated in combination with standard of care treatment (ADT) in the STAMPEDE study with high-risk locally advanced PCa and showed no evidence of survival improvement [42]. Denosumab, an anti-RANK ligand monoclonal antibody, demonstrated a higher efficacy in the prevention of skeletal-related events in patients with mCRPC than zoledronic acid with no effect on overall survival or disease progression rate [43].
Several studies evaluated bone targeted agents in the nmCRPC setting but demonstrated no or modest effects in terms of overall disease progression (bone or no bone sites) or overall survival [15, 16, 44, 45]. Mason et al investigated clodronate, in patient with nmCRPC (PRC PR04-IRSCTN61384873) in a randomized double-blind placebo-controlled study [44, 46]. The primary endpoint was time to symptomatic bone metastases or to specific prostate cancer death. After a median follow-up of almost 10 years, no evidence of a benefit to the clodronate group was observed in terms of bone MFS or OS. PSA progression was observed in 77/101 patients in the clodronate arm vs 66/101 patients in the placebo arm.
Wirth et al investigated the effect of addition of zoledronic acid every 3-months (5-time more potent than clodronate) to standard of care treatment (SoC) vs SoC alone (ADT) on the prevention of bone metastasis in high-risk nmCRPC patients (ZEUS, IRSTCTN66626762) [45]. A total of 1,433 patients were enrolled in the study and 1040 patients developed bone metastasis at 4  0.5 years. Bone metastases were diagnosed using local bone-imaging procedures in 17.1% of patients in the zoledronic acid group and 17.0% in the control group (p=0.95). After a median follow-up of 4.8 years the estimated proportion of bone metastasis was 14.7% (95% IC 11.8-17.5) in the zoledonic acid group versus 13.2% (95% CI 10.4-16.0) in the control group (p=0.65). This study showed that zoledronic acid was ineffective for the prevention of bone metastasis in high-risk nmCRPC patients at 4 years. A phase III trial evaluated the efficacy of the endothelin A receptor antagonist, atrasentan vs placebo in this setting [16]. The primary endpoint was time to disease progression, defined as the onset of metastases. Atrasentan increased PSAdt (p=0.031) but did not significantly delay time to disease progression compared to placebo (p=0.288).
A Phase III randomized study of zibotentan (ZD4054), another endothelin receptor A antagonist vs placebo [47], was terminated early due to failure of the efficacy data to meet the defined criteria for continuation at interim analysis. There was no difference in terms of OS (HR: 1.13; 95%CI: 0.73-1.76; p=0.59) or PFS between the groups (based on early analysis, 4% chance of ultimately achieving a HR<0.75). Another phase III study evaluated the ability of denosumab, to prevent bone metastasis or death from any cause in men with nmCRPC [15]. A total of 1432 men with nmCRPC at high risk of developing bone metastases (PSA ≥ 8 ng/mL and/or PSAdt ≤ 10 months) were randomized 1:1 to receive a monthly subcutaneous 120mg dose of denosumab (n=716) or placebo (n=716). Bone MFS increased by a median of 4.2 months in the denosumab compared to placebo arm (29.5 months vs 25.2 months; HR: 0.85, 95% IC 0.73-0.98; p=0.028). Denosumab also delayed time to first bone metastasis (median time: 33.2 vs 29.5 months; HR: 0.84, 95% IC 0.71-0.98; p=0.032). However OS were similar between groups (HR 1.1, 95% IC 0.85-1.20; p=0.91). Rates of AE and serious AE were also similar between groups with the exception of osteonecrosis of the jaw and hypocalcaemia, which were more frequent in the denosumab group. In an exploratory analysis, denosumab consistently increased bone metastatis-free survival (bMFS) by a median of 6.0, 7.2, and 7.5 months among men with nmCRPC and a PSAdt ≤10 (HR, 0.84; p = 0.042), ≤ 6 (HR, 0.77; p = 0.006), and ≤ 4 months (HR, 0.71; P = 0.004), respectively [27]. Denosumab also consistently increased time to bone metastasis by PSAdt subset. No difference in survival was observed between treatment groups for the overall study population or PSAdt subsets.
Therefore, denosumab consistently improved bMFS in men with shorter PSAdt and seems to have the greatest treatment effects in men at high-risk of progression with a satisfactory safety profile. However, despite the statistically significant improvement of bMFS, the 4.2 months delay observed is relatively short compared to the long natural history of nmCRPC. Thus, longer follow-up is needed to ascertain the benefit of denosumab in this setting.

