Docetaxel based chemotherapy has been shown to modestly extend life, relieve pain and improve the quality of life in patients with metastatic castration-resistant prostate cancer. Current trials are attempting to build on the backbone of docetaxel by combining it with novel biological agents. Trials are also investigating the role of docetaxel for earlier stages of prostate cancer. No standard second-line systemic therapy exists and such patients are candidates for clinical trials. The increased understanding of the mechanisms of progressive castration-resistant prostate cancer is being translated into an increasing pipeline of novel therapies.
Castration-resistant prostate cancer (CRPC) comprises patients with diverse clinical subtypes including a rising prostate-specific antigen (PSA) alone or with metastases, radiological progression (bone scan, nodal, or visceral) and clinical progression (worsening pain, urinary obstruction, spinal cord compression). Until the emergence of docetaxel chemotherapy, efficacious agents that objectively improved outcomes were not available for metastatic CRPC. Two large phase III trials showed the extension of survival in conjunction with palliative benefits in men receiving frontline docetaxel-based chemotherapy for metastatic CRPC.1,2 In contrast, the earlier standard of mitoxantrone-prednisone (MP) chemotherapy conferred palliative benefits but had not been proven to extend survival.3,4 The present paper reviews the data that establish docetaxel as the standard frontline chemotherapy and its role as a platform to further develop combination therapy with novel emerging biologic agents.
Survival and palliative benefits with docetaxel-based frontline chemotherapy
Based on encouraging PSA response rates, as well as survival data in early trials of docetaxel alone or in combination with estramustine phosphate (EMP), randomized studies were carried out comparing docetaxel-based therapy with MP. In the phase III TAX-327 study, two schedules of docetaxel were compared with the standard mitoxantrone regimen (12 mg/m2 every 3 weeks), with all patients receiving prednisone.1 This was the largest randomized trial in metastatic CRPC to date, with 1006 patients accrued. Patients with a Karnofsky Performance Score (KPS) ≥60 were eligible and those with brain or leptomeningeal metastases, peripheral neuropathy ≥grade 2 and abnormal cardiac function were excluded. Acceptable hematological parameters (neutrophil count ≥1500 per cubic millimeter, hemoglobin ≥10.0 g per deciliter, platelet count ≥100 000 per cubic millimeter), hepatic function (total bilirubin < upper limit of the normal; serum alanine aminotransferase/aspartate aminotransferase ≤1.5 upper limit of normal) and renal function (creatinine ≤1.5 upper limit of normal) were required. Patients were stratified according to baseline pain level and performance status (KPS). The weekly regimen consisted of docetaxel 30 mg/m2 every week for 5 of 6 weeks and the every 3-week regimen consisted of docetaxel 75 mg/m2 every 3 weeks. Patients in all groups received prednisone 5 mg twice a day. Therapy was given until progressive disease was detected, and up to a maximum of 10 cycles for the groups given docetaxel every 3 weeks or mitoxantrone and up to 5 cycles (of 6 weeks each) in the weekly-docetaxel group. Progressive disease was defined as pain progression (defined as an increase in the present pain intensity [PPI] score of ≥1 point from the nadir, an increase in the analgesic score of ≥25%, or a requirement for palliative radiotherapy), PSA progression (defined as an increase from the nadir of either ≥25% for men with no PSA response or ≥50% for all others) or objective progression of measurable disease. Pain response was defined as a reduction in the PPI score of ≥2 points from baseline without an increase in the analgesic score or as a reduction of ≥50% in the analgesic score without an increase in the PPI score, either of which was maintained for ≥3 weeks.
In an update of this study, median survival was 19.2 months in the 3-week docetaxel group, 17.8 months with weekly docetaxel, and 16.3 months with mitoxantrone.5 The 3-year survivals were 17.9%, 16.7% and 13.7%, respectively. Only 3-week docetaxel plus prednisone attained statistical superiority when compared with MP. The survival benefit of docetaxel given every three weeks was consistent across subgroups defined according to the presence or absence of pain, KPS score (≤70 vs≥80) and age (<65 years vs≥65 years). More patients in the 3-week docetaxel group experienced a significant reduction in pain compared with mitoxantrone (35% vs 22%, P = 0.01). Nearly a quarter of patients in each docetaxel group (22% with 3-week and 23% with weekly) showed a significant improvement in quality of life compared with mitoxantrone (13%). Measurable tumor response rates were low and comparable in all groups. PSA response rate was better in the docetaxel groups: 45% with every 3-weeks administration and 48% with weekly administration vs 32% with mitoxantrone.
Grade 3/4 neutropenia occurred in 32% of patients treated with every 3-weekly docetaxel, 22% treated with mitoxantrone, and 1.5% treated with weekly docetaxel. However, febrile neutropenia and infection were uncommon in all groups (0–3%), and there were no septic deaths. There was a higher incidence of grade 3–4 cardiac dysfunction among patients who received mitoxantrone compared with both docetaxel groups (7% vs 1–2%). Docetaxel induced more fatigue, alopecia, diarrhea, nail changes, sensory neuropathy, anorexia, changes in taste, stomatitis, dyspnea, tearing, peripheral edema and epistaxis. Most adverse events associated with docetaxel were low grade and not life-threatening, with loss of sensation in the fingers and toes being particularly bothersome to many patients. However, the overall outcomes suggest that docetaxel has superior palliative effects despite the increase in toxicity.
