Treatment of Nonmetastatic Castration-Resistant Prostate Cancer

Patients with nonmetastatic castration-resistant prostate cancer (CRPC) are a heterogeneous population with regard to risk of progression to metastatic disease. Treatment selection for nonmetastatic CRPC must balance the risk of disease progression with the side effects of available therapies. Several medication classes are available for use in treating these patients, and other newer agents are under active clinical trial investigation. Here we review current therapies for nonmetastatic CRPC and discuss the recently completed and ongoing trials for this emerging disease state.

Introduction

Epidemiology and definitions

Prostate cancer is the second most commonly diagnosed cancer in men worldwide and accounts for over one-quarter of newly diagnosed cancer in men in the United States.[1,2] It is the sixth cancer-related cause of death among men worldwide and the second leading cause of cancer death in US men. Prostate-specific antigen (PSA) screening tests have helped diagnose the disease at an earlier stage so that less than 20% of men have imaging evidence of metastasis at the time of diagnosis.

If biochemical recurrence (ie, rising PSA level) occurs after an attempt at cure with radiation or surgery, either observation or androgen deprivation therapy (ADT) is the standard of care.[3] Prostate cancer was first shown to be androgen-dependent in seminal work in the 1940s, and since then, ADT, which results in apoptosis and growth inhibition of prostate cancer cells, has become essential to treating advanced prostate cancer.[3] Castration, either surgical or medical, results in a serum testosterone level of < 50 ng/dL. ADT is not curative when it is used alone, but it is highly active, and treatment results in PSA responses in most men with a rising PSA level. Prostate cancer eventually becomes resistant to ADT in nearly all patients, at which point serum PSA levels begin to rise and/or radiographically detectable metastases emerge, despite a serum testosterone level of < 50 ng/dL. This is termed “castration-resistant disease.” If the imaging studies-typically nuclear medicine technetium-99m scintigraphy (bone scan) as well as computed tomography (CT) of the chest, abdomen, and pelvis-remain negative for metastatic lesions, this disease state is known as nonmetastatic castration-resistant prostate cancer (CRPC). The current most accepted definition of PSA rise or progression is from the Prostate Cancer Working Group 2 (PCWG2): a 25% increase from the nadir, with a minimum rise of 2 ng/mL.[4] This needs to be confirmed with a second value, typically obtained 1 to 3 weeks later.

If the disease progresses to metastatic CRPC, the prognosis is poor. The most common site of disease metastasis is bone, followed by lymph nodes, lungs, and liver.[5] Median survival for this stage is about 3 years with best medical therapy.[6] Delay of time to metastatic disease has the potential to delay cancer-related symptoms and may help prolong survival. Clinical trials with this goal are underway and are described below.

Overview of Nonmetastatic CRPC

Nonmetastatic CRPC is a heterogeneous disease state. The control arms of several phase III trials involving patients with nonmetastatic CRPC have been helpful in elucidating its natural history. A 2005 publication outlined the outcomes of 201 men with nonmetastatic CRPC randomly assigned to the placebo arm in a phase III study evaluating the efficacy of zoledronic acid in preventing progression to metastatic disease.[7] Enrollment in the trial included documentation of castrate testosterone levels at the start of the study, three serial rises in PSA, and radiographic screening to exclude patients with overt metastatic disease. Nuclear medicine bone scans were obtained every 4 months. At 2 years, 33% of patients in the placebo arm had developed bone metastases. Neither overall survival nor median bone metastasis–free survival (BMFS) was improved with the addition of zoledronic acid. BMFS was defined as the time to first occurrence of bone metastasis or death from any cause. Analysis of this population showed that baseline PSA level > 10 ng/mL (relative risk [RR], 3.18 [95% CI, 1.74–5.80]) and PSA velocity (RR, 1.5 for each year increase in PSA velocity [95% CI, 1.26–1.78]; P < .001) were independent predictors of time to first bone metastasis in multivariate analysis; they also predicted overall survival and BMFS. Prior prostatectomy, Gleason score > 7, bilateral orchiectomy, regional lymph node metastasis at diagnosis, time from ADT to randomization > 2 years, and time from diagnosis to randomization (years) were not predictive of these clinical outcomes.

A second trial in nonmetastatic CRPC examined the efficacy of the endothelin antagonist atrasentan vs placebo with respect to time to disease progression in 941 patients.[8] The placebo group contained 331 patients with complete baseline data; they had a median BMFS of 25 months.[9] The analysis showed that PSA velocity was significantly associated with shorter overall survival (RR, 1.15 for each year increase in PSA velocity [95% CI, 1.05–1.26]; P = .002) but not shorter BMFS. Higher baseline PSA level was associated with shorter BMFS (RR, 1.44 for each 1 log [ng/mL] increase [95% CI, 1.24–1.67]; P < .001). Predictors of shorter overall survival also included baseline PSA level ≥ 13.1 (RR, 2.34 [95% CI, 1.71–3.21]; P < .0001) and shorter BMFS (RR, 1.98 [95% CI, 1.45–2.70]; P < .0001). PSA doubling time was not reported in this group.