3.2.2. Hormone therapy

Initial treatment of patients with biochemical failure on ADT typically includes adding a second-line hormonal agent, such as an androgen receptor inhibitor to ADT [48, 49]. In patients who have not received combined androgen blockade previously bicalutamide, a non-steroidal androgen receptor inhibitor, is commonly used. The efficacy of bicalutamide, with a dose escalation from 50 mg to 150 mg in CRPC patients (n=61, 70% non metastatic) on combined androgen blockade with LHRH (goserelin) was evaluated in a phase II study [50]. The increase in dose to 150mg of bicalutamide resulted in a PSA response of >50% in 13/59 (22%) of patients. At 1 year, 15% (95% CI: 0.02–40.7%) of patients continued to show some PSA response. The median response duration was 5.1 months (95% CI of 0.43–6.21) in 13 PSA responders and 2.3 months (95% CI: 0.92–3.71) in six partial responders, which was not a significant difference by log-rank test (p=0.270). Toxicity was mild with non-frequent grade 1-2 only adverse events. Bicalutamide dose intensification may thus benefit a subset of patients with CRPC. However, the duration of biochemical response remains relatively short.
Finally, the dietary complement BR-DIM (BioResponse 3,3′- Diindolylmethane) which modulates oestrogen metabolism and acts as an anti-androgen was also evaluated in a phase I study. This molecule was well tolerated but showed modest efficacy as 1 patient out of 12 had a PSA response greater than 50% [51].
There is thus at this time no high level of evidence for a benefit of hormonal therapy in terms of disease progression (PSA increase or onset of metastasis) in nmCRPC.

3.2.3. New generation hormone therapy (NGHT)

Enzalutamide and apalutamide are oral androgen receptor (AR) inhibitors that target the AR ligand binding domain and prevent AR nuclear translocation, DNA binding and transcription of AR target genes while abiraterone acetate is a prodrug of abiraterone, which is an inhibitor of androgen synthesis (CYP17A1 inhibitor). Enzalutamide and abiraterone acetate plus prednisone have been shown to improve survival of men with metastatic CRPC prior to and following chemotherapy [52-54]. Abiraterone acetate plus prednisone has also been recently approved for the treatment of high-risk metastatic hormone-sensitive PC in combination with ADT with regards to the results of the LATITUDE (NCT01715285) [55] and STAMPEDE [56] trials which led to an update of the EAU recommendations [13]. Darolutamide (ODM-201, BAY1841788) is another AR inhibitor, which showed AR inhibitory activity without evidence agonism and encouraging anti-tumor efficacy in mCRPC patients in a phase I/II trial [57, 58].
The Phase II study STRIVE evaluated enzalutamide versus bicalutamide in combination with ADT in CRPC patients included 139/396 patients (35.1%) with nmCRPC [59]. Enzalutamide significantly reduced the risk of prostate cancer progression or death by 76% compared to bicalutamide in patients with nmCRPC or mCRPC. However, the risk of death was included in the definition of PFS and no data are available on the OS gain. The median PFS was 19.4 months with enzalutamide vs 5.7 months with bicalutamide (HR 0.24, 95% CI, 0.18 – 0.32; p<0.001). In the nmCRPC subgroup, the median PFS was not reached in the enzalutamide group and 8.6 months in the bicalutamide group (HR 0.24, 95% CI 0.14 -0.42). Enzalutamide was associated with a decreased risk of radiographic progression or death compared with bicalutamide of 68% in metastatic disease and 76% in non-metastatic disease. Enzalutamide was also associated with an 81% reduction in the risk of PSA progression. PSA response ≥ 50% was achieved by 156 (81%) of 192 patients in the enzalutamide group compared with 61 (31%) of 195 patients in the bicalutamide group (p<0.001). PSA response ≥ 90% was achieved by 124 (65%) of 192 patients in the enzalutamide group compared with 17 (9%) of 195 patients in the bicalutamide group (p<0.001). Both treatments were generally well tolerated and the enzalutamide safety profile was consistent with previous reports.
