Tackling non-metastatic castration-resistant prostate cancer: special considerations in treatment

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1 Expert Review of Anticancer Therapy ISSN: (Print) (Online) Journal homepage: Tackling non-metastatic castration-resistant prostate cancer: special considerations in treatment Archana Anantharaman & Eric J. Small To cite this article: Archana Anantharaman & Eric J. Small (2017): Tackling non-metastatic castration-resistant prostate cancer: special considerations in treatment, Expert Review of Anticancer Therapy, DOI: / To link to this article: Accepted author version posted online: 23 May Published online: 31 May Submit your article to this journal Article views: 17 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at Download by: [Cornell University Library] Date: 10 June 2017, At: 11:39

2 EXPERT REVIEW OF ANTICANCER THERAPY, REVIEW Tackling non-metastatic castration-resistant prostate cancer: special considerations in treatment Archana Anantharaman and Eric J. Small Department of Medicine, University of California, San Francisco, San Francisco, CA, USA ABSTRACT Introduction: Prostate cancer (PCa) is currently the second most common cancer affecting men worldwide. Metastatic castration-resistant prostate cancer (mcrpc) is the incurable form of PCa, carrying the poorest prognosis, and can develop from non-metastatic CRPC (M0 CRPC). CRPC is defined as progression of the disease with castrate level testosterone levels, achieved with primary androgen deprivation therapy (ADT). M0 CRPC is a highly heterogeneous disease process lacking clear standard of care therapies. Areas covered: In this review, a broad literature search was undertaken to explore data available for therapeutic options and guidelines in the management of M0 CRPC. Expert commentary: While there are compelling data for various therapeutics for the treatment of M0 CRPC, no clear standard of care is apparent at this time. Furthermore, technological advances in imaging may have a significant impact on this future of this disease state. ARTICLE HISTORY Received 10 February 2017 Accepted 19 May 2017 KEYWORDS Prostate cancer; castration resistant prostate cancer; androgen deprivation therapy; bone targeted therapy; immunotherapy 1. Introduction Prostate cancer (PCa) is the most common malignancy in the United States. In 2016, approximately 180,890 men were newly diagnosed with PCa and 26,120 died from this disease [1]. An important diagnostic tool that has influenced screening, diagnosis, and management of PCa is the serum prostatespecific antigen (PSA) level. In general, changes in PSA can often be observed prior to radiographic evidence of disease progression, making it a powerful tool. This is particularly important since the development and progression of PCa (in some cases defined by PSA changes) is considered a dynamic process along a continuum. Key time points at which therapeutic changes are made (termed transition points between disease states) have become important landmarks in disease progression and in many cases provide more insight into prognosis than the traditional TNM staging widely used in other malignancies [2]. Milestones in the disease states of PCa include localized disease, locally advanced disease, biochemical recurrence (rising PSA in the absence of radiographically evident metastases), and hormone-sensitive prostate cancer (HSPC) with metastases (mhspc) (see Figure 1). Following the development of recurrent disease after definitive local therapy, whether biochemical relapse only, or with evidence of metastases, androgen deprivation therapy (ADT) has long been established as the standard of care systemic therapy [3]. ADT can be achieved surgically by an orchiectomy, or pharmacologically. Normally, luteinizing hormone releasing hormone (LHRH) is released by the hypothalamus to stimulate the pituitary gland to release luteinizing hormone which in turn stimulates testicular testosterone production. Therapeutic pharmacologic testosterone suppression is typically achieved with the use of LHRH agonists (leuprolide, goserelin, and triptorelin) that result in desensitization of the pituitary, and subsequent reduction of testicular testosterone production. The development of metastases resistant to castrate levels of testosterone (less than 50 ng/dl), termed metastatic castration-resistant prostate cancer (CRPC), is a lethal event, with a median survival in some series as short as 3 years despite optimal sequencing of advanced therapies [4]. Metastatic CRPC evolves either from metastatic hormonesensitive PCa, or from nonmetastatic (M0) CRPC. Nonmetastatic CRPC in turn develops from M0 HSPC biochemically relapsed PCa that is increasingly being treated with ADT and subsequently develops resistance to ADT. While new treatment paradigms and change in guidelines continue to develop for patients with metastatic disease, whether HSPC or CRPC, there is no standard of care for the management of M0 CRPC. M0 CRPC has long been considered the clinical stage at highest risk for progression to mcrpc, suggesting the need for better therapeutic options and life-prolonging strategies in this subgroup [2]. In this review, we will outline the definition of M0 CRPC, available imaging modalities that are used to define the presence of metastases, explore current guidelines and available clinical trials, and discuss the evolution of this disease subgroup over the past several decades. 