What's New in the Treatment of Prostate Cancer? Updates From ASCO 2008
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From: J on 13 Aug 2008 08:59 http://www.medscape.com/viewarticle/577724 What's New in the Treatment of Prostate Cancer? Updates From ASCO 2008 Joshi J. Alumkal, MD Disclosures Introduction In the United States, more than 186,000 new cases and 28,000 deaths from prostate cancer are predicted for 2008.[1] Virtually all of these deaths will occur in those with castrate-resistant, metastatic prostate cancer. This highlights the need for better therapies in this group of patients to extend survival and alleviate symptoms. Recent data have shown that the androgen receptor (AR) and AR signaling remain active in in vitro prostate cancer models of long-term castration and in men with castrate serum levels of testosterone.[2,3] Several of the therapies discussed below highlight the importance of targeting AR even in the castrate-resistant or post-docetaxel states -- the latter remains a clear area of unmet need. The survival duration of men with castrate-resistant disease can be quite variable, which also underscores the need for better prognostic tools. Novel AR-Targeted Therapies Since Huggins and Hodges[4] first noted that castration of men with prostate cancer leads to clinical benefit, hormonal therapy, which either lowers androgen levels or antagonizes the effect of androgens on AR, has been the first-line treatment of men with advanced prostate cancer. Several antiandrogens are already in use including bicalutamide, flutamide, and nilutamide, but each of them is associated with eventual resistance and/or androgen agonist-like activity. MDV3100 Charles Sawyers previously identified a novel antiandrogen, MDV3100, which was effective in bicalutamide-resistant models of prostate cancer and which had no androgen agonist activity. At the 2008 annual meeting of the American Society of Clinical Oncology (ASCO), Howard Scher and colleagues[5] presented the findings of a Prostate Cancer Clinical Trials Consortium phase 1 dose-escalation study of MDV3100, an oral drug, in men with castrate-resistant prostate cancer (with or without metastases) who were either chemotherapy-naive or who had received ? 2 chemotherapy regimens. The primary endpoints were safety, pharmacokinetics, prostate-specific antigen (PSA) response, objective response, change in numbers of circulating tumor cells (CTCs), and change in PET scan uptake. Data were presented for 87 patients treated with doses of 30 mg, 60 mg, 150 mg, or 240 mg per day. Fifty-five percent of the chemotherapy-naive patients had > 50% declines in PSA, whereas 42% of the postchemotherapy patients achieved similar results. There was the suggestion of a dose-response relationship, inasmuch as 9% of the patients who received 60 mg of MDV3100 daily, 13% of the 150-mg patients, and 29% of the 240-mg patients achieved > 90% reductions in PSA. Fifteen patients were evaluable for soft-tissue response at 12 weeks; 80% of these had stable disease whereas 20% had progressed. Bone scan response data were not available at the time of the presentation. These preliminary results highlight the worthiness of targeting AR in both castrate-resistant, chemotherapy-naive and castrate-resistant, post-docetaxel patients. We await the full results of this trial, including the data associated with use of the higher doses (360 mg, 480 mg, and 600 mg). Abiraterone Acetate It is clear that the testis is not the only site of androgen synthesis; the adrenal gland represents a sanctuary site where androgens are produced. For several years, ketoconazole has been used as second-line therapy for men with castrate-resistant prostate cancer.[6] Several abstracts were presented that highlight the oral drug abiraterone acetate, which is a 17-alpha-hydroxylase and C17,20-lyase inhibitor that acts in the adrenal gland. De Bono and colleagues[7] presented findings from their experience with 2 trials with this drug. They conducted a phase 1/2 study, with 18 patients in the first phase, in men with castrate-resistant, docetaxel-naive disease. Doses of abiraterone acetate ranged from 250 mg to 2 g orally per day; no significant toxicities were found. The phase 2 portion of this study included 36 patients treated with 1000 mg of abiraterone acetate per day. Overall, 70% of patients had > 50% declines in PSA levels, and the median time to progression (TTP) was 231 days. Of note, the median duration of response in the TAX-327 study was similar at 7.7 months[8]; 15 of the 29 patients (52%) with measurable disease had a partial response by RECIST criteria. Charles Ryan and colleagues[9] presented findings with abiraterone acetate from a phase 1 trial that included 33 castrate-resistant, docetaxel-naive patients. Doses ranged from 250 mg to 1000 mg orally per day, and the study found a 53% PSA response rate. The study authors explored the relationship between prior ketoconazole use and abiraterone acetate response and found that the proportion of patients with > 50% declines in PSA was similar between those who had received prior ketoconazole (52%) and those who had not (55%). From their PSA waterfall plots it seemed, however, that those with prior ketoconazole exposure were more likely to have no decline in PSA with abiraterone acetate treatment. Finally, Johan De Bono and Daniel Danila each presented data for abiraterone acetate in castrate-resistant, post-docetaxel patients. De Bono and colleagues[7] accrued 34 patients to the Abiraterone 003 phase 2 trial with abiraterone acetate 1000 mg orally daily. Steroids could be used at the discretion of the treating provider. The primary endpoint was PSA Working Group 1 criteria.