Very recently, the results of the double-blind placebo-controlled phase III trial PROSPER (NCT02003924){Hussain, 2018 #120}, evaluating the impact of enzalutamide addition to ADT on the MFS of patients with nmCRPC, were released [61]. A total of 1401 patients were randomized 2:1 to receive enzalutamide or placebo. A PSA doubling time (PSA dt)  10 months was mandatory for eligibility, and the median PSA dt was 3.8 and 3.6 months in the enzalutamide and placebo arm, respectively. The results showed that the primary objective MFS was significantly improved in the enzalutamide group: 36.6 months vs 14.7 months (HR= 0.29, CI 95 %: 0.24-0.35, p < 0.001). The time to PSA progression was 37.2 months vs 3.9 months (HR= 0.07, CI 95%: 0.05-0.08, p < 0.001) and the time to first subsequent antineoplastic therapy initiation was 39.6 months vs 17.7 months. At the first interim analysis of overall survival, 103 patients (11%) receiving enzalutamide and 62 (13%) receiving placebo had died. Grade 3+ adverse events were more frequent in the enzalutamide group (31% vs 23%) and the most common were hypertension (5%) and fatigue (3%). Patients in the enzalutamide group had a higher AE-related mortality rate (3% vs 1%). Treatment discontinuation for AE occurred in 9% of patients treated with enzalutamide vs 6% of patients with placebo.
Apalutamide (ARN-509) is being developed for the treatment of men with prostate cancer (localized, HSPC and CRPC) [62]. A phase II trial evaluated the safety and anti-tumor activity of apalutamide in high-risk nmCRPC (n=51) [63]. High-risk for progression was defined as PSA ≥ 8 ng/mL or PSAdt ≤ 10 months. Overall 89% of patients (42 of 47) had a ≥ 50% PSA decline at 12 weeks and a maximal response in 94% of patients (44 of 47). At a median follow-up of 28.8 months, the median time to progression was 24 .0 months (95% CI, 16.3 months-not reached) and median MFS was not reached (95% CI 33.4 months-not reached). Most patients discontinued treatment (n=33, 65%) due to disease progression (n=11, 22%) or AE (n=9, 18%). Grade 3 and 4 treatment emergent AEs (TEAE) were infrequent. The most common TEAE was fatigue (any grade n=31, 61%). These results demonstrated a robust activity of apalutamide in high-risk nmCRPC, with a favorable toxicity profile.
The double-blind placebo-controlled phase III trial SPARTAN (NCT01946204) was designed to evaluate the efficacy and safety of apalutamide addition to ADT in patients with nmCRPC at high-risk of progression, defined as a PSAdt ≤ 10 months. A total of 1207 patients were randomized 2:1 in the apalutamide or placebo arm [64]. Median PSAdt was 4.4 and 4.5 months in the apalutamide and placebo arm, respectively. Recently published results showed a significant improvement of MFS, the primary objective, in the apalutamide arm with a 72% risk reduction (median: 40.5 months vs 16.2 months, HR=0.28, CI 95%:0.23-0.35, p < 0.001). This benefit was observed in all subgroups. All the key secondary endpoints were also improved in the apalutamide arm: median time to metastasis (HR=0.27, CI 95%:0.22-0.34, p<0.001), PFS (HR=0.29, CI 95%:0.24-0.36, p<0.001), time to symptomatic progression (HR=0.45, CI 95%: 0.32-0.63, p<0.001) and time to initiation of cytotoxic chemotherapy (HR=0.44; CI 95%:0.29-0.66). In the SPARTAN study design, patients that developed metastases were offered secondary treatment at the discretion of their treating physician or abiraterone acetate + prednisone (AAP) by study coordinators. The time from randomization to the time they progressed on secondary therapy was defined as Progression-Free Survival-2 (PFS2). 165 men in the apalutamide arm (53% of the 314 men who discontinued apalutamide) and 217 men in the placebo arm (78% of the 279 who discontinued placebo) received subsequent therapy for mCRPC (primarily AAP through the trial). 68% of the patients in the placebo arm and 48% of the patients in the apalutamide arm ended up receiving either enzalutamide or AAP for mCRPC. Men treated with apalutamide had a 51% risk reduction in PFS2 compared to men treated with placebo (HR 0.49, p<0.0001). Grade 3 adverse events were more frequent in the apalutamide group (45% vs 34%) and the most common were hypertension (14.3%), rash (5.2%) and fracture (2.7%). Treatment discontinuation for AE occurred in 11% of patients in the apalutamide arm vs 7% of patients in the placebo arm. Patient-reported outcomes (PRO) were reported as exploratory endpoints. Baseline scores for the FACT-P and EQ-5D-3L instruments were within normal range. Adding apalutamide to ADT did not significantly change either PRO during the course of the study.