In the Southwest Oncology Group (SWOG)-9916 phase III trial, 770 patients with metastatic CRPC were randomized to combination docetaxel-EMP or MP.2 Patients were required to have a SWOG performance status of 0–2 (score of 3 was allowed if due to bone pain) and adequate hematological, hepatic and renal function. Patients were ineligible if they had received prior radioisotope or anticoagulant therapy (excluding aspirin), had active thrombophlebitis, hypercoagulability, a history of pulmonary embolus, or pleural effusion or ascites. Patients were stratified for the type of progression (i.e. progression of disease that could be measured or evaluated vs increasing PSA level alone), grade of bone pain and SWOG performance-status score.
Patients in the docetaxel-EMP group received docetaxel 60 mg/m2 every 3 weeks plus five consecutive days of EMP 280 mg given orally three times a day. Patients in the MP group received mitoxantrone 12 mg/m2 every 3 weeks plus continuous prednisone at a dose of 5 mg twice a day. Patients who did not experience grade 3/4 toxicity in the first cycle of therapy had the docetaxel dose escalated to 70 mg/m2 or the mitoxantrone dose escalated to 14 mg/m2. With studies showing the utility of prophylactic anticoagulation in decreasing EMP-related vascular events, the protocol was amended to include daily coumadin (2 mg) and aspirin (325 mg) in the docetaxel-EMP group. Treatment continued until disease progression or unacceptable adverse effects occurred or until a maximum of 12 cycles of docetaxel-EMP or 144 mg/m2 of mitoxantrone had been given. Progression was defined as objective or PSA progression (≥25% and ≥5 ng/ml increase in the serum PSA over the last preregistration or nadir measurement, with confirmation of the increase at least 4 weeks later) or death. Median survival was significantly improved with the docetaxel-EMP combination (17.5 vs 15.6 months, P = 0.02), the relative risk of death was reduced by 20% and the PSA response rate was significantly better (50% vs 27%, P < 0.001). The median time to progression was 6.3 months for docetaxel-EMP and 3.2 months for MP (P < 0.001). Greater toxicity was observed in the docetaxel-EMP group: grade 3/4 gastrointestinal (20% vs 5%), hematological (neutropenic fever, 5% vs 2%), cardiovascular (15% vs 7%), metabolic disturbances (6% vs 1%), and neurological events (7% vs 2%) were all more frequent in the docetaxel-EMP arm.
Clearly, significant improvements in overall survival and palliative benefits have been shown with the 3-weekly docetaxel based regimen, establishing it as the cornerstone of frontline systemic chemotherapy for metastatic CRPC. EMP is associated with significant gastrointestinal and thromboembolic toxicities that have led to decreased usage. Given the toxicities attributable to EMP and the similar benefit with docetaxel plus prednisone and docetaxel plus EMP, the combination of docetaxel plus prednisone has been approved by regulatory authorities and has become the preferred regimen for the frontline treatment of metastatic CRPC.
Prognostic factors in patients with metastatic CRPC
Ten independent prognostic factors were identified in a multivariate analysis of the TAX-327 trial: liver metastases, number of metastatic sites, significant pain, Karnofsky performance status, type of progression (measurable disease or bone scan progression), pretreatment PSA-doubling time (DT), absolute PSA level, tumor grade, alkaline phosphatase and hemoglobin.6 These factors have been incorporated into a nomogram from this large randomized trial, which might be useful for stratification in future trials. Further validation of this nomogram is necessary.
Second-line chemotherapy after docetaxel
Effective salvage chemotherapy after prior docetaxel is lacking, as only modest and similar efficacy has been shown with mitoxantrone or ixabepilone in this setting. In a randomized phase II trial comparing mitoxantrone plus prednisone with ixabepilone without prednisone in patients progressing after docetaxel, the median time to progression was approximately 2.2 months, the median survival was 10.4 months with ixabepilone and 9.8 months with MP, and ≥50% PSA declines were noted in 17% of ixabepilone and 20% of MP patients.7 The combination of mitoxantrone, ixabepilone and prednisone has also been reported to be feasible and active.8 A randomized phase III trial is planned to compare second-line therapy with MP or the combination of MP-ixabepilone. Another randomized phase III trial, the TROPIC trial, is comparing second-line mitoxantrone with XRP6258, a novel taxane. Other randomized phase II trials are evaluating the combination of second-line mitoxantrone with biological agents (e.g. cixutumumab, insulin-like growth factor receptor-1 monoclonal antibody; or IMC-3G3, a monoclonal antibody targeting platelet derived growth factor receptor [PDGFR]-α).