2. Definition of M0 CRPC CRPC is defined as progression of disease despite castrate levels of testosterone (i.e. testosterone < 50 ng/ml). Patients with M0 CRPC have no evidence of metastases by CONTACT Archana Anantharaman archana.anantharaman@ucsf.edu University of California, San Francisco, 505 Parnassus Avenue, M1286, San Francisco, CA , USA 2017 Informa UK Limited, trading as Taylor & Francis Group

3 2 A. ANANTHARAMAN AND E. J. SMALL Figure 1. Summary of progression of disease states in prostate cancer. conventional imaging modalities typically cross-sectional imaging of the abdomen/pelvis (computed tomography [CT] or magnetic resonance imaging [MRI]), and Technecium-99 scintigraphy (bone scan). The most commonly used definition of progression in the absence of radiographic disease is adopted from the consensus criteria developed by the Prostate Cancer Working Group 3 (PCWG3). This definition requires a minimum PSA level of 1.0 ng/ml, a rising PSA that is at least 2 ng/ml higher than the nadir PSA with this rise being at least 25% over the nadir PSA, castrate levels of testosterone (<50 ng/ml), and without radiographic evidence of metastases [5]. The current guidelines set by the Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence Group for patients with M0 CRPC recommend radiographic assessment with conventional imaging once the serum PSA level is greater than 2 ng/ml. If there is no evidence of metastases, imaging should again be pursued once the PSA is greater than or equal to 5 ng/ml. Subsequent reimaging is recommended with doubling of the PSA value [6]. However, the incidence of this disease state is rapidly changing with the advent of advanced imaging technologies. Imaging modalities such as 18F-sodium fluoride positron emission tomography scan (NaF PET), 11C-choline PET/CT, and prostate-specific membrane antigen (PSMA) PET scans represent much more sensitive imaging modalities that result in earlier detection of occult metastatic lesions in PCa [7 11]. For example, a prospective comparison of choline PET imaging versus PSMA PET imaging suggests increased sensitivity of detecting occult metastases with PSMA-based imaging at any PSA level, including below 1 ng/ml. However, both imaging modalities appear to lack sensitivity in patients with PSA < 1 ng/ml [9]. The current National Comprehensive Cancer Network (NCCN) guidelines for the management of PCa recommend considering use of 18F NaF and 11C-choline PET scans. Use of PSMA PET scans is still under evaluation with phase III clinical trials underway. While advances in radiographic imaging will certainly affect staging of PCa, optimal use of these new technologies remains under evaluation at this time. 3. Medical management of M0 CRPC M0 CRPC is thought to be a highly heterogeneous disease state with some men exhibiting indolent, slow growing process while others experiencing a more rapid progression and development of metastases. One pivotal report that evaluated bone metastasis-free survival in men with M0 CRPC helped identify independent prognostic factors that were predictive of developing metastases and/or death [12]. In this study, the natural history of 201 M0 CRPC patients who had been randomized to a placebo arm (vs. zoledronic acid in the treatment arm) was studied. Evaluation of these patients revealed that 33% of men had developed bony metastases within 2 years, with a median bone metastasis-free survival of 30 months. A baseline PSA level greater than 10 ng/ml (relative risk, 3.18; 95% confidence interval [CI], ; P <.001) and PSA velocity (4.34 for each 0.01 increase in PSA velocity; 95% CI, ; P <.001) each independently predicted shorter time interval to development of first bone metastasis. These same factors also independently predicted overall survival and metastasis-free survival, while other covariates tested (prior prostatectomy, initial Gleason score >7, bilateral orchiectomy vs. LHRH antagonist, time from diagnosis to randomization in years, regional lymph node metastasis present at diagnosis, time from ADT to randomization >2 years) did not. A similar phase III placebo controlled study of denosumab versus placebo also demonstrated that PSA doubling time (PSADT) of 10 months was a