Finally, the control arm of a phase III, double-blind study of 1,432 men comparing the receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL) inhibitor denosumab vs placebo showed that PSA doubling time was a predictor of BMFS and overall survival.[10] In the placebo arm, median BMFS was 25.2 months and median time to first bone metastasis was 40.8 months. For patients with PSA doubling times of ≤ 10 months, ≤ 6 months, and ≤ 4 months, the median BMFS in the placebo arm was 22, 19, and 18 months, respectively. The trial found that for a PSA doubling time of ≤ 10 months, BMFS was shorter (hazard ratio [HR], 0.84; P = .042). In this analysis, baseline PSA level was not associated with BMFS.

Based on the results of the foregoing studies, a general consensus has emerged that risk stratification is important when making treatment decisions. For nonmetastatic CRPC, the rate of change of PSA is the best predictor we currently have of BMFS. Patients with a relatively favorable prognosis-in general, patients with a PSA doubling time of > 10 months-may do best with observation. A possible goal of treating nonmetastatic CRPC would be to delay the development of metastases in the hope of delaying symptoms and extending survival. However, to date, we lack level 1 evidence to show that such intervention improves long-term outcomes. Currently, the National Comprehensive Cancer Network consensus guidelines recommend observation if PSA doubling time is > 10 months and secondary hormonal therapy if PSA doubling time is shorter.[11]

Since 2010, several new agents have become available to treat metastatic CRPC (Table 1), and ongoing clinical trials are testing additional therapies (Table 2). There are also several completed and ongoing trials specifically for patients with nonmetastatic CRPC. New imaging modalities may detect metastatic disease earlier than bone scan or CT scan-such as 18F-sodium fluoride positron emission tomography (PET), 11C-choline PET/CT, or whole-body multiparametric magnetic resonance imaging.[12,13] These novel modalities may redefine the future of prostate cancer staging but, at this point, they are in need of more analytical and clinical validation to better determine their accuracy and cost-effectiveness. The Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence Group recommended that in nonmetastatic CRPC, the first imaging scan occur when the PSA level is ≥ 2 ng/mL. If that scan is negative, repeat imaging should occur when the PSA level is 5 ng/mL and with every subsequent doubling of PSA, with the recommendation that the PSA level be measured every 3 months.[13]

Nonimaging techniques for earlier disease detection or prognostication (eg, enumeration and/or molecular analysis of circulating tumor cells and sequencing of cell-free circulating tumor DNA) are being investigated.[14,15] These investigational imaging and molecular analysis strategies may redefine nonmetastatic CRPC in the future.

Medical Management of Nonmetastatic CRPC

GnRH therapy

The luteinizing hormone−releasing hormone (LHRH) or gonadotropin-releasing hormone (GnRH) agonists leuprolide, goserelin, and triptorelin are peptides that mimic GnRH and that, over time, inhibit luteinizing hormone (LH) and, to a lesser extent, follicle-stimulating hormone (FSH) via desensitization. Pulsatile physiologic GnRH stimulates LH and FSH production in the pituitary gland, which leads to androgen production. However, continuous long-term treatment with GnRH agonists downregulates this pathway and leads to medical castration. In fact, these agents are commonly used to induce medical castration.

Degarelix is a GnRH antagonist that blocks the GnRH receptor and that does not cause the initial clinical surge of testosterone production seen with GnRH agonists. A retrospective review was conducted of 39 patients who switched LHRH agonists (from goserelin to leuprolide or vice versa) after progression, as defined by two consecutive PSA increases. The median time to PSA increase was 5.2 months (95% CI, 3.5–17.4).[16] The evidence to date does not support routine switching from one GnRH-targeting agent to another in patients with adequate testosterone suppression.

First-generation antiandrogens

First-generation antiandrogens (ie, bicalutamide, nilutamide, flutamide) have been used to treat nonmetastatic CRPC. These agents block the ligand-binding site of the androgen receptor (AR). Bicalutamide has increased affinity for the AR and has a longer half-life of 1 week. These medications are usually used in combination with GnRH agonists to achieve “maximal” or combined androgen blockade. Side effects of flutamide and nilutamide include interstitial lung disease, hepatotoxicity, alcohol intolerance, and diarrhea; nilutamide also affects color and light perception. When used without GnRH agonists, these medications are less likely to lead to impotence, anemia, decreased bone density, and hot flashes compared with use with GnRH agonists.