Satraplatin is a third-generation orally available, platinum analog which showed a 33% reduction in the risk of progression or death in patients with metastatic CRPC after one prior chemotherapy regimen in the 950 patient phase III SPARC (Satraplatin and Prednisone Against Refractory Cancer) trial.9 Satraplatin also showed beneficial effects on pain and biological activity with PSA declines and objective responses. Unfortunately, satraplatin did not significantly extend survival (median survival of approximately 13 months in both groups), although this analysis might have been confounded by post-study therapy. Therefore, approval by regulatory agencies has not been granted. Given the dismal outcomes with currently available second-line agents, patients with progressive metastatic CRPC after docetaxel-based chemotherapy are excellent candidates for clinical trials
Surrogate end-points for response and progression
Prostate cancer is characterized by a poor ability to measure response and progression due either to immeasurable bone-only metastases or PSA-only disease. Optimal surrogate end-points for measuring the status of disease-burden are lacking. PSA response has historically been defined as a ≥50% decline. However, a PSA decline of ≥30% at 3 months appears to be a more useful, albeit imperfect, intermediate surrogate for improved long-term outcomes with cytotoxic chemotherapy. Data from the TAX-327 trial were used to analyze PSA declines ranging from 0% to 90%, PSA velocity and pain response as intermediate surrogate end-points.10 A PSA decline of ≥30% within 3 months of chemotherapy initiation had the highest degree of surrogacy for overall survival. Other changes in PSA, PSA kinetics, PSA normalization and pain responses were weaker surrogates for survival. A similar retrospective analysis of the SWOG-9916 trial analyzed PSA velocity and PSA declines ranging from 5% to 90% within 3 months for surrogacy.11 The optimal biochemical surrogate was again found to be a ≥30% PSA decline. A recent analysis by SWOG suggests that a ≥25% PSA increase at 3 months might be a useful surrogate for poor survival in patients with metastatic CRPC.12 Alternatively, time to event end-points might be clinically useful surrogates, can be used to make clinical decisions, and are currently recommended in the setting of clinical trials by the prostate cancer working group (PCWG)-2 guidelines.13 In particular, progression-free survival defined as a composite end-point constituted by symptomatic or radiological progression might be a clinically relevant end-point and preliminarily appears to be a useful intermediate surrogate for survival in the setting of frontline chemotherapy.14 Recent and ongoing trials are frequently defining bone progression as the presence of ≥2 new lesions confirmed by further new lesions on repeat bone scanning after ≥4 weeks. Other useful intermediate surrogates are emerging, such as an early change of circulating tumor cells (CTC).15 All of these intermediate surrogates for outcomes require prospective validation, especially in the setting of novel biological agents. Therefore, survival remains the only objective end-point in the setting of clinical trials for prostate cancer.
Docetaxel for earlier stages of prostate cancer
Given the significant improvement in outcomes with docetaxel-based chemotherapy for metastatic CRPC, the application of docetaxel to earlier stages of prostate cancer is being investigated (Table 1). Chemotherapy is not accepted as standard for patients with non-metastatic CRPC with PSA-only disease. Randomized trials are evaluating the benefit of adding docetaxel to androgen deprivation therapy (ADT) for metastatic and/or non-metastatic castration-sensitive prostate cancer (STAMPEDE and CHAARTED trials). Trials are evaluating docetaxel for patients with non-metastatic prostate cancer with high risk features such as PSA ≥20 ng/mL, Gleason ≥8, T2c disease or rapid PSA-doubling after prostatectomy, and after combination radiation and ADT (Table 1).
Table 1. Ongoing phase III trials evaluating docetaxel chemotherapy for earlier stages of prostate cancer†
|US Intergroup (CHAARTED)||Metastatic CSPC||ADT||ADT + D|
|European (STAMPEDE)||Metastatic or non-metastatic CSPC||ADT||ADT + D‡|
|Multicenter TAX-3503 trial||Non-metastatic biochemical CSPC with PSADT ≤9 months following prior prostatectomy||ADT||ADT + D|
|RTOG, Finnish§||Locally advanced prostate cancer||RT + ADT → ADT||XRT + ADT → ADT + (D + P)|
|US Veterans Affairs||Localized high-risk prostate cancer||Prostatectomy||Prostatectomy → D|
|European||Localized high risk with positive margin||Prostatectomy||Prostatectomy → D|
|US Intergroup||Localized high-risk prostate cancer||Prostatectomy||ADT + D → prostatectomy|
|NCIC||Localized high-risk prostate cancer||ADT → RT + ADT||D + ADT → RT + ADT|
|DFCI||Localized intermediate/high-risk prostate cancer||ADT → RT||D + ADT → RT|
|European (GETUG)||Localized high-risk prostate cancer||ADT → prostatectomy/RT||ADT + (D + EMP) → prostatectomy/RT|
Unfortunately, adjuvant mitoxantrone therapy after radical prostatectomy for high-risk localized prostate cancer induced an increase in acute leukemia in a randomized trial carried out by SWOG, leading to early closure of that trial.16 Another industry-sponsored trial that was comparing adjuvant versus delayed ADT with or without docetaxel was terminated prematurely as a result of poor accrual. Separate randomized trials in the US Veterans Affairs hospital system and Europe are evaluating the role of adjuvant docetaxel alone without ADT for patients with high-risk localized prostate cancer after radical prostatectomy. Trials are evaluating docetaxel and ADT versus ADT alone after radiation therapy (RT) in high-risk locally advanced patients (Table 1).
