ABSTRACT: Prostate cancer will be diagnosed in one of six men during their lifetimes, and a small portion of these will progress after primary and salvage therapies. For many years, there were few treatment options for these patients after routine hormonal maneuvers, and standard of care since the early 2000s has consisted primarily of docetaxel(Drug information on docetaxel), which improved survival over the previous first-line therapy mitoxantrone(Drug information on mitoxantrone). In recent years, however, new therapies have begun to emerge to treat this devastating form of prostate cancer. This review examines the mechanisms behind these therapeutics and the key trials seeking to validate their clinical use.
Treatment of metastatic, hormone-refractory prostate cancer has posed a significant challenge for urologists and oncologists given the paucity of available treatments in this setting. Prior to the early 2000s, mitoxantrone was considered approved for use in prostate cancer on the basis of improved quality of life measures in men with progression of disease in spite of castrate levels of androgens which drive prostate cancer growth. Docetaxel later displaced mitoxantrone as the first-line chemotherapy of choice, offering increased overall survival by a few months and additional palliative benefits over mitoxantrone. Other therapies have also been described, but without a clear survival advantage, leaving clinicians with few other effective medical options for advanced disease. In the last decade, however, a renaissance in our understanding of the molecular mechanisms associated with castration-resistant prostate cancer (CRPC) has led to the emergence of several new treatment options for men with advanced prostate cancer, ranging from immunotherapies to a new generation of androgen receptor (AR)-targeted therapies. This review will examine five emerging therapies for CRPC, detailing the molecular basis for their activity and describing the clinical trials supporting their potential use in this setting.
In the late 1990s, researchers began to investigate the concept of tumor-specific immunity, whereby an immune response is stimulated in order to target tumor cells for destruction. This idea was applied to the development of sipuleucel-T (Provenge). In the course of treatment with Provenge, the patient’s antigen-presenting cells (APCs, specifically dendritic cells) are collected via leukapheresis and then loaded ex-vivo with a fusion protein consisting of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF). After culturing this fusion protein with the dendritic cells, the product is then re-infused into the patient, activating T-cells via class I and class II HLA molecules and resulting in a beneficial immune response against PAP.
In a phase I-II trial, 31 patients were treated with sipuleucel-T. The phase I portion examined patient response to dose escalation in three tiers of patients with metastatic CRPC, all of whom had undergone androgen deprivation with androgen blockade and subsequent antiandrogen withdrawal. The most common adverse reactions were fever, myalgia, and mild urinary complaints. Only three patients were noted to have had a prostate-specific antigen (PSA) decline of ≥ 50% from baseline, despite all patients exhibiting a measurable immune response to the fusion protein and 38% developing an immune response specific to PAP. While some patients demonstrated a clear clinical response in the form of a significant drop in PSA, the authors noted that PSA may not be a valid indicator of meaningful anticancer activity for immune-based therapies as future trials would eventually demonstrate.
A second phase II trial of sipuleucel-T in 21 patients with metastatic CRPC was conducted and resulted in a similar overall lack of effect on PSA levels. However, one patient exhibited a potent, durable biochemical response, with PSA falling from 221 ng/mL to undetectable and sustaining these levels for more than four years. To address the potential inadequacy of PSA as a measure of meaningful clinical activity, investigators altered the definition of “progression” from a biochemical change (in PSA level), to objective enlargement of soft tissue disease or the appearance of two or more new lesions on radionuclide bone scan. Using this new definition, median time to progression was 118 days.
A phase III trial enrolled 127 asymptomatic men with metastatic CRPC randomized in a 2:1 ratio to receive either sipuleucel-T or placebo. The trial was designed to measure a primary outcome of time to progression (defined as pathologic fracture, spinal cord compression, new-onset pain associated with metastasis, two or more lesions on bone scan, or > 50% increase in measurable cancer burden). Overall, there was no significant difference in time to progression between the two treatment arms, but there was a 4.5 month improvement (P = .01) in overall survival in the sipuleucel-T arm. However, because this study was not originally designed to detect an increase in overall survival, more evidence was requested to support its use in men with CRPC when initially evaluated by the FDA for approval in 2007.
To bolster proof of clinical efficacy, investigators proceeded with a second phase III, double-blind, placebo-controlled, multicenter trial of sipuleucel-T that was designed to measure its effect on overall survival, and the results were published in July 2010. In this trial, 512 patients were randomized in a 2:1 ratio to receive either sipuleucel-T or placebo. The study detected a 4.1-month improvement in overall survival over placebo, despite allowing 109 of 171 patients in the placebo group to cross over and receive salvage sipuleucel-T (prepared and cryopreserved at the time of placebo preparation). Adverse events in the treated group were primarily limited to fever, chills, and headache at or near the time of the infusion. Similar to previous studies, there were no differences in the time to disease progression (measured radiographically at 6, 14, 26, 34 weeks and every 12 weeks thereafter) between the two groups.