The use of first-generation antiandrogens in patients with nonmetastatic CRPC is limited to results of phase II trials in men with CRPC that showed a modest amount of activity. A subgroup of a trial investigating bicalutamide in patients with prostate cancer consisted of 51 patients with progression after orchiectomy or GnRH therapy.[17] Progression was defined as three consecutive PSA rises, imaging evidence of metastasis, and/or > 25% linear increase in tumor mass. Patients were given 200 mg of bicalutamide daily and followed with PSA levels every 3 months and imaging every 6 months. Of the 51, 14% showed a PSA response of at least 50%, but the duration of the response is unknown. Another trial examined flutamide in patients with localized or metastatic CRPC.[18] The trial recruited 45 patients with localized prostate cancer who were given flutamide, 250 mg three times daily, after their PSA levels started rising despite ADT. They were followed with monthly PSA levels and bone scans every 12 to 24 months or on progressive PSA elevation. There was an 80% PSA response of at least 50%, but duration of response was not reported. Randomized studies that address overall survival or BMFS are not available.

Switching the antiandrogen and antiandrogen withdrawal

If patients receiving an antiandrogen along with an LHRH agonist (combined androgen blockade) develop nonmetastatic CRPC, the antiandrogen should be discontinued and the patient should be observed for antiandrogen withdrawal (AAWD). This response was first described with flutamide withdrawal in 1993 and subsequently shown with bicalutamide and nilutamide.[19,20] First-generation antiandrogens can act as partial AR agonists, possibly through specific AR mutations and/or AR gene amplification.[21,22] In a multi-institutional trial of 210 patients with PSA progression despite combined androgen blockade, there was a 21% PSA response rate (95% CI, 16%–27%), defined as a PSA decrease of ≥ 50% from baseline, to AAWD. The median overall survival after withdrawal was 40 months for those who had no radiographic evidence of metastatic disease (22% of patients enrolled).[23]

Another strategy is to switch the antiandrogen. One single-center prospective trial of switching from a prior antiandrogen to high-dose bicalutamide (150 mg daily) in 38 patients showed a ≥ 50% confirmed PSA decline in 44.7% of patients.[24] The median response duration was 18.5 months for partial responders and 37.5 months for those who had a complete response. Another multicenter trial of 232 patients with progression who received combined androgen blockade demonstrated a PSA response after switching to a second-line androgen blockade.[25] Patients were switched to the new therapy after a period of antiandrogen discontinuation. No primary endpoint was defined, but a partial response-defined as 50% or greater PSA response-was seen in 35.8% of the patients after switching the antiandrogen. Although withdrawal of an antiandrogen in the face of a rising PSA on treatment is a standard strategy, rotating antiandrogens is a strategy based solely on small studies that demonstrate occasional responses. The strategy is not known to improve overall survival.

Other hormonal manipulations

Although the testicles produce the vast majority of serum androgens, the adrenal glands contribute to overall androgen production, and intratumoral androgen production is also increasingly recognized.[26-28] Other therapies that can be considered in nonmetastatic CRPC include adrenal synthesis inhibitors such as ketoconazole, which has the side effects of hepatitis, rash, nausea, and fatigue. This drug inhibits cytochrome P450 enzymes in the steroid synthesis pathway and requires steroid supplementation. Low-dose corticosteroids, such as hydrocortisone, dexamethasone, and prednisone, have also been used in this setting but can lead to osteopenia and glucose intolerance. Estrogens have the side effects of gynecomastia and hypercoagulability, and megestrol acetate may lead to increased appetite or edema. The data regarding use of these agents are mostly from phase II trials, with PSA response ≥ 50% (in trials of 30 or more patients) ranging from 27% to 56% for ketoconazole, 12% to 54% for estrogen derivatives, and 14% to 61% for corticosteroids.[29]

In summary, observation is the standard approach to patients with good-prognosis nonmetastatic CRPC, while patients with a poor prognosis are usually offered additional lines of hormonal therapies, for which the clinical evidence is quite limited. No approved therapy has been shown to improve overall survival or definitively delay the development of symptomatic metastasis.

Agents Recently Studied for Nonmetastatic CRPC

Recent years have brought an increasing interest in clinical trials designed to test new drugs in the hope of favorably modifying the natural history of nonmetastatic CRPC.

Atrasentan

Atrasentan is a selective endothelin-A receptor antagonist thought to prevent activation of this pathway on the surface of osteoblasts, leading to decreased bone remodeling.[30] It was studied in a phase III randomized controlled 1:1, double-blind, multicenter trial that enrolled patients from July 2001 through April 2003.[8] Eligibility criteria included nonmetastatic CRPC with PSA levels that were at least 20 ng/mL, that had increased by 50% within 6 months, or that had exhibited three consecutive increases within 12 months. Patients were excluded if they used chemotherapy for their prostate cancer, took bisphosphonates, or had New York Heart Association (NYHA) class > II heart failure. The trial recruited 941 patients and had a primary endpoint of time to disease progression, defined as time from randomization to onset of earliest confirmed metastasis by imaging. PSA level was measured every 4 to 6 weeks, and a bone scan was obtained every 3 months. The trial failed to show an improvement in the primary endpoint.