Combination docetaxel and ADT before local therapy (surgery or RT) is being evaluated in randomized phase III trials by several groups (Table 1). Neoadjuvant docetaxel has shown biological activity in localized prostate cancer (decreased tumor volume, decreased PSA, and altered tumor genomics and proteomics), but disappointingly no pathological complete remissions (pCR) have been observed.17–19 Neoadjuvant combination docetaxel and ADT has shown pCR in 3% (of 64 evaluable patients) and ≤5% tumor volume (including three with microfoci of tumor) in the prostatectomy specimens in a substantial proportion of patients.20
Emerging biological agents as monotherapy for prostate cancer
Agents targeting androgen receptor mediated signaling
Androgen receptor mediated signaling appears to continue to be an important driver of progression in prostate cancer previously thought to be castration-resistant.21 Abiraterone and MDV3100 target signaling through the androgen receptor (AR). Abiraterone acetate (Cougar Biotechnology, Los Angeles, CA, USA) inhibits 17α-hydroxylase and C17,20-lyase, and has been shown to decrease serum androgen to undetectable levels. Significant activity has been shown with abiraterone for progressive metastatic CRPC, both in chemo-naive patients or after ketoconozole or docetaxel treatment.22,23 A phase III trial is comparing placebo-prednisone/prednisolone with abiraterone-prednisone/prednisolone in patients progressing after docetaxel chemotherapy, and another placebo-controlled randomized trial is planned in the chemo-naive setting. MDV3100 is a small molecule that blocks nuclear translocation of AR and impairs both DNA binding to androgen response elements and recruitment of coactivators.24 Antitumor activity of MDV3100 was evaluated in a phase I/II trial of 140 patients, of whom 114 had been followed for >12 weeks.25 PSA declines >50% from baseline were observed at week 12 in 57% (37/65) of naive and 45% (22/49) of post-chemotherapy patients. Data suggested a dose-response trend, particularly in post-chemotherapy patients. At 12 weeks, radiographic control (no progression) was observed in 35/47 patients (74%) with evaluable soft tissue lesions. Maintenance of favorable CTC counts and conversion from unfavorable to favorable counts were observed in the majority of patients. The toxicity profile was favorable and a dose of 240 mg/day was recommended for further study. A phase III trial will compare placebo with MDV3100 in the second-line setting after 1–2 prior chemotherapeutic agents including docetaxel.
A number of different vaccines designed to boost and harness the immune response against prostate cancer are undergoing evaluation in clinical trials. Sipuleucel-T (Provenge, Dendreon, Seattle, WA, USA) is an immunotherapy cellular product consisting of autologous peripheral blood mononuclear cells enriched for a dendritic cell fraction pulsed with PA2024, a prostatic acid phosphatase (PAP)-GM- granulocyte macrophage-colony stimulating factor (CSF) construct. Patients with asymptomatic and metastatic chemo-naive CRPC were randomized in the D9901 trial to receive sipuleucel-T (n = 82) or a placebo (n = 45) every 2 weeks for three doses (Table 1).26 The vaccine produced prostate cancer specific immune response and the median survival was 25.9 months with sipuleucel-T compared with 22.0 months for placebo (P = 0.02). At 36 months, 33% of sipuleucel-T patients were alive, compared with 11% in the placebo group. However, the PSA response rate was poor and no improvement was observed in time to progression, the primary end-point. A second phase II trial (D9902A) with similar entry criteria failed to show an improvement in its primary end-point, but did show a trend in favor of the vaccine with respect to overall survival (a secondary end-point) according to a multivariate analysis that included baseline characteristics as covariates (hazard ratio27 1.91; P = 0.023). The two phase II trials were then combined in a meta-analysis which showed a 4.3 month improvement in survival in favor of the vaccine.28
The results of the phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial with sipuleucel-T were presented at the annual meeting of the American Urological Association (AUA) in 2009.29 The IMPACT trial randomized 512 men with asymptomatic chemo-naive metastatic CRPC in a 2:1 ratio to sipuleucel-T or placebo intravenous infusions every 2 weeks × 3 in a 2:1 ratio (Table 1). The median survival was 25.8 months with sipuleucel-T compared with 21.7 months with placebo, and the 3-year survival also improved significantly (31.7% vs 23.0%, P = 0.032). The treatment effect remained consistent after adjustment for docetaxel use after investigational therapy. Prostate cancer specific survival also favored the sipuleucel-T arm. However, there was no significant delay in the time to objective disease progression, suggesting that PFS might not be an optimal intermediate end-point with biological agents or agents with delayed activity. Toxicities were manageable, with chills reported in 54.1% of patients (vs 12.5% with placebo), fever in 29.3% (vs 13.7%), headache in 16.1% (vs 5%) and flu-like symptoms in 9.8% (vs 4.3%). Formal approval by regulatory agencies is anticipated based on these data. In addition, sipuleucel-T in combination with bevacizumab appears feasible and active in patients with castration-sensitive non-metastatic prostate cancer with PSA progression.30 Thus, the strategy of combining different classes of highly tolerable biological agents (without concomitant chemotherapy) appears viable, and deserves further evaluation.