Altogether these results strongly support the use of the NGHT enzalutamide or apalutamide in combination with ADT in patients with nmCRPC, even though at this time improvement in OS could not be demonstrated due to the small number of events observed within the reporting time. Both trials had MFS as primary endpoint. While MFS has been validated as surrogate endpoints for OS in localized prostate cancer, such validation has not been demonstrated in nmCRPC. Longer follow-up is needed to ensure that enzalutamide and apalutamide have a siginficative impact on OS.
A phase II study investigated orteronel (TAK-700) a nonsteroidal, oral, inhibitor of androgen synthesis (17,20-lyase inhibitor) in the treatment of nmCRPC (NCT01046916) [65]. The primary endpoint was the proportion of patients achieving PSA  0.2 ng/dL at 3 months. Among the 39 eligible patients, a PSA decreased >30% was observed in 35 patients (90%) and 6 patients (16%) achieved PSA  0.2 ng/dL at 3 months. PSA progression rate was 57% at 12 months and 42% at 24 months. MFS rate was 94% and 62% at 12 and 24 months respectively. This study showed marked and durable PSA declines in nmCRPC patients with moderate but manageable toxicities. Thus prolonged administration of orteronel without steroids is feasible. The development of orteronel was however stopped in 2014, as it did not improve overall survival in a phase III study with mCRPC patients (NCT01193257, ELM-PC5) [66]. Another randomized, double-blind, placebo-controlled phase III study evaluating the efficacy and safety of darolutamide in men with high-risk non-metastatic castration-resistant prostate cancer (ARAMIS, NCT02200614) [67] is currently ongoing.

3.2.4. Targeted molecular agents

A phase II of bevacizumab, an anti-vascular endothelial growth factor VEGF monoclonal antibody was conducted in nmCRPC patients [68]. Fifteen patients received the treatment for a median duration of 3.1 months. Bevacizumab were judged to have minimal impact on the course of the disease as the median time to PSA progression and new metastases were 2.8 months and 7.9 months respectively.

3.2.5. Vaccine

A poxvirus-based PSA vaccine was also evaluated in a phase II randomized trial. Forty-two nmCRPC patients were randomized to receive either the vaccine (n=21) or nilutamide (androgen receptor agonist) (n=21) or the combination therapy (cross over from each arm at PSA progression) [69]. Median survival exhibited a trend toward improvement for patients in the vaccine arm (median 5.1 vs 3.4 years; p=0.13). The results also indicated that nmCRPC patients who received vaccine prior to second-line hormone therapy may potentially result in improved survival as compared to patients who receive hormone therapy and then vaccine (median OS 6.2 years vs 3.7 years, p=0.045). The benefit in OS of vaccine was greater in the subgroups of patients with Gleason score ≤ 7 (p=0.033) as well as in patients with history of radiation therapy (p=0.018).
A pilot randomized two-arm study of a DNA vaccine encoding prostatic acid phosphatase (PAP), called pTVG-HP, is still ongoing in patients with nmCRPC (NCT00849121) [70]. The approach is to try to enhance patients’ own immune response against the cancer. In this study, the investigators are testing the safety of the vaccine. Preliminary results showed that 12 of the 17 patients were metastasis-free at 1 year while 4 patients experienced serious adverse events.

3.2.6. Other agents

The anti-angiogenic activity of a selective antagonist of αvβ3 and αvβ5 integrins, cilengitide, was evaluated in a phase II study with nmCRPC patients [71]. The primary endpoint was PSA response rate (≥ 50% PSA decline). This treatment was well tolerated but no PSA responses were observed in the 13 eligible nmCRPC patients. The time to PSA progression was 1.8 months (95% CI: 0.9-2.8). With a median follow-up of 3.1 years, the median OS had not been reached.
A phase III study of lanreotide, a somatostatin analogue, combined with androgen blockade (non steroidal anti androgens and LHRH or androgen blockade alone in nmCRPC patients presenting elevated Chromogranin A levels was terminated early due to poor enrolment [72].
A phase II study of octreotide acetate, another somatostatin analogue that reduces production of Insulin-like growth factor (IGF)-1 and IGF-2, was terminated early after the interim analysis showed no sustained PSA decline after 3 cycles of treatment among the 13 first enrolled patients [73].