predictor of shorter bone metastasis-free survival and overall survival [13,14]. Another trial evaluating the efficacy of artasentan versus placebo in delaying time to progression in men with M0 CRPC confirmed that PSA velocity was significantly associated with a shorter overall survival (RR, 1.15 for each year increase in PSA velocity [95% CI, ]; P =.002)[15]. Based on the above studies, the NCCN guidelines recommend continued observation for patients with M0 CRPC with a PSADT 10 months, as they likely have indolent disease with a lower risk of progression to mcrpc. However, for patients with a PSADT 10 months, treatment is recommended, with the goal of delaying time to development of metastases. If patients are on an antiandrogen agent at the time of progression, antiandrogen withdrawal is recommended as the first therapeutic intervention [16 18]. Beyond that, enrollment in a clinical trial is recommended, given the lack of compelling data identifying a clear standard of care in this population, although additional hormonal manipulations are commonly employed. This approach is predicated on the observation that many CRPC patients continue to exhibit androgen receptor pathway activity Additional hormonal manipulations Ongoing testosterone suppression remains the backbone of therapy for men progressing to CRPC. A small, retrospective

4 EXPERT REVIEW OF ANTICANCER THERAPY 3 study evaluated PSA responses among men with progressive PCa when switched to an alternate LHRH agonist (i.e. leuprolide to goserelin or vice versa). PSA values were evaluated every 3 months after change in therapy. While 27 of 39 men (69%) did exhibit a modest PSA response with median change in PSA of 1.5 at month 3, the median time to subsequent PSA increase was 5.2 months indicating a very short lived response, at best. The small size and uncontrolled, retrospective nature of this study make it difficult to interpret [19]. Degarelix, a GnRH antagonist, is another hormonal agent more recently approved for use in treatment of PCa [20]. There is some thought that switching from an LHRH agonist such as goserelin to an antagonist at the time of development of CRPC might provide clinical benefit due to more rapid testosterone suppression achieved via an alternate mechanism. One small, open-label, multicenter, phase II study evaluated 37 men with at least 2 sequential rising PSA despite castrate levels of testosterone on an LHRH agonist who were switched to degarelix after meeting definition for CRPC. The primary end point was the proportion of patients with decreased or stable PSA (relative change +10% of baseline PSA) after 3 months. The response rate amongst all 37 men was approximately 21%. PSA progression was noted in 21 patients, most by day 28 of the trial [21]. Taken together, these data suggest that changing LHRH agonist or antagonist is not a useful therapeutic maneuver First-generation antiandrogens The antiandrogens are a class of androgen receptor blockers inhibiting the binding of testosterone to the ligand-binding domain of AR. They are sometimes used in conjunction with LHRH agonists synergistically for maximal combined androgen blockade, although their utility as agents added sequentially to an LHRH agonist has also been evaluated. Bicalutamide is a common antiandrogen added at the time of progression to CRPC. Several phase II studies evaluating its efficacy at doses of 150 or 200 mg daily in men with and without evidence of metastases at the time of progression suggested limited benefit lasting no more than 3 6 months [22 24]. One singlecenter, prospective trial enrolled 38 patients with M0 CRPC to evaluate the effect of adding bicalutamide (150 mg/day). PSA decline was observed in 17/38 patients with 7 achieving 85% decline from baseline PSA and 10 patients achieving 50 but <85% decline with a median duration of response of 37.4 and 18.5 months, respectively. The median time to metastasis was 52.5 months for responders and 15.7 months for nonresponders (log-rank test 9.3, P =.002) [25]. Recently, results from the STRIVE trial evaluating addition of a secondgeneration antiandrogen, enzalutamide, 160 mg daily versus bicalutamide 50 mg daily in a cohort of 139 patients with M0 CRPC demonstrated significant improvement in progressionfree survival (PFS) with enzalutamide. At the time of analysis, the median PFS on the enzalutamide arm had not been reached, whereas median PFS on the bicalutamide arm was 8.6 months for men with M0 CRPC. Median time to PSA progression was 8.3 months in the bicalutamide arm. However, it is not clear how this impact on PSA progression might translate to a survival advantage, and enzalutamide is not yet approved for this indication [26]. Fewer studies have reported on the benefits of sequentially added flutamide or nilutamide and these typically evaluated both M0 and mcrpc