GVAX is a vaccine composed of allogeneic prostate cancer cell lines (PC-3 and LNCaP) genetically modified to secrete GM-CSF. Stable or improved bone scans were observed with GVAX in 43% of 80 men in a phase I trial, and stable or decreasing osteolytic marker levels occurred in 62% of men.31 A phase III trial (VITAL-1) randomized 600 asymptomatic metastatic CRPC patients to GVAX or docetaxel/prednisone, whereas another trial (VITAL-2) recruited symptomatic patients to receive docetaxel/prednisone or docetaxel/GVAX. Disappointingly, preliminary analysis of the VITAL-2 trial showed a survival advantage for docetaxel/prednisone over GVAX/docetaxel.32 The study was prematurely terminated after accrual of 408 patients as the result of an imbalance in deaths, with 67 deaths in the GVAX/docetaxel and 47 deaths in the standard group. Overall survival was shorter in the GVAX group with median survival of 12.2 months versus 14.1 months (P = 0.0076). Therefore, the combination of vaccine therapy, in particular, and immunotherapy, in general, with chemotherapy warrants a more thoughtful approach. Novel combination approaches are ongoing. For example, a recent phase I trial showed promising efficacy for GVAX plus ipilimumab. Ipilimumab is a monoclonal antibody that targets CTLA-4, a negative immune regulatory checkpoint receptor on T lymphocytes and has shown single-agent activity.33,34 A placebo-controlled, randomized phase III trial is evaluating ipilimumab after radiotherapy for metastatic CRPC (with bone metastasis) after prior docetaxel. Another trial will evaluate docetaxel and predinisone plus ipilimumab as first-line therapy.
A recombinant vaccinia vector-based vaccine expressing PSA and costimulatory molecules (Prostvac®-VF) using a prime-boost approach in combination with GM-CSF has also shown activity in metastatic CRPC.35 In a recently reported double-blind, randomized phase II trial, 122 patients with chemo-naive metastatic CRPC, Gleason Score ≤7 and no visceral metastasis were treated with Prostvac®-VF or placebo in a 2:1 ratio.36 The primary end-point was PFS defined as two new lesions on bone scan or RECIST-defined progression. PFS was similar in the two groups (P = 0.56). Encouragingly, Prostvac patients showed a better median survival (24.5 vs 16 months, P = 0.016). Confirmation of these data in a phase III trial is planned in this setting. The vaccine will also be evaluated in earlier stages of non-metastatic CRPC by the Eastern Cooperative Oncology Group (E1805, Paradigm) in a phase III trial of Prostvac®/GM-CSF versus GM-CSF.
Small-molecule vascular endothelial growth factor targeting tyrosine kinase inhibitors
Given that angiogenesis and vascular endothelial growth factor (VEGF) have established roles in driving the progression of prostate cancer, several anti-angiogenic molecules are being evaluated.37,38 Significant activity was shown when using sunitinib (50 mg daily for 4 of 6 weeks) after prior docetaxel, which has led to a phase III trial comparing placebo-prednisone with sunitinib-prednisone in the second-line setting.39,40 However, toxicities led to frequent discontinuation of therapy in the phase II trial and therefore a smaller dose (37.5 mg daily) is being evaluated in the ongoing phase III trial. The combination of docetaxel and sunitinib has also been evaluated in a phase I/II trial and appears feasible and active.41 Other VEGF targeting tyrosine kinase inhibitors (TKI; sorafenib) have also shown modest single agent activity.42–44
Endothelin receptor antagonists
Vasoconstricting peptides called endothelins (ET-1) and their receptors (ETA and ETB) have been implicated in the pathophysiology of advanced prostate cancer including the genesis of osteoblastic bone metastases.45 Atrasentan is an orally administered ETA receptor antagonist that reduces bone metabolism markers in patients with CRPC. A multinational, double-blind, placebo-controlled trial enrolled 809 men with metastatic CRPC (bone metastasis was not mandated) to receive either atrasentan 10 mg per day or a placebo.46 The primary end-point was time to disease progression according to radiographic and clinical measures. The study was closed early by a monitoring committee after reviewing an unexpectedly high number of early progressions, suggesting that atrasentan would not benefit when compared with controls. Atrasentan did not reduce the risk of disease progression relative to placebo (hazards ratio 0.89; 95% confidence interval 0.76–1.04; P = 0.136). Most patients progressed radiographically at the first 12-week bone scan without concomitant clinical progression. In exploratory analyses, increases from baseline to final bone alkaline phosphatase (BAP) and PSA levels were significantly lower with atrasentan treatment (P < 0.05 for each). The median time to BAP progression (50% increase from nadir) was twice as long with atrasentan treatment (505 days vs 254 days; P < 0.01). The delay in time to PSA progression did not reach statistical significance. Thus, atrasentan did not delay disease progression in men with metastatic CRPC despite evidence of biological effects on PSA and BAP as markers of disease burden. The SWOG is carrying out a randomized phase III study evaluating docetaxel plus prednisone with or without atrasentan in men with bony metastatic disease (Table 2). A similar phase III trial is evaluating ZD4054, a novel ET-A receptor antagonist, with docetaxel in CRPC.47 A randomized phase II trial showed improved survival for ZD4054 compared with placebo in chemo-naive men with metastatic CRPC who were relatively asymptomatic. The relative enrichment of the ZD4054 study population for patients with bone metastasis might have facilitated the detection of an improved outcome, as opposed to the atrasentan trial that enrolled patients with soft tissue and/or bone metastasis.46