Investigators attributed the discordance between the observed survival benefit and the lack of effect on disease progression to a possible class effect, as a similar phenomenon has been reported in a study on poxviral-based PSA-targeted immunotherapy (PROSTVAC-VF). Similarly, other studies of metastatic CRPC have shown a lack of correlation between disease progression and overall survival.[4,7] Sipuleucel-T was approved by the FDA in April of 2010 for the treatment of metastatic CRPC which is asymptomatic or minimally symptomatic.
The use of androgen-deprivation therapy (ADT), either medically or surgically, is associated with clear metabolic changes, including a decrease in bone mineral density (BMD).[8,9] Because prostate cancer also frequently metastasizes to the bone, a second skeletal insult is often added to those with advanced disease on ADT. Zoledronic acid(Drug information on zoledronic acid) (Zometa) is a potent bisphosphonate that has been approved for use in men with metastatic CRPC. Its role was established by a study of men with metastatic CRPC by Saad et al, in which 4 mg of zoledronic acid was given every three weeks and reduced the incidence of skeletal related events (SRE) from 44% in the placebo arm to 33% in the zoledronic acid arm. SREs were defined as a pathologic fracture, spinal cord compression, orthopedic interventions, radiation therapy to the bone, or a change in antineoplastic therapy to treat bone pain. Other dosing schedules of zoledronic acid have been studied in phase II studies assessing BMD, showing that zoledronic acid administered every three months or even annually may effectively preserve BMD in those treated with ADT, although these studies were not designed to assess for changes in SRE rates. One small study has examined the oral bisphosphonate alendronate (fosamax) and found that it also appears to maintain BMD in men treated with ADT for prostate cancer.
The primary action of bisphosphates in improving bone health in those with osteoporosis is via a reduction in bone resorption, likely via inhibition of osteoclast activity. With ADT, the normal balance between osteoclast and osteoblast activity is altered, leading to bone loss or frank osteoporosis. Osteoclasts therefore play a primary role in bone resorption and are mediated via receptor activator of nuclear factor-κβ (RANK) ligand, which directly stimulates their action. Denosumab (Prolia) is a recently introduced, fully human monoclonal antibody against RANK ligand; denosumab is effective in osteoclastic bone resorption.
Denosumab has been tested in several clinical settings of BMD loss, including in groups of post-menopausal women and men wi;th CRPC. Denosumab is now FDA-approved for the treatment of post-menopausal bone loss in women at high risk for fracture. With regard to prostate cancer, one study tested denosumab in cancer patients with bone metastases (45% of whom had prostate cancer) and found persistently elevated levels of the bone turnover marker N-telopeptide in the urine, despite the use of intravenous bisphosphonates. Notably, the levels of N-telopeptide were successfully suppressed by denosumab in two-thirds of patients, suggesting that denosumab was more effective at suppressing osteoclast activity than were bisphosphonates. In a phase III study of men with non-metastatic CRPC, denosumab increased the lumbar spine BMD by 5.6%, while the placebo arm averaged a 1% loss in BMD. From a clinical outcomes standpoint, a reduction in the incidence of new vertebral fractures was also noted with denosumab, suggesting a primary preventative role in this setting. In a separate randomized, phase III study of denosuamb versus zoledronic acid in patients with metastatic CRPC, denosumab significantly improved the median time to first SRE (20.7 versus 17.1 months) compared to zoledronic acid.
From the published literature, denosumab appears to be well tolerated, however, denosumab is associated with osteonecrosis of the jaw (ONJ), as is high-potency bisphosphonate therapy (by virtue of the osteoclastic inhibition). In a recent report of metastatic CRPC patients, 2.3% of the denosumab-treated patients developed ONJ, versus 1.3% in the zoledronic acid arm (P = .09), and hypocalcemia was observed more commonly with denosumab than with zoledronic acid (13% versus 6%). Since denosumab is a monoclonal antibody, less renal toxicity is expected with this drug, in comparison to high potency bisphosphonates.
In summary, denosumab is a new monoclonal antibody directed against RANK ligand and is a potent inhibitor of osteoclast activity. It is currently approved for the treatment of osteoporosis in high-risk post-menopausal woman. Published data regarding its use in metastatic CRPC show a delay in the time to first SRE compared to zoledronic acid treatment. Osteonecrosis of the jaw will likely be observed with denosumab in a similar pattern to zoledronic acid, although denosumab use is expected to be associated with fewer cases of renal toxicity.