Experimental Agents for Patients With CRPC Who Progress Despite Approved First- & Second-line Treatments
There are currently over 20 different experimental agents under investigation for efficacy in treating CRPC. This section reviews the mechanism of action of a wide variety of modalities, the findings of recent studies utilizing those agents, and which trials are ongoing. Table 3 includes the findings from three of the most promising experimental agents for the treatment of CRPC.
Cytotoxic (Chemotherapeutic) Agents
Epothilones The epothilones, which include the drugs ixabepilone and patupilone, are a new class of cytotoxic chemotherapy agents with a mechanism of action similar to that of the taxanes but more resistant to drug efflux pumps (similar to cabazitaxel). Ixabepilone and patupilone have recently been evaluated in Phase II clinical trials to determine their efficacy as second-line agents in treating patients with metastatic CRPC. PSA declines of ≥50% ranged from 45 to 47% of patients and median overall survival from 11.3 to 12.5 months.[55,56] The most common side effects experienced by patients given ixabepilone included leukopenia and neutropenia, while those given patupilone most commonly experienced diarrhea and fatigue. Currently, there are numerous ongoing Phase II trials looking at the efficacy of epithilones as an adjuvant to radiotherapy and as a second-line therapy for CRPC patients.
Satraplatin Satraplatin (Spectrum Pharmaceuticals, NV, USA) is an orally formulated platinum analog. Preclinical data suggested that the drug has anti-tumor activity in human prostate cancer, including several cell lines resistant to other chemotherapy agents. One Phase II trial indicated that the drug had significant hematological toxicities (neutropenia, lymphopenia and thrombocytopenia) requiring dosage decreases and permanent discontinuation in patients. An international, double-blind Phase III trial of satraplatin and prednisone versus prednisone found a small, but statistically significant difference in median progression-free survival (11.1 vs 9.7 weeks for the experimental and control groups, respectively) but no increase in overall survival. As a result of these findings, the drug was not approved by the FDA. However, given its relative ease of administration (oral), potential lack of cross resistance with other platinum-based chemotherapy agents, and success in early clinical studies, there are still clinical trials actively recruiting patients with metastatic CRPC who have failed docetaxel-based chemotherapies.
MDV3100 MDV3100 (enzalutamide, Medivation, CA, USA) is a small molecule, nonsteroidal, AR antagonist that blocks nuclear translocation and coactivator recruitment, prevents DNA binding, induces apoptosis and does not act as an AR agonist when AR is overexpressed.[59,60] Unlike bicalutamide and other current antiandrogen drugs, these experimental drugs are pure AR antagonists without any cancer-stimulating effects. In preclinical trials, MDV3100 was found to have a five- to eight-fold greater affinity for the AR compared with bicalutamide. Additionally, the compound was found to decrease PSA levels, suppress growth and induce apoptosis of cells in a human prostate cancer cell line.
In a Phase I/II clinical trial in which 140 patients with progressive metastatic CRPC were administered MDV3100 daily, the agent demonstrated anti-tumor effects at all administered dosages. Serum PSA dropped >50% from baseline in 56% of subjects (62 and 51% in chemonaive and postchemotherapy patients, respectively) by week 12. Additionally, many patients experienced soft tissue disease regression and no progression of bone disease. Median time to radiological progression was 47 weeks in all patients combined. Common side effects were mild and included fatigue, nausea, constipation, diarrhea and anorexia. The most serious side effect was seizures, occurring in two patients both taking doses ≥360 mg/day.