Table 2. Ongoing phase III trials evaluating docetaxel in combination with biological agents as frontline therapy for metastatic castration-resistant prostate cancer†
|MDACC‡||Bone targeting radiopharmaceutical||D + P or KAVE → no consolidation||D + P or KAVE → consolidation strontium|
|SWOG‡||Endothelin receptor||D + P + placebo||D + P + atrasentan|
|Industry||Endothelin receptor||D + P||D + P + ZD4054|
|Industry||VEGF, PlGF||D + P||D + P + aflibercept|
|CALGB||VEGF||D + P||D + P + bevacizumab|
|Industry||Src, Kit, PDGFR||D + P||D + P + dasatinib|
|Industry||Angiogenesis, immune mechanism||D + P||D + P + lenalidomide|
|Industry||CTLA-4||D + P||D + P + ipilimumab|
|Industry||IGF-1R||D + P||D + P + cixutumumab|
Agents targeting osteoclast mediated bone lysis
Bisphosphonate therapy with zoledronic acid is an integral component of therapy for CRPC with bone metastasis. Zoledronic acid significantly decreases skeletal-related events and is an important adjunct to docetaxel and other systemic agents.48 Bone destruction is mediated by osteoclasts, whose function requires the receptor activator of NF-κB ligand (RANKL).49 Preclinical models of both osteolytic and/or osteoblastic bone metastases showed that cancer cells induce increased RANKL expression and decreased the level of the RANKL inhibitor, osteoprotegerin expression (endogenous RANKL inhibitor) by osteoblasts.50 Denosumab is a fully human monoclonal antibody that specifically inhibits RANKL and osteoclast-mediated bone destruction. In a randomized phase II trial of patients with various carcinomas or myeloma with bone lesions and elevated urinary N-telopeptide (uNTx) levels (an osteolysis marker) despite ongoing intravenous bisphosphonate therapy, denosumab normalized uNTx levels more frequently than the continuation of bisphosphonates.51 Additionally, fewer patients receiving denosumab experienced skeletal events and this agent might have a more favorable toxicity profile. An ongoing phase III double-blinded study of denosumab versus zoledronic acid for patients with CRPC and bone metastases is ongoing with an objective of showing non-inferiority.
Anti-angiogenic monoclonal antibodies
A trial by the Cancer and Leukemia Group B (CALGB) reported promising activity in CRPC with the combination of docetaxel, estramustine and bevacizumab.52 Seventy-nine patients were enrolled and 9 of 17 evaluable patients showed a partial radiographic response (53%). Of 20 patients evaluable for PSA decline, 65% had a confirmed PSA response. Based on this preliminary observation, the CALGB has completed accrual to a phase III trial comparing docetaxel plus prednisone with docetaxel/prednisone/ bevacizumab (Table 2). The combination of thalidomide and bevacizumab with docetaxel (with concurrent anticoagulation) was preliminarily associated with a high 50% PSA decline rate (90%) and objective response rate in measurable disease (64%), with osteonecrosis of the jaw and neuropathy being the most significant grade 2 toxicities.53 VEGF-trap is an engineered soluble receptor made from extracellular domains of VEGFR1 and VEGFR2 that binds to all isoforms of VEGF and placental growth factor (PlGF) with markedly higher affinity than bevacizumab.54 The VENICE phase III trial is similarly evaluating the value of adding VEGF-trap to docetaxel chemotherapy (Table 2).
Thalidomide and lenalidomide
Preclinical data support thalidomide's role as an inhibitor of prostate cancer.55 Thalidomide produced PSA responses in 18% of patients with CRPC.56 In another phase II trial, patients with chemotherapy-naive metastatic CRPC were assigned to receive standard docetaxel and prednisone (n = 60) with or without thalidomide 200 mg orally daily.57 In a recent update, an improvement in 18-month survival was observed (69.3% vs 47.2%, P < 0.05). However, the toxicities of thalidomide (especially neurotoxicity) and the need for routine prophylactic anticoagulation render it a difficult agent to administer and further develop in combination with docetaxel. Lenalidomide is a more tolerable immunomodulatory thalidomide analogue that appears active and administration is also feasible in combination with ketoconazole or docetaxel.58,59 The Mainsail phase III trial will evaluate frontline docetaxel/prednisone alone or in combination with lenalidomide for men with metastatic CRPC.