patients together. Madan et al. evaluated 42 men with M0 CRPC and randomized them to receive a pox-virus-based vaccine versus nilutamide with crossover to alternate arms at the time of progression. Their follow-up analysis after 6.5 years described a median survival of 3.7 years for patients receiving nilutamide [27]. Similarly, another study evaluated 45 men with and without metastases after development of CRPC to determine efficacy of flutamide 250 mg three times daily. Eighty percent of patients experienced a PSA decline of at least 50%; however, the study did not report their duration of response or survival [28]. While bicaluatmide and flutamide act as potent reversible AR inhibitors, under some circumstances, they have been demonstrated to have partial AR agonistic activity as well, potentially fueling disease progression [29]. Withdrawal of the antiandrogen can subsequently act as a therapeutic intervention in M0 CRPC, with approximately 15% of men having clinically meaningful PSA declines. However, the response to antiandrogen withdrawal is relatively short lived, on average 6 months [16,30,31]. Switching from one antiandrogen agent to another is another proposed therapy with some demonstrated responses in small studies. One recent study published by Yokomizo et al. evaluated PSA response to switching combined androgen blockade from leuprolide + bicalutamide to leuprolide + flutamide in 20 patients with two consecutive rises in PSA on the former therapy. Eight (40%) had a PSA decline of greater than 50% with a median duration of PSA response of 18.4 months [32]. While these data represent a small group of patients at a single institution, it is certainly compelling Other hormonal manipulation therapies In the majority of patients with CRPC, AR signaling remains the primary oncogenic driver despite castrate testosterone levels, and its activation has been observed to be mediated through a multitude of mechanisms, including utilization of extra-testicular androgen synthesis [33]. The adrenal cortex is the predominant source of non-testicular androgen production. Ketoconazole is an androgen synthesis inhibitor inhibiting the side chain cleavage enzyme cytochrome P450 14αdemethylase, which is responsible for the conversion of cholesterol to pregnenolone, a necessary step in the production of all androgens. However, it also limits steps in the production of some corticosteroids, necessitating the concurrent use of low doses of hydrocortisone, dexamethasone, or prednisone. CALGB 9583 was a phase III randomized controlled trial of antiandrogen withdrawal versus ketoconazole with supplemental hydrocortisone in men with a history of metastatic CRPC. Of the 260 patients enrolled, 11% of patients in the AAWD arm versus 27% of patients in the ketoconazole/hydrocortisone arm demonstrated greater than 50% decline in PSA (P <.001). These data have formed the basis for the use of ketoconazole for the treatment of CRPC patients, including men with M0 disease [16]. Estrogen compounds, such as diethylstilbesterol, have also been found to be efficacious in the treatment of CRPC [34,35]. It is postulated that estrogen-based therapy leads to a decline

5 4 A. ANANTHARAMAN AND E. J. SMALL in endogenous androgen levels [36]. Though data for use of ketoconazole and estrogen compounds have not been specifically evaluated in large, prospective trials in men with M0 CRPC, they remain reasonable options to utilize in a disease group with no current standard of care therapy Recent advances and ongoing clinical trials Secondary hormonal therapies Abiraterone acetate is a potent, irreversible CYP17 inhibitor targeting androgen biosynthesis in the testicles, adrenal glands, and within the tumor. It has been approved for use in mcrpc based on increased radiographic PFS and overall survival in this population [37,38] but is not approved for use in M0 CRPC. The IMAAGEN trial was a phase II, multicenter study that evaluated PSA responses to abiraterone acetate in 131 men with high-risk M0 CRPC, defined as patients with a PSA 10 ng/ml or a PSADT of 10 months. The primary end point of the study was PSA response at 6 months. At 6 months, 87% of patients exhibited a PSA decline of 50%, 60% of patients had a PSA decline of 90%. Median time to PSA progression was 28.7 months and median time to radiographic progression had not been reached. Toxicities reported on study were comparable to safety data presented in phase III studies evaluating its efficacy in mcrpc patients [39,40]. While these data are promising, to date, there exist no phase III data supporting the use of abiraterone acetate in M0 CRPC patients. Orteronel (TAK-700) is a potent androgen synthesis inhibitor, similar to abiraterone acetate. However, it preferentially inhibits CYP 17, 20 lyase rather than CYP 17 hydroxylase, thereby avoiding fluctuations