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. 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. 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. 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. Median survival for this stage is about 3 years with best medical therapy. 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.
Definition of Nonmetastatic Castration-
Resistant Prostate Cancer
- No evidence of metastatic disease by any imaging modality, including technetium-99m scintigraphy (bone scan) and computed tomography
- Castrate level of testosterone (ie, testosterone < 50 ng/dL)
- Rising PSA level despite castrate level of testosterone
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. 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. The placebo group contained 331 patients with complete baseline data; they had a median BMFS of 25 months. 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. 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.
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.
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
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). 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 (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. 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. 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).
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. 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. 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.
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 is a selective endothelin-A receptor antagonist thought to prevent activation of this pathway on the surface of osteoblasts, leading to decreased bone remodeling. It was studied in a phase III randomized controlled 1:1, double-blind, multicenter trial that enrolled patients from July 2001 through April 2003. 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 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. 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.
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%.
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. 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.
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