4. Discussion

Treatment delaying distant site metastasis in patients with nmCRPC remained an unmet medical need until the publication of recent results of apalutamide and enzalutamide [59, 61, 63, 64] (Table 2). The MFS of patients with nmCRPC was estimated to be approximately 25-30 months [17, 22] but can now significantly prolonged with the combination of NGHT with ADT. The MFS in patients treated with apalutamide and ADT was 45 months and 36.6 months in patients treated with enzalutamide plus ADT compared to ADT alone (HR= 0.20, CI 95 %: 0.24-0.35, p < 0.001 and HR=0.28, CI 95%:0.23-0.35 respectively) [61, 64]. A decreased risk of symptoms and complications related to the development of metastases was also observed with apalutamide [64]. Differences in OS are not statistically significant as few events occurred at the time of publication. However, MFS, the primary endpoint of these studies, is relevant in this setting as delaying the onset of metastases probably improves psychological impact on patients. Both studies had very similar results demonstrating their robustness (Table 1). However, the safety profiles of the two agents were different with an increase in grade 3 cutaneous adverse events and hypertension in the apalutamide group and an increase in hypertension and fatigue, in the enzalutamide group compared to placebo. The benefice/risk of these treatment options needs to be weighted. Introduction of associated treatment to prevent AE such as falls and fractures for apalutamide should also be considered. Nevertheless OS data will be necessary to conclude whether or not this strategy provides a better benefit than sequential treatments.
Altogether these results demonstrate a rational for using NGHT in this population and bring a new perspective in the management of nmCRPC patients. Apalutamide was approved by the FDA on February 14th 2018, becoming the first treatment approved in this setting. Pending mature OS data, older AR inhibitors may have still a role in countries where next-generation AR inhibitors are not ailable or hardly accessible.
The challenge in the management of nmCRPC remains to rule out the presence of metastasis. The Prostate Cancer Radiographic assessments for detection of Advanced Recurrence (RADAR) group recommended for these patients to do the first CT scan when PSA level is between 5-10 ng/mL. If negative it is recommended to do further CT scan when PSA reaches 20 ng/mL and then at every doubling PSA (based on PSA testing every 3 months) [74]. Bone scan and CT scan are the routine techniques. Newer more sensitive imaging techniques will improve the diagnosis and result in earlier discovery of metastases. Choline-PET/CT -scan (11C- and 18F- radio-labelled versions of choline) was proposed as a promising imaging technique for intermediate or high-risk disease however a meta-analysis gave a pooled sensitivity of 49% and pooled specificity of 95% [75]. It is currently recommended for recurrent disease when PSA > 5 ng/mL [76] with a sensitivity and specificity for all recurrent sites of diseases of 86% and 93% respectively [75, 77]. Fluciclovine (18F)-PET/CT has been approved by the FDA in 2016 for its use in PCa recurrence [78]. It showed a detection rate of 41.4% in a retrospective analysis in patients with recurrent disease after RT or RP and PSA  0.79 ng/mL [79] and superiority compared to choline-PET CT with better sensitivity, specificity and accuracy as well as a higher number of patients with detected metastasis in all PSA level subgroups in the context of a biochemical recurrence after radical prostatectomy [80]. 68Ga PSMA (Prostate Specific Membrane Antigen)-PET currently developed, offers a high oncotropic affinity [81 , 82] and has a better detection rate compared to 18F-choline with more detected lesions in low PSA patients (< 5ng/mL), higher SUVmax (in 80% of lesions) and high tumor to background (in 95% lesions).
The introduction of these more sensitive imaging techniques in routine practice might be accompanied by a reduction of the incidence of nmCRPC as the discrimination between nmCRPC and mCRPC depends strongly on the sensitivity of the diagnostic tools employed. Important screening failure related to detection of previously unidentified metastatic disease has been reported in a phase III trial of zibotentan vs placebo with patients with nmCRPC [83].

References:

[1] Ferlay, J., et al., Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer, 2015. 136(5): p. E359-86.
[2] Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2018. CA Cancer J Clin, 2018. 68(1): p. 7-30.
[3] Winter, A., et al., Comparison of prostate cancer survival in Germany and the USA: can differences be attributed to differences in stage distributions? BJU Int, 2017. 119(4): p. 550-559.
[4] Patrikidou, A., et al., Who dies from prostate cancer? Prostate Cancer Prostatic Dis, 2014. 17(4): p. 348-52.
[5] Hussain, M., et al., Prostate-specific antigen progression predicts overall survival in patients with metastatic prostate cancer: data from Southwest Oncology Group Trials 9346 (Intergroup Study 0162) and 9916. J Clin Oncol, 2009. 27(15): p. 2450-6.
[6] Hong, J.H. and I.Y. Kim, Nonmetastatic castration-resistant prostate cancer. Korean J Urol, 2014. 55(3): p. 153-60.