in mineralocorticoids often seen with abiraterone acetate or ketoconazole. Unlike these other androgen synthesis inhibitors, concurrent use of hydrocortisone/prednisone/dexamethasone is not necessary. In a phase II study, 38 patients with M0 CRPC were treated with orteronel at a dose of 300 mg twice daily, without prednisone. After completing 3 months of therapy, 16% achieved PSA 0.2 ng/ml, 76% achieved 50% decrease, 32% achieved 90% PSA reduction, and median time to PSA progression was 14.8 months [41]. Phase III clinical trials have not been pursued yet. Enzalutamide is a potent, second-generation, irreversible AR ligand-binding domain inhibitor. Much like abiraterone acetate, enzalutamide has been approved for use in the mcrpc setting demonstrating prolongation of disease-free progression and overall survival [42,43]. Like Abiraterone acetate, it is not approved for use in M0 CRPC. The recently published STRIVE trial was a phase II, double-blinded, randomized controlled trial evaluating the addition of enzalutamide 160 mg versus bicalutamide 50 mg in 396 men with M0 or mcrpc. One hundred thirty-nine men had M0 CRPC. Enzalutamide reduced the risk of progression or death by 76% compared with bicalutamide (hazard ratio [HR], 0.24; 95% CI, ; P <.001). Median PFS was 19.4 months with enzalutamide versus 5.7 months with the addition of bicalutamide. Enzalutamide also demonstrated significant improvements in time to PSA progression (HR, 0.19; 95% CI, ; P <.001), and proportion of patients with a 50% PSA response (81% vs. 31%; P <.001) [26]. While promising, the use of low-dose bicalutamide in the comparator arm and a relatively small study not powered for survival analysis have been raised as concerns about these data. On the basis of this study, the PROSPER trial was launched. PROSPER is a phase III, randomized, double-blinded, placebo-controlled trial whose primary end point is metastasis-free survival in patients with high-risk M0 CRPC, defined as PSADT 10 months at screening. The trial is ongoing and no results have been reported (Clinicaltrials.gov: NCT ). Apalutamide (previously known as ARN509) is a newer second-generation antiandrogen that inhibits activated AR complex nuclear translocation and DNA binding. A phase II multicenter trial evaluated the efficacy of apalutamide 240 mg daily in men with high-risk M0 CRPC, defined as a PSA value 8 within 3 months of enrollment and/or PSADT of 10 months. The primary end point of the study was PSA response measured at 12 weeks, as defined by PCWG2. By week 12, 89% of patients had 50% PSA decline, median time to PSA progression was 24 months, and median metastasis-free survival had not been reached [44]. The single arm, phase II nature of this study limits any meaningful conclusions. On the basis of this study, the SPARTAN trial was launched. SPARTAN is a phase III, multicenter, double-blind, placebocontrolled 1200 patient trial randomizing M0 CRPC patients to apalutamide + ADT versus placebo + ADT with a primary end point of metastasis-free survival. This trial is also ongoing and results from this trial have not been reported to date (Clinicaltrials.gov: NCT ) [45]. ODM-201 is another novel AR inhibitor that is currently being evaluated for use in both the mcrpc and M0 CRPC setting. The ARAMIS trial is a phase III randomized, double-blinded, placebo-controlled study evaluating the efficacy and safety of ODM-201 in men with high-risk M0 CRPC (defined as PSADT < 10 months, PSA > 2 ng/dl) (Clinicaltrials.gov: NCT ). Taken together, these data suggest that second-generation AR targeting agents hold great potential in delaying time to development of metastases in M0 CRPC patients. However, until mature phase III data are reported, none of these agents can be recommended as standard of care Bone-targeted therapies Bones are the most common site of metastatic disease in men with PCa. Several studies have evaluated the use of bonetargeted therapies in delaying time to development of skeletal metastases in patients with M0 CRPC. Prior to the understanding that high-risk patients could be selected by PSA level or PSADT, a number of studies tested bone-targeted therapies in unselected M0 CRPC patients. A first-generation bisphosphonate, clodranate, was evaluated in a phase III randomized, double-blinded, placebo-controlled trial, which included men with biochemical recurrence as well as men with M0 CRPC. After a median follow-up of 10 years, no significant benefit was seen either in bone metastases-free survival or overall survival [46]. Similarly, a second-generation bisphosphonate (zolendronic acid) was evaluated in men with M0 CRPC to delay time to first bony metastasis. Two hundred one men were enrolled onto this placebo-controlled trial. However, it