Targeting survival pathways
The anti-apoptotic regulatory protein, bcl-2, represents an attractive molecular target because increased bcl-2 expression occurs in CRPC and might mediate resistance to chemotherapy.60 In a phase I/II trial of a combination of docetaxel and oblimersen sodium (bcl-2 antisense oligonucleotide), PSA responses were observed in 14 of 27 (52%) patients, whereas 4 of 12 (33%) patients with bidimensionally measurable disease had objective responses.61 The median survival of all patients was 19.8 months. The EORTC (European Organization for Research and Treatment of Cancer) reported a randomized phase II trial comparing docetaxel to docetaxel plus oblimersen sodium.62 A total of 115 patients were randomized to docetaxel 75 mg/m2 every 3 weeks with or without oblimersen by continuous infusion for 7 days repeated up to 12 cycles. Unfortunately, no significant improvements were noted in PSA and measurable disease response rates, which was presumed to be due in part to the highly advanced patients enrolled in this trial with a substantial proportion having received prior EMP (23–26%). Novel small molecule, orally administered compounds that inhibit the bcl-2 family, for example AT-101 (Ascenta Therapeutics, Malvern, PA, USA), preliminarily appear active as monotherapy. Additionally, AT101 was feasible in combination with docetaxel and the addition of AT101 to docetaxel-resistant CRPC yielded responses.63,64 A randomized phase II trial is comparing docetaxel/prednisone with docetaxel/prednisone plus AT-101 (Table 2).
Monoclonal antibodies against tumor-associated antigens
Prostate cancer is well suited to therapy with monoclonal antibodies targeting antigens specific for prostate tissue and tumors. Prostate-specific membrane antibody (PSMA) is a cell-surface glycoprotein expressed in both benign and malignant prostate tissue. J591, an anti-PSMA antibody, binds the extracellular PSMA epitope and has been de-immunized by engineering it into a human immunoglobulin G1. In a phase I trial, 35 patients with progressing CRPC received (177) Lu-J591 (radionuclide 177-Lutetium-labeled J591).65 Biological activity was seen with four patients experiencing PSA responses lasting from 3 to 8 months. In another phase I trial, 29 patients with CRPC received (90) Y-J591 (yttrium-90-labeled J591).66 Antitumor activity was seen, with two patients experiencing 85% and 70% declines in PSA lasting 8 and 8.6 months in association with objective responses. Further studies are underway to refine the agent and evaluate activity.
Monoclonal antibodies against the epidermal growth factor receptor (EGFR) family that are generally over-expressed in epithelial malignancies include trastuzumab (anti-HER2) and cetuximab (anti-EGFR). In a phase II trial that attempted to evaluate trastuzumab in selected patients, HER-2 overexpression by immunohistochemistry (IHC) in archival prostate carcinoma specimens was too infrequent to justify continuing accrual.67 Pertuzumab is a monoclonal antibody that binds to HER2 and sterically inhibits dimerization with other HER receptors. Unfortunately, this agent, failed to show activity in a phase II trial of a population not enriched for HER-2 expression.68 In patients with progressive metastatic CRPC after prior docetaxel, a randomized phase II trial is comparing MP with MP plus cetuximab, a monoclonal antibody that targets EGFR (Table 2). The insulin-like growth factor (IGF) and its corresponding receptor (IGF-1R) appear to be associated with the androgen-independent progression of prostate cancer. Humanised monoclonal therapeutic antibodies against IGF-1R (e.g. CP751 871 and cixutumumab) are being evaluated in clinical trials and small molecule orally administered IGF-1R inhibitors are also emerging.69,70 A randomized, phase II trial of docetaxel with or without CP-751 871 has been conducted. A phase III trial is planned to compare docetaxel-prednisone with or without cixutumumab.
TKI targeting non-VEGF receptor tumor targets
Gefitinib has shown no significant activity against metastatic CRPC.71,72 Erlotinib has been reported to slow the rate of PSA doubling and appears feasible to administer in combination with docetaxel.73,74 Lapatinib, a dual EGFR and HER-2 TKI, appears to have a modest level of activity in unselected patients.75 Dasatinib is a TKI that targets the Src-family of kinases, which are overexpressed in CRPC and induce proliferation and migration, as well as osteoclastic bone destruction.76–78 A phase II trial in patients with metastatic CRPC preliminarily reported modest activity.79 A randomized phase III trial is comparing docetaxel-prednisone alone or in combination with dasatinib (Table 2).
Clusterin anti-sense oligonucleotide
The clusterin gene encodes a cytoprotective chaperone protein and custirsen is a second-generation anti-sense oligonucleotide (ASO) targeting human clusterin mRNA that has preclinically reversed docetaxel resistance. Custirsen appears feasible to administer alone or in combination with docetaxel.80,81 A randomized phase II trial of frontline docetaxel/prednisone with or without custirsen showed enhanced outcomes with a median survival of 16.9 months for docetaxel and 27.5 months for docetaxel–OGX-011.82 Another randomized phase II trial of custirsen in combination with either docetaxel/prednisone or mitoxantrone/prednisone as second-line therapy for progressive disease within 3 months after prior docetaxel was recently reported. This study showed that in patients who progressed during or soon after first-line docetaxel, both custirsen regimens were well tolerated and associated with PSA and pain responses, and ‘better than expected’ overall survival.83 Custirsen/docetaxel/prednisone appeared superior in both efficacy and safety with overall survival from start of second-line therapy being 14.7 months and survival from start of first-line therapy being 30.4 months compared with mitoxantrone/prednisone/custirsen which had 11.4 months and 23.5 months survival, respectively. A phase II frontline study is planned utilizing docetaxel/prednisone plus custirsen.