Overall, MDV3100 is a potent antiandrogen with advantages over current AR antagonists. There is currently one ongoing Phase III clinical trial (PREVAIL) for chemotherapy-naive patients. A second Phase III clinical trial (the AFFIRM trial), which sought to determine the effectiveness of MDV3100 in patients previously treated with docetaxel, was halted in November 2011 after an interim analysis revealed that patients given the drug lived approximately 4.8 months longer than those given placebo (18.4 vs 13.6 months), experienced a 5.4-month greater progression-free survival, and 54% of patients given the drug saw a PSA decrease of ≥50% compared with 1.5% in the placebo group. These favorable results, coupled with the fact that the drug can be administered once a day orally, make MDV3100 a promising drug for the treatment of CRPC in patients who have previously failed chemotherapy and hormone therapy. FDA approval for the drug is expected in 2012.
TAK-700 Similar to AA, TAK-700 (orteronel, Millennium Pharmaceuticals, MA, USA) is a highly selective oral inhibitor of the CYP17A1 enzyme C17,20-lyase. The Phase I data of a Phase I/II study was encouraging. All patients given ≥300 mg twice daily experienced decreases in PSA, and 80% of those patients had ≥50% PSA reductions from their baselines. The most common side effects were fatigue, nausea, constipation, anorexia and vomiting. Two Phase III trials are actively recruiting. One is comparing TAK-700 and prednisone with placebo and prednisone in chemotherapy-naive patients with metastatic CRPC, while the other is comparing the same regimen in patients who have progressed despite previously receiving docetaxel-based chemotherapy.
VT-464 Similar to TAK-700 and AA, VT-464 is a CYP17A1 protein inhibitor that blocks two distinct enzyme activities: C17,20-lyase and 17α-hydroxylase. VT-464, which is still in early trial stages, has a fourfold greater affinity for C17,20-lyase than 17α-hydroxylase as compared with AA. One research team compared the percentages of tumor growth inhibition in mice containing androgen-sensitive human prostate adenocarcinoma cell lines treated with castration, VT-464 or AA. They found that VT-464-treated mice had significantly reduced tumor volume ratios (V/V0) compared with those given AA, but these ratios were comparable to the mice receiving castration. Given VT-464's higher selectivity for enzymes involved in prostate cancer cell proliferation and favorable animal studies, VT-464 may become a viable alternative or replacement for AA.
A number of characteristics of prostate cancer make immunotherapy a promising approach. Since prostate cancer is a relatively indolent cancer, this may allow the immune system, when stimulated, sufficient time to generate an anti-tumor response. It was recently discovered that prostate cancer has an ability to induce the formation of autoantibodies in patients, which suggests that prostate cancer is more immunogenic than originally understood.[67–69]
PROSTVAC PROSTVAC (Bavarian Nordic, Kvistgård, Denmark) is a therapeutic PSA-targeted cancer vaccine consisting of either fowlpox or vaccinia vectors. It is administered subcutaneously to induce a targeted immune response against prostate cancer tumor cells.[22,69] In a Phase II randomized-controlled trial that included 125 CRPC patients with metastatic disease, the investigational group that had received the vaccine experienced a significantly longer median overall survival of 8.5 months (25.1 vs 16.6 months) compared with patients in the placebo group (p = 0.006). The vaccine (regardless of vaccina or fowlpox vector composition) was generally well tolerated; the most common adverse events were injection-site reactions, with a subset of those patients going on to develop systemic side effects including fatigue, fever, chills, nausea and peripheral edema. The data from this trial provide the initial evidence that the vaccine induces anti-tumor activity, but larger Phase III randomized control trials need to be conducted to confirm the efficacy of this agent. PROSTVAC is currently being developed through a collaborative effort by Bavarian Nordic ImmunoTherapeutics and the National Cancer Institute.
Ipilimumab Ipilimumab (Yervoy™, Bristol-Myers Squibb, NY, USA) is a T-cell potentiator that works by blocking the cytotoxic T-lymphocyte antigen-4 (CTLA-4) found on T cells from interacting with B7 on antigen-presenting cells, thereby subsequently blocking the inhibitory modulation of T-cell activation promoted by the CTLA-4/B7 interaction. Ipulimumab has been studied in several Phase I trials containing small subsets of patients with metastatic CRPC. In the most recent study, three of the six patients on the highest dose of the drug (3 mg/kg) had a PSA response of ≥50% and one developed a near-complete radiological response.[70,71] There is currently an ongoing multicenter Phase III trial investigating whether or not there is a survival benefit for chemotherapy-naive metastatic CRPC patients who are given ipilimumab versus placebo. Ipilimumab was FDA approved in March 2011 for the treatment of unresectable or metastatic melanoma.