Zibotentan

Zibotentan is another endothelin-A receptor antagonist. It was studied in a phase III multicenter, double-blind, randomized controlled trial of 1,421 patients with nonmetastatic CRPC.[31] Patients were recruited between January 2008 and May 2011 and randomly assigned to either oral zibotentan, 10 mg daily, or placebo daily. The primary endpoints were progression-free survival and overall survival. The trial was discontinued early due to an independent data monitoring committee review analysis showing that it would unlikely reach its primary endpoints. In addition, results from phase III trials of patients with metastatic prostate cancer assigned to zibotentan monotherapy (ENTHUSE M1) and to zibotentan plus docetaxel (ENTHUSE M1C) showed no significant improvement in overall survival.[32,33] Based on these negative trials, this agent is no longer under investigation for prostate cancer treatment.

Studies in metastatic CRPC also have not shown a benefit from endothelin-A receptor antagonists, given alone or in combination with docetaxel, so there is not a role for these agents at this time.[34]

Denosumab

Osteoblasts of the bone express RANKL, which binds to the receptor RANK found on osteoclasts and their precursors. The RANK/RANKL pathway mediates osteoclast function and survival, and dysregulation may lead to prostate cancer bone metastases.[35,36] Denosumab is an anti-RANKL human monoclonal antibody that is indicated for men with metastatic CRPC who have bone metastases or for men receiving ADT who are at risk for osteoporosis. Denosumab was studied in a phase III international, multicenter, double-blind, randomized controlled trial of men with nonmetastatic CRPC to determine if it could delay progression to metastatic disease.[10,37,38] The trial recruited patients from February 2006 through July 2008. Inclusion criteria included nonmetastatic CRPC and high risk for progression, defined as baseline PSA level ≥ 8 ng/mL and/or PSA doubling time of ≤ 10 months. Subjects were randomly assigned 1:1 to 120-mg subcutaneous denosumab (716 patients) vs sterile saline (716 patients) every 4 weeks. Exclusion criteria included history of osteomyelitis or osteonecrosis of the jaw (ONJ), prior second malignancy in the past 5 years, and prior IV bisphosphonate or oral bisphosphonate use in the preceding 3 years. Patients were followed by bone scan every 4 months. The primary endpoint was metastasis-free survival, defined as time to first bone metastasis or death from any cause. The secondary endpoint was time to first bone metastasis and overall survival. The results of the trial showed that denosumab prolonged BMFS by a median of 4.2 months (HR, 0.85 [95% CI, 0.73–0.98]; P = .028) and delayed time to first bone metastasis (HR, 0.84 [95% CI, 0.71–0.98]; P = .032). The median time to first bone metastasis in the denosumab group was 33.2 months, compared with 29.5 months with placebo. However, there was no difference in overall survival (median, 43.9 months with denosumab vs 44.8 months with placebo) or progression-free survival. Based on these results, the US Food and Drug Administration did not approve the drug for delay of bone metastatic disease in nonmetastatic CRPC. Denosumab is approved for the prevention of skeletal-related events and castration-induced bone thinning. Principal adverse events (AEs) included ONJ in 5% and hypocalcemia in 2%.

Bevacizumab

This humanized anti–vascular endothelial growth factor monoclonal antibody was studied in patients with nonmetastatic CRPC in a phase II trial. Bevacizumab IV 10 mg/kg was given every 14 days; primary endpoints included PSA response rate, time to PSA progression, and treatment-related toxicities.[39] Inclusion criteria included prostate cancer without metastasis and three rising PSA levels despite ADT and AAWD. Exclusion criteria included uncontrolled hypertension, NYHA grade > II heart failure, stroke/transient ischemic attack within 6 months, and coagulopathy. The trial enrolled from December 2007 through November 2010 and recruited 15 patients. PSA levels were obtained every 6 weeks and imaging every 3 months. Three patients had grade 3 AEs (one with proteinuria, two with hypotension, one with pulmonary embolism). None of the patients met the 50% cutoff for a partial response, and median time to PSA progression was 2.8 months. This agent does not have a role in prostate cancer treatment.

