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Novel therapeutic strategies for metastatic prostate cancer in the post-docetaxel setting.

ABSTRACT: Prostate cancer is the most common noncutaneous cancer and the second leading cause of death from cancer in men in most western countries. Advanced prostate cancer is typically sensitive to androgen-deprivation therapy, but invariably progresses to the castration-resistant state. Most current prostate cancer treatments are based on cytotoxicity directed against tumor cells via androgen-deprivation therapy or chemotherapy. Chemotherapy with docetaxel represents the standard first-line treatment in patients with castration-resistant prostate cancer (CRPC). Following progression after treatment with docetaxel, cabazitaxel (XRP6258)-prednisone treatment leads to a significantly longer overall survival (OS) time than with mitoxantrone-prednisone. Several other novel agents are currently being evaluated, including sipuleucel-T, abiraterone acetate, and MDV3100, as well as the radionuclide alpharadin. The cell-based immunotherapy sipuleucel-T produces longer OS times in chemotherapy-naïve patients, whereas the androgen biosynthesis inhibitor abiraterone acetate results in longer OS times following docetaxel. It is envisioned that these agents will change the standard of care for patients with metastatic CRPC. This review focuses on the clinical development of cabazitaxel and abiraterone acetate.

SUBMITTER: Sartor O

PROVIDER: S-EPMC3233282 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Novel therapeutic strategies for metastatic prostate cancer in the post-docetaxel setting.

Sartor Oliver O Michels Ross M RM Massard Christophe C de Bono Johann Sebastian JS

The oncologist 20111102 11

Prostate cancer is the most common noncutaneous cancer and the second leading cause of death from cancer in men in most western countries. Advanced prostate cancer is typically sensitive to androgen-deprivation therapy, but invariably progresses to the castration-resistant state. Most current prostate cancer treatments are based on cytotoxicity directed against tumor cells via androgen-deprivation therapy or chemotherapy. Chemotherapy with docetaxel represents the standard first-line treatment i ...[more]

PMID: 22048000

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Project description:Despite the proven success of hormonal therapy for prostate cancer using chemical or surgical castration, most patients eventually will progress to a phase of the disease that is metastatic and shows resistance to further hormonal manipulation. This has been termed metastatic castrate-resistant prostate cancer (mCRPC). Despite this designation, however, there is evidence that androgen receptor (AR)-mediated signaling and gene expression can persist in mCRPC, even in the face of castrate levels of androgen. This may be due in part to the upregulation of enzymes involved in androgen synthesis, the overexpression of AR, or the emergence of mutant ARs with promiscuous recognition of various steroidal ligands. The therapeutic options were limited and palliative in nature until trials in 2004 demonstrated that docetaxel chemotherapy could significantly improve survival. These results established first-line docetaxel as the standard of care for mCRPC. After resistance to further docetaxel therapy develops, treatment options were once again limited. Recently reported results from phase 3 trials have shown that additional therapy with the novel taxane cabazitaxel (with prednisone), or treatment with the antiandrogen abiraterone (with prednisone) could improve survival for patients with mCRPC following docetaxel therapy. Compared with mitoxantrone/prednisone, cabazitaxel/prednisone significantly improved overall survival, with a 30% reduction in rate of death, in patients with progression of mCRPC after docetaxel therapy in the TROPIC trial. Similarly, abiraterone acetate (an inhibitor of androgen biosynthesis) plus prednisone significantly decreased the rate of death by 35% compared with placebo plus prednisone in mCRPC patients progressing after prior docetaxel therapy in the COU-AA-301 trial. Results of these trials have thus established two additional treatment options for mCRPC patients in the "post-docetaxel space." In view of the continued AR-mediated signaling on mCRPC, results from additional phase 3 studies with novel antiandrogens which are directed at inhibition of the AR (e.g., MDV3100), as well as other agents, are awaited with interest and may further expand the treatment choices for this difficult-to-manage population of patients.

Project description:Diffusion of new cancer treatments can be both inefficient and incomplete. The uptake of new treatments over time (diffusion) has not been well studied. We analyzed the diffusion of docetaxel in metastatic prostate cancer. We identified metastatic prostate cancer patients diagnosed from 1995 to 2007 using the Surveillance, Epidemiology, and End Results Program (SEER)-Medicare database. Medicare claims through 2008 were analyzed. We assessed cumulative incidence of docetaxel by socioeconomic, demographic, and comorbidity variables, and compared diffusion patterns to landmark events including release of phase III results and FDA approval dates. We compared docetaxel diffusion patterns in prostate cancer to those in metastatic breast, lung, ovarian, and gastric cancers. To model docetaxel use over time, we used the classic "mixed influence" deterministic diffusion model. All statistical tests were two-sided. We identified 6561 metastatic prostate cancer patients; 1350 subsequently received chemotherapy. Among patients who received chemotherapy, docetaxel use was 95% by 2008. Docetaxel uptake was statistically significantly slower (P < .01) for patients older than 65 years, blacks, patients in lower income areas, and those who experienced poverty. Eighty percent of docetaxel diffusion occurred prior to the May, 2004 release of phase III results showing superiority of docetaxel over standard-of-care. The maximum increase in the rate of use of docetaxel occurred nearly simultaneously for prostate cancer as for all other cancers combined (in 2000). Efforts to increase the diffusion of treatments with proven survival benefits among disadvantaged populations could lead to cancer population survival gains. Docetaxel diffusion mostly preceded phase III evidence for its efficacy in castration-resistant prostate cancer, and appeared to be a cancer-wide-rather than a disease-specific-phenomenon. Diffusion prior to definitive evidence indicates the prevalence of off-label chemotherapy use.

Project description:ObjectivesTo assess cabazitaxel versus docetaxel re-challenge for the treatment of metastatic castrate refractory prostate cancer (CRPC) patients previously treated with docetaxel at inception of primary hormone therapy.Patients and methodsThe CANTATA trial was a prospective, two-arm, open-label, phase II study conducted in eight UK centres. Patients over the age of 18, with histologically proven, metastatic prostate cancer who had been previously treated with up to 6 cycles of docetaxel as part of the STAMPEDE trial (or treated with the same drug outside of the trial at primary diagnosis) and had a performance status (PS) of 0-2, were eligible. Patients who progressed during primary treatment with docetaxel or had received prior systemic chemotherapy were excluded. Cabazitaxel (25 mg/m2) or docetaxel (75 mg/m2) was administered via intravenous infusion every 3 weeks with oral prednisolone (10 mg) for up to 10 cycles, until disease progression, death or unacceptable toxicity. The primary outcome was clinical progression-free survival (PFS) as defined by either date of pain progression, date of a cancer-related skeletal-related event, or date of death from any cause. Analyses were by intention to treat. EudraCT number: 2012-003835-40.ResultsBetween 7 March 2013 and 4 January 2016, 15 patients with a median age of 70 years (range 54-76) were recruited; seven received cabazitaxel, eight docetaxel. The study was halted due to slow accrual. The median clinical PFS time in the cabazitaxel group was 6.2 months compared with 8.4 for the docetaxel group (95% confidence intervals were not reached due to the small number of patients). A total of 13 serious adverse events were reported.ConclusionDue to the low number of patients recruited, meaningful comparisons could not be made. However, toxicity was in line with known outcomes for these agents, demonstrating it is feasible and safe to deliver chemotherapy to men relapsing with CRPC after upfront chemotherapy.

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Novel therapeutic strategies for metastatic prostate cancer in the post-docetaxel setting.

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Novel therapeutic strategies for metastatic prostate cancer in the post-docetaxel setting.

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