6 EXPERT REVIEW OF ANTICANCER THERAPY 5 was aborted prior to completing accrual because the observed event frequency in an unselected group of patients was too low [12]. The endothelin-1 pathway in osteoclasts has been implicated in development of metastases in PCa. The predominant endothelin receptor on normal prostatic epithelium is ET B. However, expression of ET B is typically lost in PCa, while ET A is overexpressed. Osteoblasts have a high density of ET A receptors, thereby inhibiting bone resorptive activity of osteoclasts. This leads to the development of osteoblastic metastatic lesions in PCa [47]. Two potent endothelin-a receptor antagonsits, atrasentan and zibotentan, were consequently studied to determine their efficacy in preventing development of bony metastases in M0 CRPC patients. Atrasentan was evaluated in a phase III, randomized, double-blind, placebocontrolled trial in 941 patients with M0 CRPC. Though median time to progression was delayed by 93 days with the addition of atrasentan, this was not a statistically significant difference. Interestingly, different results were reported geographically with 81-day longer time to progression with placebo in the United States versus 180-day longer time to progression with atrasentan in non-us sites. Atrasentan did significantly prolong PSADT compared to placebo (P =.31) and slowed the rise in bone alkaline phosphatase levels (P <.01). However, it did not meet its primary end point nor increase median overall survival time [15]. Zibotentan was another endothelin-a receptor antagonist, which was evaluated in a phase III randomized, double-blinded, placebo-controlled study in 1421 men with M0 CRPC. The study was terminated early after another ENTHUSE trial using the agent did not meet its primary end point in PCa. At interim analysis, there was no significant difference between zibotentan and placebo in overall survival (HR: 1.13; 95% CI: , P =.589) or PFS (HR: 0.89; 95% CI, , P =.330) and the study was terminated [48]. Denosumab is a RANK ligand (RANKL) inhibitor that binds to RANKL expressed on osteoblasts. The expression of RANKL is thought to be upregulated by growth factors secreted by cancer cells in the bone microenvironment. RANKL typically binds to RANK found on osteoclasts and its precursors to influence their survival and function. Activation of osteoclasts through this pathway is thought to increase bone turnover and promote the release of growth factors that aid in establishment and development of PCa metastases in the skeleton [49]. Denosumab has been approved for use to delay time to skeletal-related events in men with bone metastases and aids in prevention of osteoporosis for those at increased risk while on ADT [50,51]. Furthermore, its efficacy in preventing skeletal-related events relative to zoledronic acid suggested that it could be useful in metastasis prevention in M0 CRPC patients. A phase III multicenter, randomized, double-blinded, placebo-controlled trial in 1432 men with M0 CRPC evaluated the efficacy of denosumab in delaying time to development of metastatic disease. Importantly, this study was the first to use PSADT as an entry criterion, thereby enriching the study for patients more likely to develop bone metastases. Denosumab was shown to significantly increase bone metastasis-free survival by a median of 4.2 months (HR 0.85 [ ]; P =.028) and delay time to first bone metastasis (median months to metastasis with denosumab = 33.2 months, placebo = 29.5 months; HR 0.84 [ ]; P =.032). Overall survival was similar between denosumab (median, 43.9 months) and placebo arms (median, 44.8 months) as was PFS. The incidence of osteonecrosis of the jaw was less than 5% and hypocalcemia less than 2% over 5 years in the denosumab arm [52]. Although there was a modest increase in the metastasis-free survival, the failure to demonstrate an improvement in overall survival led the US FDA to not approve the use of denosumab in men with M0 CRPC. Thus, although bone targeted therapies intuitively are appropriate agents to use for the prevention of detectable metastases in patients with M0 CRPC, to date, no trial has been sufficiently compelling to lead to regulatory approval in this setting Other therapies Bevacizumab is an anti-vascular endothelial growth factor monoclonal antibody. In phase II studies of men with mcrpc, the addition of bevacizumab to docetaxel demonstrated 37 49% objective response rates in patients who had been previously treated with docetaxel [53,54]. Subsequently, the ability of bevacizumab monotherapy to delay time to metastasis was tested in men with M0 CRPC. Fifteen patients were enrolled and received bevacizumab 10 mg/kg IV every 14 days until time of PSA progression or poor tolerability (median time = 3.1 months). Median PSADT was prolonged from 4.7 to 6.5 months. Median time to PSA progression and development of metastasis were 2.8 and 7.9 months, respectively, deemed