PSA-TRICOM

PSA-TRICOM is a vector-based therapeutic cancer vaccine regimen consisting of recombinant poxviruses containing transgenes from PSA and three T-cell costimulatory molecules.[40] The vaccine was studied in a nonblinded phase II trial of patients with nonmetastatic CRPC and a rising PSA level, despite a castrate level of testosterone; the participants were randomly assigned to either the vaccine or nilutamide.[41,42] Patients were only required to have castrate levels of testosterone, to have undergone AAWD for 4 to 6 weeks, and to not be immunocompromised. Prior nilutamide therapy was an exclusion criterion. Nilutamide was given at a dosage of 300 mg daily for 1 month, followed by 150 mg daily subsequently. The vaccine was given as an initial priming dose of admixed recombinant vaccinia-based vaccine (transgenes for PSA and for human T-cell costimulatory molecule B7-1) and then as a booster of recombinant fowlpox-based vaccine monthly. Subjects were followed every 3 months with CT and bone scans and with monthly PSA testing. Patients who developed rising PSA levels could cross over to the other arm. The time to treatment failure-defined as progression, secondary malignancy, or toxicity-was 9.9 months with the vaccine and 7.6 months with nilutamide (P = .28). The median survival was 5.1 years for patients who received the vaccine vs 3.4 years for patients who received nilutamide alone (P = .13). There were no grade 3 toxicities in the vaccine arm.

This vaccine is being tested in an ongoing phase II trial (ClinicalTrials.gov identifier: NCT00450463) that randomly assigns patients to flutamide and vaccine (given as monthly injections) vs flutamide alone. The primary endpoint is time to treatment failure, defined as biochemical recurrence as shown by PSA increase or development of metastases on imaging.[43] It is not yet known whether this agent will have a role in prostate cancer.

Orteronel

Orteronel is a nonsteroidal selective inhibitor of the cytochrome P450 17-alpha-hydroxylase/17,20 lyase enzyme (CYP17), a critical enzyme catalyzing two distinct steps in endogenous testosterone production. A phase II multicenter trial examined oral orteronel in 39 patients with nonmetastatic CRPC.[44,45] Inclusion criteria included nonmetastatic CRPC with PSA level ≥ 2 ng/mL and higher risk for metastases, defined as PSA doubling time of ≤ 8 months or PSA level ≥ 8 ng/mL if doubling time was > 8 months. Exclusion criteria included previous chemotherapy, ketoconazole, or concurrent use of corticosteroids. The primary endpoint was percentage of patients with PSA level ≤ 0.2 ng/mL after 3 months. PSA levels and imaging were obtained every 3 to 4 months. At 3 months, six patients (15%) had achieved the primary endpoint. The 39 total patients provided 90% power to give a one-sided significance of 0.1, assuming 20% of patients achieved the primary endpoint. Median time to PSA progression was 13.8 months, and median time to metastatic disease was 25.4 months. There were grade 3 AEs in 16 patients. AEs that occurred in more than 5% of patients included dyspnea, hypertension, fatigue, hypokalemia, and pneumonitis. Six patients had drug-related serious AEs, including two with grade 3 pneumonitis, one with hypoxia, one with syncope, one with atrial fibrillation, and one with adrenal insufficiency. There have been two negative phase III studies of orteronel in metastatic CRPC, so further development of the drug in prostate cancer has been suspended, except in one ongoing trial of newly diagnosed metastatic disease (ClinicalTrials.gov identifier: NCT01809691).[46]

Abiraterone

The antiandrogen abiraterone is an inhibitor of CYP17A1 that is given with prednisone.[47] Two phase III clinical trials have demonstrated a survival advantage for abiraterone over prednisone alone for patients with metastatic CRPC.[48,49] The phase II, single-arm, multicenter IMAAGEN trial enrolled 131 patients with high-risk nonmetastatic CRPC between May 2011 and July 2013 and treated them with 1,000 mg of abiraterone and 5 mg of prednisone daily.[50,51] High risk was defined as PSA level ≥ 10 ng/mL or PSA doubling time of ≤ 10 months. The primary endpoint was PSA response at 6 months. At the end of 6 months of treatment, 87% of patients had a ≥ 50% PSA response, and 60% had a ≥ 90% PSA response. The median time to PSA progression was 28.7 months. More than 50% of patients had grade 3 or higher AEs, and serious AEs of grade 3 or higher occurred in 35.9% of patients, with four patients suffering AEs that resulted in death. Of the patients with AEs, 13% had to discontinue their participation in the study. To our knowledge, no phase III studies are currently being conducted with abiraterone in nonmetastatic CRPC. Abiraterone shows activity in nonmetastatic CRPC, as one would expect based on its activity in metastatic CRPC. However, it is not currently approved in the nonmetastatic setting.

