ABSTRACT: The rapid approval of several novel agents has given prostate cancer patients and their treating physicians many new and effective therapeutic options. Three new medical therapies were recently approved on the basis of prolonged overall survival in castration-resistant prostate cancer patients: sipuleucel-T (Provenge), cabazitaxel (Jevtana), and abiraterone acetate (Zytiga). Additionally, there are several other promising prostate cancer agents in late-stage development, including MDV3100, PROSTVAC-VF (Prostvac), orteronel (TAK-700), and radium-223 chloride (Alpharadin), each with a novel mechanism of action. Taken together, we have entered a period of accelerated drug development and optimism in the care of advanced prostate cancer. The treatment paradigm for these patients is rapidly evolving, with future study needed to define the optimal sequencing and potential combinations of these new agents.
Last year marked the start of an accelerated period of drug development for advanced prostate cancer. While gonadotropin-releasing hormone (GnRH) agonists and anti-androgens were approved in the 1980s, docetaxel(Drug information on docetaxel), approved for prostate cancer in 2004, had been the only modern chemotherapy agent to demonstrate an overall survival advantage for men with castration-resistant prostate cancer (CRPC). Three new medical therapies were recently approved on the basis of prolonged overall survival in CRPC patients: sipuleucel-T (Provenge), cabazitaxel (Jevtana), and abiraterone acetate (Zytiga). Tables 1 and 2 provide further information about these agents; Table 2 also compares them with docetaxel and highlights their efficacy, safety, and costs. In addition, a novel new bone-targeting monoclonal antibody, denosumab (Xgeva), and an LHRH antagonist, degarelix (Firmagon), have been introduced into clinical practice.
With the rapid introduction of these agents, questions arise about their optimal sequencing, in the context of our existing therapies. There are also many other novel agents currently under active development for prostate cancer, including a significant number in late-stage, phase III clinical trials for prostate cancer.
Sipuleucel-T was approved by the FDA in April 2010 for use in men with metastatic CRPC that is asymptomatic or minimally symptomatic (Table 1). It represents a first-in-class agent, classified as an autologous cellular immunotherapy. The manufacturing process for sipuleucel-T is unique and integral. Patients initially undergo collection of peripheral-blood mononuclear cells via leukapheresis, for enrichment for antigen-presenting cells. The patient’s blood is then delivered to a central manufacturing site, where it is processed with the recombinant fusion protein PA2024 (ProACT), which contains both antigenic (prostate acid phosphatase) and stimulatory (granulocyte-macrophage colony-stimulating factor) elements. This autologous, ex vivo loaded product is then shipped back to the patient and infused approximately 3 days after collection. This process takes place three times over a period of approximately 4 weeks.
Sipuleucel-T was initially tested in a small study of 127 patients with symptomatic CRPC. Subjects were randomized in 2:1 fashion to sipuleucel-T vs placebo. The primary endpoint was time to progression (TTP), with a secondary endpoint of overall survival; crossover to active therapy in those initially randomized to placebo was allowed. The median TTP was 11.7 weeks vs 10.0 weeks, favoring sipuleucel-T, but this was not statistically significant (P = .052). Median overall survival, however, was statistically significantly improved with sipuleucel-T, at 25.9 months vs 21.4 months with placebo (P = .01).
To follow up on these findings, a larger study was initiated. This phase III trial included 512 subjects with metastatic CRPC who were randomized in 2:1 fashion to sipuleucel-T or placebo. Overall, therapy was well tolerated, with serious adverse events (grade 3-5) observed in 31.7% of sipuleucel-T-treated subjects, vs 35.1% of those in the placebo group. Adverse events that were more frequently observed in the sipuleucel-T group included chills (54.1%), pyrexia (29.3%), and headache (16.0%). The median overall survival time was 25.8 months with sipuleucel-T treatment vs 21.7 months in those randomized to placebo, remarkably similar to the survival results from the earlier randomized study. It is notable that 63.7% of those in the placebo arm did receive sipuleucel-T at some point in their subsequent treatments. The median survival of those in the placebo group who received delayed sipuleucel-T was 23.8 months vs 11.6 months in those who did not. The median time to objective disease progression and clinical disease progression was not different between the two treatment groups. One of the challenges with the use of sipuleucel-T is the lack of prostate-specific antigen (PSA) responses as a marker to evaluate activity.
There are few published data on activity of sipuleucel-T in the hormone-responsive or hormone-naive prostate cancer state. In a study by Beer et al, 176 patients with hormone-dependent prostate cancer and biochemical relapse after radical prostatectomy were randomized in a 2:1 ratio to 3 to 4 months of androgen-deprivation therapy (ADT), with or without sipuleucel-T. The median time to biochemical failure was not statistically different in the sipuleucel or control groups (18.0 vs 15.4 months, respectively), although those with sipuleucel-T treatment did have a longer PSA doubling time (155 vs 105 days; P = .038). Based on the previous CRPC studies, overall survival may be more informative than TTP endpoints, and survival data for this study will require additional follow-up.
Cabazitaxel was approved by the FDA in June 2010 for treatment of metastatic CRPC after treatment failure with docetaxel chemotherapy (Table 1). As discussed, docetaxel was approved for CRPC in 2004, and until 2010 it was the only agent to demonstrate a survival advantage in patients with CRPC.[5,6] Like docetaxel, cabazitaxel is a non–cross-resisted microtubule target agent, promoting tubulin assembly and thereby stabilizing the microtubule to the point of biological consequence.