Angiogenesis is vital for growth and metastasis of solid tumors. Plasma levels of VEGF, a marker of angiogenesis, have been correlated with lymph node metastasis, biochemical progression and survival time of patients with prostate cancer.[72,73] Additionally, VEGF levels are significantly higher in patients with metastatic disease compared with patients with localized prostate cancer. These findings have served as the impetus to develop therapeutic agents that target and block VEGF signaling.
Bevacizumab Bevacizumab (Avastin®, Genentech, CA, USA) is a recombinant humanized monoclonal antibody that inhibits VEGF. Numerous Phase II trials have shown improved overall survival when bevacizumab is added to docetaxel-based regimens, some of which include thalidomide and estramustine. A Phase III study comparing docetaxel and prednisone with or without bevacizumab in over 1000 chemotherapy-naive men with metastatic CRPC reported a statistically significant 2.4-month improvement in progression-free survival but no improvement in overall survival for patients receiving bevacizumab. Additionally, grade ≥3 toxicities were more commonly experienced by patients receiving bevacizumab and included neutropenia (30%), fatigue (18%) hypertension (7%) and gastrointestinal hemorrhage (6%), and there was a higher number of treatment-related deaths in patients receiving bevacizumab. This large Phase III trial has reinforced the notion that bevacizumab is not an effective treatment agent for metastatic CRPC.
Aflibercept Aflibercept (Zaltrap™, Sanofi-Aventis, NJ, USA and Regeneron Pharmaceuticals, NY, USA) is a soluble form of human VEGF receptor that binds all isoforms of VEGF, thereby preventing angiogenesis. Although there are no Phase I/II trials conducted on patients with prostate cancer, a prior study in patients with solid tumors found that 20 of the 38 patients in the study maintained stable disease for ≥1 month and two of those patients had stable disease for >1 year. The drug was generally well tolerated as grade ≥3 side effects were uncommon and reversible. They included dehydration, pulmonary embolism, hypertension, leukopenia and cerebral ischemia. There is an ongoing double-blinded Phase III trial that is looking at the difference in overall survival in patients given aflibercept versus placebo in patients with metastatic CRPC receiving docetaxel and prednisone.
Tasquinimod Tasquinimod is an orally administered antiangiogenic drug that has a demonstrated ability to inhibit tumor growth in human prostate cancer models. It is believed to work by upregulating an endogenous angiogenesis inhibitor, thrombospondin-1. In a double-blind, placebo-controlled Phase II trial of 201 men with minimally symptomatic metastatic CRPC, men given tasquinimod had a significantly longer progression-free survival compared with patients given placebo (7.6 vs 3.3 months; p = 0.0042). The most common side effects were gastrointestinal disorders, fatigue and musculoskeletal pain. Grade 3/4 toxicities were rare but serious, including deep vein thrombosis (4%) and myocardial infarction (1%). A Phase III trial is currently recruiting men with asymptomatic or minimally symptomatic metastatic CRPC to compare tasquinimod and placebo.
XL-184 XL-184 (cabozantinib, Exelixis, CA, USA) is an oral, potent inhibitor of VEGF and c-MET, a proto-oncogene that encodes HGF and is known to give rise to invasive cell growth and metastasis. One Phase II trial, including subjects with CRPC, randomized patients to receive XL-184 or placebo for 12 weeks. At the end of the therapy, disease control was seen in 68% of patients, 86% of patients had complete or partial resolution of bony metastases based on bone scan and 64% had improved pain control. The trial was so successful that randomization was halted and patients were unblinded due to bone scan resolution and pain relief. Side effects (grade ≥3) included fatigue (11%) and hypertension (7%). Although few clinical trials have been completed and progression-free survival data are not available, early data suggest that XL-184 has a palliative effect on patients with CRPC with bony metastases.