Enzalutamide

Enzalutamide is an antiandrogen that in two phase III studies demonstrated a survival advantage over placebo alone for metastatic CRPC.[6,52] The phase II, multicenter, double-blind STRIVE trial randomly assigned 396 patients with progressive nonmetastatic or metastatic CRPC to enzalutamide, 160 mg/day, or bicalutamide, 50 mg/day.[53] The primary endpoint was progression-free survival, which was defined as the time from randomization to radiographic progression, PSA progression, or death from any cause. Of the 396 patients enrolled, 35% had M0 disease. Thus far, for both M0 and M1 disease combined, patients treated with enzalutamide have had a median progression-free survival of 19.4 months, compared with 5.7 months in the bicalutamide arm (HR, 0.24 [95% CI, 0.18–0.32]; P < .0001). The median time on treatment has been 14.7 months in the enzalutamide arm compared with 8.4 months with bicalutamide. Of the 139 patients with M0 disease, median progression-free survival and median time to PSA progression have not been reached thus far in the enzalutamide arm. This trial continues to be under analysis.

PROSPER, an ongoing phase III trial, is randomly assigning patients with high-risk nonmetastatic CRPC-defined as PSA doubling time of ≤ 10 months and PSA level > 2 ng/mL-to enzalutamide, 160 mg daily, or placebo (ClinicalTrials.gov identifier: NCT02003924). The primary endpoint is metastasis-free survival. At this time, enzalutamide is not approved for nonmetastatic CRPC.

ARN-509

ARN-509 is another antiandrogen being actively investigated in the nonmetastatic CRPC setting.[54,55] This compound inhibits binding of androgens to the AR and prevents nuclear translocation and DNA binding of the receptor to androgen response elements. An ongoing phase II trial of ARN-509 that recruited 47 patients between November 2011 and June 2012 is studying this drug in patients with nonmetastatic CRPC.[56-58] The primary endpoint is PSA response at 12 weeks according to PCWG2 criteria. Inclusion criteria included nonmetastatic CRPC and high risk for disease progression, based on PSA level ≥ 8 ng/mL within 3 months of enrollment and/or PSA doubling time of ≤ 10 months. Patients were given 240 mg of ARN-509 per day and had their PSA level checked every 4 weeks and imaging studies every 16 weeks. The median follow-up was 13.4 months. The PSA response rate at both 12 and 24 weeks was 91%, and the median metastasis-free survival has not been reached. AEs in the metastatic CRPC group included grade 3 or higher fatigue, back pain, constipation, musculoskeletal pain, and vomiting.

An ongoing phase III trial is randomly assigning men with nonmetastatic CRPC 2:1 to ARN-509 vs placebo (ClinicalTrials.gov identifier: NCT01946204). Participants must have a PSA doubling time of ≤ 10 months. The primary endpoint of this study is metastasis-free survival.

ODM-201

ARAMIS is a current ongoing trial of the second-generation oral AR inhibitor ODM-201 (ClinicalTrials.gov identifier: NCT02200614). This phase III trial is randomly assigning patients with high-risk nonmetastatic CRPC-defined as PSA doubling time of ≤ 10 months and PSA level > 2 ng/mL-to ODM-201 (2,300-mg tablets bid) or to placebo. The primary endpoint is metastasis-free survival, defined as time from randomization to evidence of metastasis or death from any cause.

Conclusions

Nonmetastatic CRPC encompasses a wide spectrum of disease. In analyses of the placebo arms of randomized controlled trials enrolling patients with nonmetastatic CRPC, median BMFS appears to be around 25 months. However, patients with short PSA doubling times have substantially shorter time to first bone metastasis and median BMFS. To enrich for patients at risk for progression and to limit heterogeneity, trials recruiting patients with nonmetastatic CRPC now use inclusion criteria of high-risk disease, which is usually a PSA doubling time of ≤ 10 months.

To date, no level 1 evidence supports the use of any cancer-directed treatment in nonmetastatic CRPC. Based on small studies that show evidence of antitumor activity, most practitioners offer traditional second-line hormonal therapies to such patients if they are at an elevated risk for progressing to metastases. Such treatment strategies include the addition of first-generation AR antagonists to medical or surgical castration; withdrawal of the first-generation AR antagonists; increased doses of first-generation AR antagonists; and use of ketoconazole, estrogens, and occasionally corticosteroids. Supportive care therapies, such as denosumab or zoledronic acid, may be used in appropriate patients to treat bone loss, but they are not indicated for anticancer effects. Second-generation androgen signaling inhibitors (ie, enzalutamide and abiraterone) are in routine use for metastatic CRPC, have clinical activity in nonmetastatic CRPC, and are being studied in this patient population. There is currently no role for chemotherapy or immunotherapy in this setting.

In summary, we recommend that patients who have nonmetastatic CRPC and high-risk disease consider enrolling in a clinical trial. If clinical trial participation is not possible, the treatment options include observation, first-generation AR antagonists (ie, bicalutamide, nilutamide, flutamide), high-dose bicalutamide, inhibition of the adrenal glands (ketoconazole), or estrogen therapy along with continued LHRH agonist therapy. Patients with lower-risk disease can be safely observed.