[10] A total of 55% of the patients had progressed on docetaxel whereas 45% had stopped the drug due to toxicity. Forty-seven percent of the patients achieved > 50% declines in PSA, and the median TTP was 161 days. Danila and colleagues[11] presented results of the Abiraterone 004 trial, in which 38 patients were treated with abiraterone acetate 1000 mg orally daily and with prednisone 5 mg orally twice daily. The primary endpoint was PSA response. Sixty-eight percent of patients had received prior docetaxel only, whereas 32% of patients had received prior docetaxel and another second-line chemotherapy. Forty-five percent of the patients treated with abiraterone had > 50% declines in PSA, and no grade IV toxicities were seen. Electrolyte abnormalities were the most common side effect reported. Further testing of abiraterone acetate is worthwhile, and accrual to a randomized phase 3 trial of abiraterone acetate (1000 mg orally daily) and prednisone vs placebo and prednisone is ongoing. We eagerly await the results of this trial, which are expected in the next few years. Chemotherapy and Prostate Cancer Oliver Sartor and colleagues[12] presented findings from the SPARC (Satraplatin and Prednisone Against Refractory Cancer) randomized phase 3 trial of satraplatin 80 mg/m2 orally on days 1-5 of a 35-day cycle and prednisone vs placebo and prednisone in patients with castrate-resistant, metastatic prostate cancer who had failed 1 prior chemotherapy regimen. There were 2 primary endpoints: overall survival and a composite progression-free survival endpoint comprised of tumor progression, skeletal events, symptomatic progression, or death. Whereas progression-free survival was improved [11.1 weeks for satraplatin and 9.7 weeks for placebo with a hazard ratio (HR) of 0.67 (95% confidence interval [CI]: 0.57-0.77, log-rank P value < .0001)], overall survival was not statistically different [61.3 weeks for satraplatin and 61.4 weeks for placebo with an HR of 0.98 (95% CI: 0.84-1.15, log-rank P value < .7999)]. Given that this study began accrual prior to the US Food and Drug Administration approval and widespread use of docetaxel, the investigators did a subgroup analysis of those patients with prior docetaxel exposure. The investigators did not find a statistically significant difference in median overall survival (66.1 weeks for satraplatin and 62.9 weeks for placebo with an HR of 0.91 (95% CI: 0.72-1.14). Thus, there does not appear to be a good rationale for further development of satraplatin as a single agent for use in patients with castrate-resistant, metastatic prostate cancer. New Prognostic Marker? Gerhardt Attard presented findings from a study of CTC counts in men with castrate-resistant prostate cancer who were to begin a new line of therapy at the Royal Marsden Hospital.[13] Danila and colleagues[14] previously found that high levels of CTCs in patients with castrate-resistant prostate cancer were associated with worse overall survival. In this study by Attard and colleagues, CTC counts were performed at baseline and post-cycles 1 and 2 after beginning a new line of treatment. This assay was done using the CellSearch platform from Veridex (Raritan, New Jersey). A threshold of 5 CTCs/7.5 mL of blood was used for statistical analysis of survival. The investigators found that the median overall survival was not reached for men with CTC counts < 5 at baseline, and that those with CTC counts > 5 at any point (baseline or during therapy) had shorter overall survival. Those with a CTC count > 50 at baseline had a median overall survival of only 6.3 months, although the investigators did not account for the types of therapies the patients with various CTC counts had received (ie, did those with high CTC counts receive less aggressive treatment for some reason?). It is also unclear whether the cutpoints in their multivariable model (hemoglobin, lactate dehydrogenase, PSA, albumin, and alkaline phosphatase) were predefined or defined post hoc. Nonetheless, these results are worthy of further testing and may, if validated in larger, independent cohorts of patients, help refine clinical tools such as the Halabi and Armstrong nomograms.[15,16] Summary The 2008 ASCO meeting, with the preliminary results of the MDV3100 trial and data from 3 trials with abiraterone acetate, demonstrated the utility of targeting ARs in advanced, castrate-resistant phases of prostate cancer. The results of the SPARC study highlight the need for better agents that are well tolerated and active in patients who have previously received docetaxel. Finally, the preliminary work with CTC counts as prognostic markers is worthy of further exploration in larger, independent groups of patients. This activity is supported by an independent educational grant from Bristol-Myers Squibb. Contents of: ASCO 2008: Genitourinary Cancer All sections of this activity are required for credit. 1. Advances in the Treatment of Renal Cell CarcinomaBrian I. Rini, MD 2. What's New in the Treatment of Prostate Cancer? Updates From ASCO 2008Joshi J. Alumkal, MD Go to CME Test Questions �
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