Tyrosine Kinase Inhibitors Sorafenib (Nexavar®, Onyx Pharmaceuticals, Inc., CA, USA and Bayer HealthCare Pharmaceuticals, Inc., NJ, USA), dasatinib (Sprycel®, Bristol-Myers Squibb, NY, USA) and sunitinib (Sutent®, Pfizer, NY, USA) are small molecule inhibitors of several tyrosine kinases (TKIs) including VEGF receptors. In a Phase II clinical trial of 39 patients with chemotherapy-naive CRPC given sorafenib and bicalutimide (an AR blocker), 32% of patients experienced a PSA decline of ≥50% and median time to treatment failure was 5.5 months. The most common adverse effects were fatigue, gastrointestinal complaints and musculoskeletal pain. This study helps to make the case that sorafenib, in combination with antiandrogen therapy, may become an accepted therapy for patients with CRPC in the future.
Early Phase II studies on dasatinib have also been encouraging. One study involving chemotherapy-naive men with CRPC and increasing PSA given daily dasatinib trended the alkaline phosphatase and urinary N-telopeptide levels (uNTX) throughout the trial. uNTX is a type I collagen biomarker that correlates with the presence and extent of bone metastases, and whose levels were found to be directly related to risk of death in an earlier study. After 15 weeks of daily administration of dasatinib, 60% of patients experienced decreased alkaline phosphatase and 80% had a decrease in uNTX levels. A second Phase II trial including a similar patient population obtained similar promising results and noted that the drug was well tolerated. Early results from combining dasatinib with docetaxel have been positive: a Phase I/II trial found that 30% experienced disappearance of bone lesion on bone scan and 57% of patients had PSA decreases ≥50%. There is currently an ongoing Phase III trial looking into the effects of combining dasatinib with docetaxel on overall survival, progression-free survival, PSA and other markers.
Results from clinical trials of sunitinib have not been as positive. A Phase III trial that included men with CRPC pretreated with docetaxel who were given either sunitinib and prednisone or prednisone was terminated prematurely when an interim analysis found that the combination therapy was unlikely to improve survival over prednisone alone. Other trials have reported that the drug caused severe drug reactions, leading to >50% of subjects to withdraw from the trial.
Radium-223 Radium-223 (Ra223; Alpharadin®, Algeta ASA, Oslo, Norway and Bayer Pharmaceuticals, NJ, USA) is the newest radioisotope under investigation. A randomized Phase II trial that included patients with CRPC and bone pain found that patients given Ra223 had a 65.6% decline in bone alkaline phosphatase while those in the placebo group had a 9.3% increase. Patients receiving Ra223 also had improved overall survival (65.3 vs. 46.4 weeks). Data from the ALYMPCA Phase III trial that included men with CRPC and bone metastases are overwhelmingly positive: patients receiving radium-223 experienced a prolonged time to first SRE and a significantly improved overall survival of 5.1 and 2.8 months, respectively, compared with placebo. It was also very well tolerated, with consistently lower adverse event rates compared with placebo.[91,92] The improved overall survival seen in these patients puts this drug in the category of agents that can be used in docetaxel-failure patients, which includes AA, cabazitaxel and possibly MDV3100 (pending FDA approval). Furthermore, since it is also effective at delaying the onset of SREs, it may become the new standard of care for treatment of CRPC in patients with bony metastases. Due to overwhelming success, the trial was terminated early and the company is filing for a new drug application.
Expert Rev Anticancer Ther. 2012;12(7):951-964. © 2012 Expert Reviews Ltd.