Financial Disclosure: Dr. Graff receives research funding from Astellas Pharma Global, Janssen, and Medivation; she received honoraria from Janssen. Dr. Beer receives research funding from Astellas Pharma Global, Janssen, and Medivation; he receives consulting fees from Astellas Pharma Global.

References:

1. Siegel R, Miller K, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5-29.

2. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65: 87-108.

3. Huggins C, Hodges CV. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293-7. [Reprinted in: J Urol. 2002;168:9-12.]

4. Scher HI, Halabi S, Tannock 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;26:1148-59.

5. Bubendorf L, Schöpfer A, Wagner U, et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol. 2000;31:578-83.

6. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424-33.

7. Smith MR, Kabbinavar F, Saad F, et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol. 2005;23:2918-25.

8. Nelson JB, Love W, Chin JL, et al. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer. 2008;113:2478-87.

9. Smith MR, Cook R, Lee K-A, Nelson JB. 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;117:2077-85.

10. Smith MR, Saad F, Oudard S, 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;31:3800-6.

11. Mohler J, Armstrong AJ, Bahnson RR, et al. NCCN Guidelines. Prostate cancer. http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed March 5, 2016.

12. Lecouvet FE, El Mouedden J, Collette L, et al. Can whole-body magnetic resonance imaging with diffusion-weighted imaging replace Tc 99m bone scanning and computed tomography for single-step detection of metastases in patients with high-risk prostate cancer? Eur Urol. 2012;62:68-75.

13. Crawford ED, Stone NN, Yu EY, et al. Challenges and recommendations for early prostate cancer. Urology. 2014;83:664-9.

14. Ellinger J, Müller SC, Stadler TC, et al. The role of cell-free circulating DNA in the diagnosis and prognosis of prostate cancer. Urol Oncol. 2011;29:124-9.

15. Friedlander TW, Fong L. The end of the beginning: circulating tumor cells as a biomarker in castration-resistant prostate cancer. J Clin Oncol. 2014;32:1104-6.

16. Lawrentschuk N, Fernandes K, Bell D, et al. Efficacy of a second line luteinizing hormone-releasing hormone agonist after advanced prostate cancer biochemical recurrence. J Urol. 2011;185:848-54.

17. Scher HI, Liebertz C, Kelly WK, et al. Bicalutamide for advanced prostate cancer: the natural versus treated history of disease. J Clin Oncol. 1997;15:2928-38.

18. Fowler JE, Pandey P, Seaver LE, Feliz TP. Prostate specific antigen after gonadal androgen withdrawal and deferred flutamide treatment. J Urol. 1995;155:1704-5.

19. Kelly WK, Scher HI. Prostate specific antigen decline after antiandrogen withdrawal: the flutamide withdrawal syndrome. J Urol. 1993;149:607-9.

20. Scher HI, Zhang ZF, Nanus D, Kelly WK. Hormone and antihormone withdrawal: implications for the management of androgen-independent prostate cancer. Urology. 1996;47:61-9.

21. Taplin ME, Bubley GJ, Shuster TD, et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med. 1995;332:1393-8.

22. Palmberg C, Koivisto P, Kakkola L, et al. Androgen receptor gene amplification at primary progression predicts response to combined androgen blockade as second line therapy for advanced prostate cancer. J Urol. 2000;164:1992-5.

23. Sartor AO, Tangen CM, Hussain MH, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426). Cancer. 2008;112:2393-400.

24. Lodde M, Lacombe L, Fradet Y. Salvage therapy with bicalutamide 150 mg in nonmetastatic castration-resistant prostate cancer. Urology. 2010;76:1189-93.

25. Suzuki H, Okihara K, Miyake H, et al. Alternative nonsteroidal antiandrogen therapy for advanced prostate cancer that relapsed after initial maximum androgen blockade. J Urol. 2008;180:921-7.

26. Cai C, Balk SP. Intratumoral androgen biosynthesis in prostate cancer pathogenesis and response to therapy. Endocr Relat Cancer. 2011;18:R175-R182.

27. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68:6407-15.

28. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68:4447-54.

29. Tombal B. Non-metastatic CRPC and asymptomatic metastatic CRPC: which treatment for which patient? Ann Oncol. 2012;23(suppl 10):x251-8.

30. Nelson JB, Nabulsi AA, Vogelzang NJ, et al. Suppression of prostate cancer induced bone remodeling by the endothelin receptor A antagonist atrasentan. J Urol. 2003;169:1143-9.