[7] Roehl, K.A., et al., Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: long-term results. J Urol, 2004. 172(3): p. 910-4.
[8] Freedland, S.J., et al., Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. Jama, 2005. 294(4): p. 433-9.
[9] Kupelian, P.A., et al., Use of different definitions of biochemical failure after external beam radiotherapy changes conclusions about relative treatment efficacy for localized prostate cancer. Urology, 2006. 68(3): p. 593-8.
[10] Luo, J., T.M. Beer, and J.N. Graff, Treatment of Nonmetastatic Castration-Resistant Prostate Cancer. Oncology (Williston Park), 2016. 30(4): p. 336-44.
[11] Oefelein, M.G., et al., Clinical predictors of androgen-independent prostate cancer and survival in the prostate-specific antigen era. Urology, 2002. 60(1): p. 120-4.
[12] Tombal, B., Non-metastatic CRPC and asymptomatic metastatic CRPC: which treatment for which patient? Ann Oncol, 2012. 23 Suppl 10: p. x251-8.
[13] Cornford, P., et al., EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer. Eur Urol, 2017. 71(4): p. 630-642.
[14] Scher, H.I., et al., Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol, 2008. 26(7): p. 1148-59.
[15] Smith, M.R., et al., Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet, 2012. 379(9810): p. 39-46.
[16] Nelson, J.B., et al., Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer, 2008. 113(9): p. 2478-87.
[17] Smith, M.R., et al., Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol, 2005. 23(13): p. 2918-25.
[18] Liede, A., Günther, O., Bennett, B., Wong, S., Prevalence of non-metastatic castration-resistant prostate cancer in Europe. European Society for Medical oncology, Vienna, Austria, Sept 28-Oct 2, 2012, 2012.
[19] Liede, A., Arellano, J., Hechmati, G., Bennett, B., Wong, S., International prevalence of nonmetastatic (M0) castration-resistant prostate cancer (CRPC). Journal of Clinical Oncology, 2013. 31( 31, no. 15_suppl -published online before print.).
[20] Cetin, K., et al., Prevalence of patients with nonmetastatic prostate cancer on androgen deprivation therapy in the United States. Urology, 2013. 81(6): p. 1184-9.
[21] Murray, N.P., et al., Differential expression of matrix metalloproteinase-2 expression in disseminated tumor cells and micrometastasis in bone marrow of patients with nonmetastatic and metastatic prostate cancer: theoretical considerations and clinical implications-an immunocytochemical study. Bone Marrow Res, 2012. 2012: p. 259351.
[22] Smith, M.R., et al., Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer. Cancer, 2011. 117(10): p. 2077-85.
[23] NCCN, NCCN clinical pratice guidelines in oncology. Prostate Cancer. 2017.
[24] ESMO, Prostate Cancer Treatment Algorithms. 2016.
[25] EAU. European Assocation of Urology. Pocket Guidelines 2016 edition. 2016 [cited; Available from: http://uroweb.org/wp-content/uploads/Pocket-Guidelines-2016-complete-file.pdf.
[26] Mottet, N., et al., EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol, 2017. 71(4): p. 618-629.
[27] Smith, M.R., et al., Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol, 2013. 31(30): p. 3800-6.
[28] Gillessen, S., et al., Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015. Ann Oncol, 2015. 26(8): p. 1589-604.
[29] Rozet, F., et al., Non-metastatic castrate-resistant prostate cancer: a call for improved guidance on clinical management. World J Urol, 2016. 34(11): p. 1505-1513.
[30] Thoms, J., et al., Neoadjuvant radiotherapy for locally advanced and high-risk prostate cancer. Nat Rev Clin Oncol, 2010. 8(2): p. 107-13.
[31] Amzalag, G., et al., Target Definition in Salvage Radiotherapy for Recurrent Prostate Cancer: The Role of Advanced Molecular Imaging. Front Oncol, 2016. 6: p. 73.
[32] Carrie, C., et al., Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol, 2016. 17(6): p. 747-756.
[33] White, R., et al., Efficacy of high-dose palliative radiotherapy for localised, castration-resistant prostate cancer. Clin Oncol (R Coll Radiol), 2015. 27(1): p. 16-21.
[34] Sanguineti, G., et al., Is there a "curative" role of radiotherapy for clinically localized hormone refractory prostate cancer? Am J Clin Oncol, 2004. 27(3): p. 264-8.
[35] Botticella, A., et al., May non-metastatic clinically localized castration-resistant prostate cancer after primary androgen ablation benefit from salvage prostate radiotherapy? J Cancer Res Clin Oncol, 2013. 139(11): p. 1955-60.