to represent no more than a minimal impact on disease progression. This approach has not been further pursued. Immunotherapeutic approaches have also been evaluated in this disease space. PSA-TRICOM is a pox-virus-based PSA vaccine. Madan et al. reported its benefits in a randomized trial of the vaccine versus nilutamide monotherapy versus the combination for patients with M0 CRPC with the primary end point of improvement in overall survival. Forty-two men were randomized to receive either the vaccine or nilutamide. At the time of progression, patients were crossed over to receive the alternative therapy in combination with the primary agent. Median survival was only minimally improved for patients initially randomized to the vaccine arm (median, 5.1 vs. 3.4 years; P =.13). Subgroup analysis of patients on the vaccine arm versus the nilutamide arm showed survival benefits for patients with a Gleason score <7 (P =.033)andPSA <20 ng/dl (P =.013) or who had prior radiation therapy (P =.018) [27]. However, the extremely small sample size and retrospective subset analysis make these data difficult to interpret. There is an ongoing phase II trial evaluating the combination of PSA-TRICOM and flutamide versus flutamide alone in M0 CRPC patients, including those previously treated with bicalutamide and nilutamide (Clinicaltrials.gov: NCT ). Sipuleucel-T is an immunotherapeutic agent designed to elicit a T-cell-mediated response against the antigen prostatic acid phosphatase in PCa cells. It is approved for use in patients with mcrpc who are asymptomatic from their disease and have no evidence of visceral metastases. Its utility in the M0

7 6 A. ANANTHARAMAN AND E. J. SMALL Table 1. Summary of significant clinical trials. Radiographic progression-free survival Bicalutamide Bicalutamide 150 mg daily 2 Responders: 52.5 months Nonresponders: Drug category Agents Experimental arm Control arm Phase First-generation hormonal manipulation Secondgeneration hormonal manipulation Bone-targeted therapy Nilutamide PSA-TRICOM IM on D1 4 6MIU/M2 IL-2 on D8 12 Nilutamide 300 mg daily 1 month, then nilutamide 150 mg daily 18.5 months PSA-TRICOM: 9.9 months Nilutamide 7.6 months PSA decline >50% Comments References 44.70% Small study without a [25] control arm PSA-TRICOM: 59.1% Nilutamide: 76% Patients receiving the vaccine followed by combo had a trend toward improved survival Flutamide Flutamide 250 mg daily 2 Not reported 80% Very small study evaluating only PSA response Ketoconazole Ketoconazole 400 mg BID AAWD 3 Ketoconazole: 27% AAWD: 11% Abiraterone Acetate Abiraterone Acetate 1000 mg + Prednisone 5 mg daily Enzalutamide Enzalutamide 160 mg daily Bicalutamide 50 mg daily Patients had prior evidence of metastatic disease 2 Not yet reached 87% Small study without a control arm, awaiting longer follow-up 2 Enza: 19.4 months Bical: 5.7 months Enza: 81% Bical: 31% Awaiting longer followup Enzalutamide Enzalutamide 160 mg daily Placebo 3 Not completed Not completed Currently being analyzed Apalutmaide Apalutmaide 240 mg daily 2 Not yet reached 89% Awaiting longer followup Apalutmaide Apalutmaide 240 mg daily Placebo 3 Not completed Not Currently being completed analyzed Orteronel Orteronel 300 mg BID 2 PSA 76% No longer under progression: evaluation in prostate 14.8 months cancer due to other Clodronate Clodronate 2080 mg daily Placebo 3 Bone events clod: 80 Bone events placebo: 62 Denosumab Denosumab 120 mg SQ q4 weeks Placebo 3 Denosumab: 33.2 months Placebo: 29.5 months Atrasentan Atrasentan 10 mg daily Placebo 3 Atrasentan: 764 days Placebo: 641 days negative studies No significant benefit was seen either in bone metastases-free survival or overall survival Results were not statistically significant Results varied significantly by location (United States vs. not United States) Zibotentan Zibotentan 10 mg daily Placebo 3 Trial discontinued early because it was unlikely to reach primary end points Immunotherapy PSA-TRICOM PSA-TRICOM IM on D1 4 6MIU/M2 IL-2 on D8 12 Nilutamide 300 mg daily 1 month, then nilutamide 150 mg daily PSA-TRICOM: 9.9 months Nilutamide 7.6 months PSA-TRICOM: 59.1% Nilutamide: 76% Patients receiving the vaccine followed by combo had a trend toward improved survival [27] [28] [16] [39,40] [26] [44] [41] [46] [52] [15] [48] [27] CRPC setting has previously been evaluated in a small study consisting of 18 patients. PSA was measured at baseline and monthly until there was evidence of disease progression, defined as a doubling of the baseline or nadir PSA value (whichever was lower) or evidence of distant metastases. While a PSA decline 50% was not achieved by patients on the study, 13/18 patients did demonstrate an increase in PSADT (4.9 months before treatment vs. 7.9 months after treatment, P = 0.09) [55]. Larger, more definitive randomized trials have not been undertaken. A summary of the major clinical trials addressed in this review is presented in Table Expert commentary Review of the current literature for M0 CRPC highlights the heterogeneous nature of this disease group. While some patients have indolent disease and can be observed for years off therapy, others exhibit more rapid progression of their disease. Patients with short PSADTs should be considered for