31. Miller K, Moul JW, Gleave M, 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;16:187-92.

32. Nelson JB, Fizazi K, Miller K, et al. Phase III study of the efficacy and safety of zibotentan (ZD4054) in patients with bone metastatic castration-resistant prostate cancer (CRPC). J Clin Oncol. 2011;29(suppl 7):abstr 117.

33. Fizazi KS, Higano CS, Nelson JB, et al. Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2013;31:1740-7.

34. Qi P, Chen M, Zhang LX, et al. A meta-analysis and indirect comparison of endothelin A receptor antagonist for castration-resistant prostate cancer. PLoS One. 2015;10:e0133803.

35. Roodman G. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-64.

36. Dougall WC, Chaisson M. The RANK/RANKL/OPG triad in cancer-induced bone diseases. Cancer Metastasis Rev. 2006;25:541-9.

37. Smith MR, Saad F, Coleman R, et al. Denosumab and bone metastasis-free survival in men with castration-resistant prostate cancer: results of a global phase 3, randomised, placebo-controlled trial. Lancet. 2012;379:39-46.

38. Lacey DL, Boyle WJ, Simonet WS, et al. Bench to bedside: elucidation of the OPG–RANK–RANKL pathway and the development of denosumab. Nat Rev Drug Discov. 2012;11:401-19.

39. Ogita S, Tejwani S, Heilbrun L, et al. Pilot phase II trial of bevacizumab monotherapy in nonmetastatic castrate-resistant prostate cancer. ISRN Oncol. 2012;2012:1-7.

40. Hodge JW, Sabzevari H, Yafal AG, et al. A triad of costimulatory molecules synergize to amplify T-cell activation. Cancer Res. 1999;59:5800-7.

41. Madan RA, Gulley JL, Schlom J, 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;14:4526-31.

42. Arlen PM, Gulley JL, Todd N, et al. Antiandrogen, vaccine and combination therapy in patients with nonmetastatic hormone refractory prostate cancer. J Urol. 2005;174:539-46.

43. Bilusic M, Gulley JL, Heery C, et al. A randomized phase II study of flutamide with or without PSA-TRICOM in nonmetastatic castration-resistant prostate cancer (CRPC). J Clin Oncol. 2011;29(suppl 7):abstr 163.

44. Hussain M, Corn PG, Michaelson MD, 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;20:4218-27.

45. George DJ, Corn PG, Michaelson MD, et al. Safety and activity of the investigational agent orteronel (ortl) without prednisone in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) and rising prostate-specific antigen (PSA): updated results of a phase II study. J Clin Oncol. 2012;30(suppl):abstr 4549.

46. Saad F, Fizazi K, Jinga V, et al. Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. Lancet Oncol. 2015;16:338-48.

47. Attard G, Reid AH, Auchus RJ, et al. Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer. J Clin Endocrinol Metab. 2012;97:507-16.

48. Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008;26:4563-71.

49. de Bono JS, Leon MB, Mack MJ, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:2187-98.

50. Ryan CJ, Crawford ED, Shore ND, et al. Effect of abiraterone acetate and low-dose prednisone on PSA in patients with nonmetastatic castration-resistant prostate cancer: The results from IMAAGEN core study. J Clin Oncol. 2014;32(suppl 5):abstr 5086.

51. Ryan CJ, Crawford ED, Shore ND, et al. IMAAGEN trial update: effect of abiraterone acetate and low dose prednisone on PSA and radiographic disease progression in patients with non-metastatic castration-resistant prostate cancer. J Clin Oncol. 2015;33 (suppl):abstr 5053.

52. Scher HI, Fizazi K, Saad F. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-97.

53. Penson D, Armstrong A, Concepcion R, et al. A multicenter phase 2 study of enzalutamide (ENZA) versus bicalutamide (BIC) in men with non-metastatic (M0) or metastatic (M1) castration-resistant prostate cancer (CRPC): the STRIVE trial. J Urol. 2015;193 (suppl):e499.

54. Clegg NJ, Wongvipat J, Joseph JD, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 2012;72:1494-503.

55. Rathkopf DE, Morris MJ, Fox JJ, et al. Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2013;31:3525-30.

56. Smith MR, Antonarakis ES, Ryan CJ, et al. ARN-509 in men with high-risk nonmetastatic castration-resistant prostate cancer (CRPC). J Clin Oncol. 2013;31(suppl 6):abstr 7.

57. Smith MR, Antonarakis ES, Ryan CJ, et al. ARN-509 in men with high risk non-metastatic castration-resistant prostate cancer. Eur J Cancer. 2013;49(suppl 2):abstr 2898.

58. Rathkopf DE, Antonarakis ES, Shore ND, et al. ARN-509 in patients with metastatic castration-resistant prostate cancer previously treated with abiraterone acetate (AA). J Clin Oncol. 2014;32(suppl 5):abstr 5026.