[36] Pinkawa, M., et al., Local prostate cancer radiotherapy after prostate-specific antigen progression during primary hormonal therapy. Radiat Oncol, 2012. 7: p. 209.
[37] Zelefsky, M.J., et al., Long-term results of conformal radiotherapy for prostate cancer: impact of dose escalation on biochemical tumor control and distant metastases-free survival outcomes. Int J Radiat Oncol Biol Phys, 2008. 71(4): p. 1028-33.
[38] Agarwal, P.K., et al., Treatment failure after primary and salvage therapy for prostate cancer: likelihood, patterns of care, and outcomes. Cancer, 2008. 112(2): p. 307-14.
[39] Crehange, G., et al., Salvage reirradiation for locoregional failure after radiation therapy for prostate cancer: who, when, where and how? Cancer Radiother, 2014. 18(5-6): p. 524-34.
[40] Gontero, P., et al., Salvage radical prostatectomy in nonmetastatic castration-resistant prostate cancer patients who received previous radiotherapy: a feasibility study. Eur Urol, 2014. 65(1): p.
[41] Michaelson, M.D. and M.R. Smith, Bisphosphonates for treatment and prevention of bone metastases. J Clin Oncol, 2005. 23(32): p. 8219-24.
[42] James, N.D., et al., Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet, 2016. 387(10024): p. 1163-77.
[43] Fizazi, K., et al., Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet, 2011. 377(9768): p. 813-22.
[44] Mason, M.D., et al., Oral sodium clodronate for nonmetastatic prostate cancer--results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873). J Natl Cancer Inst, 2007. 99(10): p. 765-76.
[45] Wirth, M., et al., Prevention of bone metastases in patients with high-risk nonmetastatic prostate cancer treated with zoledronic acid: efficacy and safety results of the Zometa European Study (ZEUS). Eur Urol, 2014. 67(3): p. 482-91.
[46] Dearnaley, D.P., et al., Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol, 2009. 10(9): p. 872-6.
[47] Miller, K., et al., Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis, 2013. 16(2): p. 187-92.
[48] National Comprehensive Cancer Network: Clinical Practice Guidelines for Prostate Cancer. 2015 [cited; Available from: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
[49] Hotte, S.J. and F. Saad, Current management of castrate-resistant prostate cancer. Curr Oncol, 2010. 17 Suppl 2: p. S72-9.
[50] Klotz, L., et al., An open-label, phase 2 trial of bicalutamide dose escalation from 50 mg to 150 mg in men with CAB and castration resistance. A Canadian Urology Research Consortium Study. Prostate Cancer Prostatic Dis, 2014. 17(4): p. 320-4.
[51] Heath, E.I., et al., A phase I dose-escalation study of oral BR-DIM (BioResponse 3,3'- Diindolylmethane) in castrate-resistant, non-metastatic prostate cancer. Am J Transl Res, 2010. 2(4): p. 402-11.
[52] Scher, H.I., et al., Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med, 2012. 367(13): p. 1187-97.
[53] Beer, T.M., et al., Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med, 2014. 371(5): p. 424-33.
[54] Ryan, C.J., et al., Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol, 2015. 16(2): p. 152-60.
[55] Fizazi, K., et al., Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med, 2017. 377(4): p. 352-360.
[56] James, N.D., et al., Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med, 2017. 377(4): p. 338-351.
[57] Fizazi, K., et al., ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer. Expert Rev Anticancer Ther, 2015. 15(9): p. 1007-17.
[58] Fizazi, K., et al., Activity and safety of ODM-201 in patients with progressive metastatic castrationresistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial. Lancet Oncol, 2014. 15(9): p. 975-85.
[59] Penson, D.F., et al., Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial. J Clin Oncol, 2016. 34(18): p. 2098-106.
[60] US National Library of Medecine. Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer (PROSPER). NCT02003924. 2018 [cited; Available from: https://clinicaltrials.gov/ct2/show/NCT02003924.
[61] Hussain, M., et al., PROSPER: Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC). J. Clin. Oncol., 2018. 36(suppl 6S; abstr 3).
[62] Clegg, N.J., et al., ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res, 2012. 72(6): p. 1494-503.
[63] Smith, M.R., et al., Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort. Eur Urol, 2016. 70(6): p. 963-970.
[64] Smith, M.R., et al., Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med, 2018.