8 EXPERT REVIEW OF ANTICANCER THERAPY 7 intervention, and for enrollment on a clinical trial if possible. There are no compelling data identifying a therapeutic option that provides significant improvement in delaying time to disease progression or overall survival in this group of patients, although a number of phase III trials utilizing AR targeted therapy are maturing. Given the lack of large, prospective trials identifying a clear therapeutic choice, enrollment in clinical trials should be encouraged. For those patients with shorter doubling times for whom a clinical trial is not an option, addition of a first-generation AR inhibitor (bicalutamide, nilutamide, and flutamide) or an androgen synthesis inhibitor like ketoconazole in combination with hydrocortisone or prednisone is an appropriate choice, since second-generation agents such as enzalutamide and abiraterone are currently not approved for use in this setting. 5. Five-year view In an era of rapidly evolving technology, the advent of new diagnostic modalities will likely change the prevalence of M0 CRPC. Conventional imaging modalities such as CT and MRI of the abdomen/pelvis or technecium-99 bone scans have significant limitations in the ability to detect metastases. As newer imaging tools, like the 11-C choline PET scan or PSMA PET scan, are better studied and understood, their high sensitivity will allow for earlier detection of metastatic disease and earlier intervention. This will likely, however, shrink the population of M0 CRPC patients. Oligometastatic disease, first defined by Weischelbaum and Hellman in 1995, described an entity in lung cancer where a patient has distant disease in a limited number of regions (less than five) while the primary lesion is controlled [56,57]. This concept of low burden of metastatic disease has been adopted into the highly heterogeneous population of advanced PCa. Similar to other cancers, there is a debate over ideal management of oligometastatic disease burden without clear guidelines available at this time. While some believe that definitive localized treatment measures may be appropriate in this setting, others posit that the low disease burden continues to represent a systemic disease that is far more indolent than widespread metastatic disease [58]. With the advancement of radiation oncologic techniques, focal radiation utilizing stereotactic body radiation therapy is being explored as an option for patients with oligometastatic, otherwise indolent disease. Retrospective data evaluating this approach in patients with rising PSA after definitive, local therapy for their PCa were recently published demonstrating PSA declines in approximately 60% of patients, and delaying initiation of ADT [59,60]. Whether this approach would prove useful in patients with M0 CRPC who are found to harbor oligometastatic disease is not known and bears further investigation. Key Issues M0 CRPC is a highly heterogenous disease group Use of PSA doubling time to determine risk for progression can guide appropriate time to starting therapy There is no current standard of care options for treatment of this population For patients with indolent disease, whose PSA doubling time is months, close observation is likely an appropriate approach Patients with PSA doubling time 10 months, it is likely appropriate to initiate therapy and enrollment in a clinical trial is the recommended therapy If clinical trials are not an option, treatment with a firstgeneration anti-androgen or androgen synthesis inhibitor should be considered With the advances of diagnostic imaging (PSMA PET or 11Ccholine PET scans), the prevalence of this subgroup will likely decline Funding This paper is not funded. Declaration of interest Small is the Global Health Chair of the SPARTAN trial reviewed in this paper. The other authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. References Papers of special note have been highlighted as either of interest ( ) or of considerable interest ( ) to readers. 1. Health NCIaNIo. SEER stat fact sheets: prostate cancer. 5/2015 ed. Surveillance Research Program, National Cancer Institute SEER*Stat (seer.cancer.gov/seerstat), Scher HI, Solo K, Valant J, et al. Prevalence of prostate cancer clinical states and mortality in the united states: estimates using a dynamic progression model. Plos One. 2015;10:e Huggins C, Hodges CV. Studies on prostatic cancer. 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