In preclinical studies, cabazitaxel showed activity in a variety of chemotherapy-resistant cell lines and was more active than docetaxel in several models. Phase I testing of cabazitaxel was reported in 2009, with dose-limiting neutropenia, but little neurotoxicity was observed.
In phase III testing, 775 men with metastatic CRPC who had received previous docetaxel chemotherapy were randomized to prednisone(Drug information on prednisone) with either cabazitaxel (at 25 mg/m2) or mitoxantrone(Drug information on mitoxantrone) (at 12 mg/m2), each given every 3 weeks. The overall survival was 15.1 months with cabazitaxel, vs 12.7 months with mitoxantrone (P < .0001). The most common toxicities in the cabazitaxel arm were related to bone-marrow suppression, with grade 3 or higher neutropenia in 82% of the cabazitaxel-treated patients vs 58% of the mitoxantrone-treated patients. Additionally, febrile neutropenia was seen in 8% of those in the cabazitaxel arm compared with only 1% of the mitoxantrone arm. Diarrhea was also more common with cabazitaxel therapy, seen in 47% of patients, with 6% experiencing grade 3 or higher diarrhea.
Abiraterone acetate was approved by the FDA in April 2011 for the treatment of men with metastatic CRPC following docetaxel chemotherapy (Table 1). It is an oral inhibitor of CYP17, a key driver of testosterone production. While GnRH agonist/antagonist therapy reduces systemic testosterone production by 90% to 95% (via testicular suppression), the adrenal glands and some prostate cells themselves continue to synthesize testosterone despite GnRH agonist/antagonist treatment. Abiraterone acetate therapy directly suppresses this extragonadal testosterone production, yielding systemic testosterone levels approaching 0 ng/dL.[10,11]
Early phase I and II studies established activity of abiraterone acetate in CRPC. The initial phase I study of abiraterone acetate in CRPC escalated the dose from 250 to 2000 mg daily, with a recommended phase II dose of 1000 mg daily. While generally well tolerated, increased levels of upstream steroids, including adrenocorticotropic hormone, were observed and side effects associated with mineralocorticoid excess were noted. In subsequent studies, dexamethasone(Drug information on dexamethasone), and later prednisone at 5 mg twice daily, was given with abiraterone to partially abrogate the accumulation of excess mineralocorticoid. Across several of these studies, the rate of PSA responses (reductions of ≥ 50%) ranged from 36% to 67%.[10-14] Notably, subjects with previous ketoconazole(Drug information on ketoconazole) treatment (given the similarities of ketoconazole’s adrenal-suppressive action) generally had a lower PSA response rate.
A phase III study of abiraterone randomized 1195 subjects with metastatic CRPC and progression after docetaxel chemotherapy. Participants received prednisone with or without 1000 mg of abiraterone acetate daily in a 2:1 ratio. Abiraterone acetate was well tolerated overall, although events associated with mineralocorticoid excess including fluid retention/edema (31%), hypokalemia (17%), and hypertension (10%) were observed more frequently in the abiraterone group. The median overall survival was 14.8 months with abiraterone acetate treatment, compared with 10.9 months in the placebo arm (P < .001). Secondary endpoints of PSA progression (10.2 months vs 6.6 months, respectively), progression-free survival (PFS) (5.6 months vs 3.6 months, respectively), and PSA response rate (29% vs 6%, respectively), all favored abiraterone acetate therapy.
Denosumab (Xgeva) was approved by the FDA in November 2010 for prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors (Table 1). A dynamic bone environment exists in normal bone, with a balance between bone production via osteoblasts and bone resorption via osteoclasts. SREs are common in prostate cancer due to dysregulation of bone formation/resorption, bone metastases themselves, and loss of bone mineral density associated with ADT. Receptor activator of nuclear factor kappa-B (RANK) ligand is critical to osteoclast formation and survival. Denosumab is a human monoclonal antibody against RANK ligand and it inhibits bone-resorption activity of osteoclasts.
In a phase III study of bone metastases and CRPC, 1904 men were randomized to denosumab (at 120 mg SQ) or zoledronic acid(Drug information on zoledronic acid) (Zometa; at 4 mg IV) every 4 weeks. Median time to observance of the first SREs was 20.7 vs 17.1 months, favoring denosumab (P = .008). No overall survival difference was seen. Hypo-calcemia (P < .0001) and osteonecrosis of the jaw (P = .09) were noted more frequently in the denosumab group.
In addition to its initial label indication, denosumab was approved (under the trade name Prolia) in September 2011 to increase bone mass in patients who are at high risk of fracture and also are receiving ADT for nonmetastatic prostate cancer. In contrast to the dosing for metastatic CRPC, denosumab is given as a subcutaneous injection (Prolia, at 60 mg) every 6 months in the nonmetastatic setting. In the phase III study leading to this indication, high-risk prostate cancer subjects treated with ADT who were without bone metastases were randomized to denosumab or placebo, with 734 men in each group. High-risk was defined as being 70 years of age or older, having low bone mineral density with a T score of < − 1.0, or having a history of an osteoporotic fracture. After 2 years on the study, the bone mineral density of the lumbar spine in the denosumab-treated group increased by 5.6%, while it had decreased 1.0 % in the placebo group (P < .001). Those treated with denosumab also had fewer new vertebral fractures at 36 months (1.5% vs 3.9%, P = .006).
A recently completed clinical trial in high-risk prostate cancer patients after local therapy revealed that denosumab is capable of delaying the development of bone metastasis. This study enrolled 1432 subjects with nonmetastatic CRPC and randomized them to denosumab (120 mg every 4 weeks) or placebo. The time to first metastasis was delayed by approximately 4 months in the denosumab-treated group.