[65] Hussain, M., et al., Phase II study of single-agent orteronel (TAK-700) in patients with nonmetastatic castration-resistant prostate cancer and rising prostate-specific antigen. Clin Cancer Res, 2014. 20(16): p. 4218-27.
[66] Fizazi, K., et al., Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5. J Clin Oncol, 2015. 33(7): p. 723-31.
[67] US National Library of Medecine. Efficacy and Safety Study of BAY1841788 (ODM-201) in Men With High-risk Non-metastatic Castration-resistant Prostate Cancer (ARAMIS). NCT02200614. 2018 [cited; Available from: https://clinicaltrials.gov/ct2/show/NCT02200614.
[68] Ogita, S., et al., Pilot Phase II Trial of Bevacizumab Monotherapy in Nonmetastatic CastrateResistant Prostate Cancer. ISRN Oncol, 2012. 2012: p. 242850.
[69] Madan, R.A., et al., Analysis of overall survival in patients with nonmetastatic castration -resistant prostate cancer treated with vaccine, nilutamide, and combination therapy. Clin Cancer Res, 2008. 14(14): p. 4526-31.
[70] US National Library of Medecine. Two-Arm Study of a DNA Vaccine Encoding Prostatic Acid Phosphatase (PAP) in Patients With Non-Metastatic Castrate-Resistant Prostate Cancer.
[71] Alva, A., et al., Phase II study of cilengitide (EMD 121974, NSC 707544) in patients with nonmetastatic castration resistant prostate cancer, NCI-6735. A study by the DOD/PCF prostate cancer clinical trials consortium. Invest New Drugs, 2012. 30(2): p. 749-57.
[72] US National Library of Medecine. Study of Lanreotide in Non Metastatic Castration-resistant Prostate Cancer Patients (POSEIDON). NCT01313273. 2018 January 26, 2018 [cited; Available from: https://clinicaltrials.gov/ct2/show/results/NCT01313273.
[73] Friedlander, T.W., et al., Effect of the somatostatin analog octreotide acetate on circulating insulinlike growth factor-1 and related peptides in patients with non-metastatic castration-resistant prostate cancer: results of a phase II study. Urol Oncol, 2012. 30(4): p. 408-14.
[74] Crawford, E.D., et al., Challenges and recommendations for early identification of metastatic disease in prostate cancer. Urology, 2014. 83(3): p. 664-9.
[75] Evangelista, L., et al., Utility of choline positron emission tomography/computed tomography for lymph node involvement identification in intermediate- to high-risk prostate cancer: a systematic literature review and meta-analysis. Eur Urol, 2013. 63(6): p. 1040-8.
[76] deSouza, N.M., et al., Strategies and technical challenges for imaging oligometastatic disease: Recommendations from the European Organisation for Research and Treatment of Cancer imaging group. Eur J Cancer, 2018. 91: p. 153-163.
[77] Evangelista, L., et al., Choline PET or PET/CT and biochemical relapse of prostate cancer: a systematic review and meta-analysis. Clin Nucl Med, 2013. 38(5): p. 305-14.
[78] Cancian, M. and J.F. Renzulli, 2nd, Non Metastatic Castration Resistant Prostate Cancer: a Modern Perspective. Urology, 2018.
[79] Bach-Gansmo, T., et al., Multisite Experience of the Safety, Detection Rate and Diagnostic Performance of Fluciclovine ((18)F) Positron Emission Tomography/Computerized Tomography Imaging in the Staging of Biochemically Recurrent Prostate Cancer. J Urol, 2017. 197(3 Pt 1): p. 676-683.
[80] Nanni, C., et al., (18)F-FACBC (anti1-amino-3-(18)F-fluorocyclobutane-1-carboxylic acid) versus (11)C-choline PET/CT in prostate cancer relapse: results of a prospective trial. Eur J Nucl Med Mol Imaging, 2016. 43(9): p. 1601-10.
[81] Afshar-Oromieh, A., et al., The Clinical Impact of Additional Late PET/CT Imaging with (68)GaPSMA-11 (HBED-CC) in the Diagnosis of Prostate Cancer. J Nucl Med, 2017. 58(5): p. 750-755.
[82] Eiber, M., et al., Evaluation of Hybrid (6)(8)Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. J Nucl Med, 2015. 56(5): p. 668-74.
[83] Yu, E.Y., et al., Detection of previously unidentified metastatic disease as a leading cause of screening failure in a phase III trial of zibotentan versus placebo in patients with nonmetastatic, castration resistant prostate cancer. J Urol, 2012. 188(1): p. 103-9.