The beta-emitting radioisotopes 89strontium and 153samarium have been used to relieve pain in men with multiple sites of symptomatic bone disease or those who are not candidates for external beam radiation therapy.84,85 One randomized phase II trial showed an improvement in outcomes by combining strontium with the KAVE chemotherapy regimen.86 A combination of docetaxel and samarium appeared feasible and active in recent trials.87–89 Trials are evaluating the value of consolidation with strontium after prior chemotherapy in men with metastatic CRPC and bone disease (Table 2). The alpha-emitter radium-223 is a bone-seeking radionuclide that was studied in a placebo-controlled randomized, multicenter, phase II trial. Therapy was highly tolerable and the median overall survival was 65.3 weeks for Ra-223 and 46.4 weeks for placebo (P = 0.066, log rank). A significant favorable biological effect on bone alkaline phosphatase was also observed. A larger international placebo-controlled randomized phase III clinical trial is ongoing in patients with untreated or docetaxel-treated metastatic CRPC with bone metastases.
Other biological agents
At supraphysiological concentrations, calcitriol exerts significant antiproliferative activity and enhances the activity of chemotherapy in preclinical models of prostate cancer by an incompletely understood mechanism.90 Thirty-seven patients were treated with oral calcitriol (0.5 µg/kg) on day 1 followed by docetaxel (36 mg/m2) on day 2, repeated weekly for 6 weeks of an 8-week cycle.91 Thirty of 37 patients (81%) achieved a PSA response and the median survival was 19.5 months. A randomized phase II trial (ASCENT) of 250 patients compared weekly docetaxel plus placebo with docetaxel plus high-dose calcitriol (DN-101 45 mcg orally) given a day before docetaxel (Table 1).27 The combination yielded an improvement in median survival (23.5 vs 16.4 months, P = 0.035), but no improvement in the primary end-point of PSA response (63% vs 52%, P = 0.07). Unfortunately, the subsequent confirmatory phase III trial (ASCENT-2) was halted after an interim analysis showed no improved outcome with DN-101.92
Enzastaurin is an oral serine/threonine kinase inhibitor that suppresses signaling through the protein kinase C (PKCbeta/PI3K/AKT) pathways and induces apoptosis, reduces proliferation and suppresses angiogenesis.93 A randomized phase II trial is comparing docetaxel alone with docetaxel plus enzastaurin for advanced CRPC (Table 2). Preclinical data suggest that PTEN-negative prostate cancer cells that show an activated PI3K/Akt/mTOR pathway are susceptible to temsirolimus, an mTOR inhibitor.94 Everolimus is another novel mTOR inhibitor that appears active preclinically in combination with docetaxel and zoledronic acid, and clinical evaluation might be warranted in appropriately selected patients.95 Epigenetic therapy with demethylating agents appears promising and preclinically activated repressed genes, and enhanced the sensitivity to docetaxel.96 Azacitidine favorably modulated PSA kinetics in men with chemo-naive CRPC in one trial, and the addition of azacitidine to docetaxel is being evaluated in another phase I/II trial to reverse resistance to docetaxel.97
Docetaxel remains the only agent that definitively extends survival and is approved by regulatory agencies for patients with metastatic CRPC. In addition, it provides palliative benefits. However, the benefits are limited and consolidation of these modest gains is necessary. Efforts are ongoing to further improve outcomes by combining the platform of docetaxel with one of the panoply of emerging novel biological agents, notably bevacizumab, aflibercept, atrasentan and ZD4054 are in phase III trials (Table 2). A thoughtful approach is warranted and a combination of the most tolerable biological agents with docetaxel should be pursued, given this elderly population with multiple comorbidities. Furthermore, the lack of demonstrable improvement in outcomes with the combination of some biological agents (e.g. DN101, GVAX) with docetaxel is sobering and further development of combination therapy should proceed thoughtfully before launching large and expensive phase III trials. Additionally, management decisions will soon need to take into account the sequencing of docetaxel with several emerging agents with substantial single agent activities that are expected to be approved in the near future. Sipuleucel-T extended survival in the relatively asymptomatic chemo-naive setting and approval is expected. Other novel agents with substantial single-agent activity are undergoing phase III evaluation in the chemo-naive or second-line settings (e.g. abiraterone, MDV3100) and might also add to the therapeutic armamentarium. Given the significant heterogeneity inherent to the disease, a better understanding of the molecular biology is critical and might lead to focused development of agents in specific subpopulations. Additionally, the role of docetaxel chemotherapy for earlier stages of prostate cancer is being evaluated. Further advances are possible by an improved understanding of the biology of prostate cancer and rational drug development in appropriate subpopulations.