Prostate Cancer: Poster Discussion

Post by Dana E. Rathkopf, MD:

A major focus of the prostate cancer poster discussion session was the treatment of castration-resistant prostate cancer (CRPC).

Abiraterone acetate (CB7630) is a potent, selective, and orally available inhibitor of cytochrome P17, a key enzyme involved in the synthesis of testosterone. Three phase II trials using abiraterone acetate for the treatment of CRPC were discussed today: 1 in chemonaive, ketoconazole-naive patients (Abstract #5046) and 2 in patients who had received prior docetaxel (Abstracts #5047 and #5048). Although clinical activity was observed irrespective of baseline demographics, there was a suggestion that patients who were ketoconazole-naive had better outcomes with regard to PSA decline and median time to PSA progression. Adverse events associated with abiraterone-induced mineralocorticoid excess (hypokalemia, hypertension and edema) were mitigated by low-dose prednisone. In the post-docetaxel population treated with abiraterone and prednisone, changes in the number of circulating tumor cells (CTC) with treatment correlated with a PSA decline of > 50%. (Abstract #5049)

Building on these studies, a phase III randomized, placebo-controlled trial of abiraterone for ketoconazole-naïve patients who have progressed on docetaxel has completed accrual (COU-AA-301). This trial is expected to show whether an AR-directed therapy can prolong life compared to placebo in the post-chemotherapy setting. A phase III randomized, placebo-controlled trial for CRPC patients who have not had docetaxel or ketoconazole is also underway utilizing a novel endpoint of radiographic progression free survival (COU-AA-302). Importantly, both studies will seek to validate CTC analysis as a potential biomarker of response.

Additional abstracts discussed today focused on the treatment of CRPC using cytotoxic combination therapies. Dr. Oliver Sartor reviewed many of these abstracts during the discussion period noting that comparison between trials was difficult in large part due to the variability of the study designs and reported outcomes. Notable studies included the combination of docetaxel with multiple doses of the bone-seeking radiopharmaceutical samarium-153 Lexidronam (Abstract #5057), and a separate study of docetaxel in combination with the src inhibitor dasatinib (Abstract #5061). Both studies demonstrated a tolerable toxicity profile and evidence of clinical activity in pre- and post-docetaxel populations. Further evaluation of docetaxel and samarium is in development. A randomized, placebo-controlled phase III trial of docetaxel with and without dasatinib is currently ongoing in chemonaive patients with CRPC.

Prostate Cancer: Oral Abstract Session

Post by Dana E. Rathkopf, MD:

Today at the 45th Annual Meeting of the American Society of Clinical Oncology the oral abstracts in prostate cancer were presented.

Several abstracts focused on defining the long term risk of prostate cancer specific mortality (PCSM) for patients in the PSA era. Stephenson et al. (Abstract #5007), have developed and validated a nomogram predicting the 15-year PCSM following radical prostatectomy based on the pathologic grade and stage of the cancer, suggesting that biomarkers such as PSA may have limited value in this setting. This large retrospective study of more than 20,000 men demonstrated a high accuracy with an externally validated concordance index of 0.92. Interestingly, a separate large retrospective analysis of patients with a rising PSA following prostatectomy was presented by Antonarakis et al. (Abstract #5008), suggesting that in addition to the Gleason score, PSA doubling time and time to PSA progression are in fact strong independent predictors of metastasis-free survival.

Additional abstracts presented today focused on the treatment of CRPC. For patients with disease progression despite conventional hormonal therapy, one mechanism of resistance is overexpression of the androgen receptor (AR). MDV3100 is a second generation anti-androgen that blocks the nuclear translocation of AR and has demonstrated anti-cancer activity in bicalutamide-resistant models. Scher et al. (Abstract #5011), reported the results of a first-in-man, phase 1/2 trial of oral MDV3100 which enrolled 140 men with CRPC. MDV3100 demonstrated anti-tumor activity across all dose levels based on PSA, imaging, circulating tumor cells (CTC), and time on treatment, in both chemotherapy-naïve and post-chemotherapy patients. Based on these promising results, a 2:1 randomized Phase 3 trial of MDV3100 versus placebo in post-docetaxel CRPC is planned for this year. The primary endpoint will be overall survival; CTC enumeration and profiling will be included and compared with outcomes.

Another approach to improving treatments for patients with CRPC involves potentiating the anti-tumor effects of cytotoxic therapy. Dr. Chi et al. (Abstract #5012), presented a randomized phase 2 trial of 80 chemonaive patients who received docetaxel/prednisone versus docetaxel/prednisone in combination with OGX-011, a second generation antisense molecule that inhibits clusterin. Clusterin is strongly induced by cellular stress and confers resistance to androgen deprivation, radiation, and cytotoxic drugs. In this study, both arms met the primary endpoint of PSA response rate. Serum clusterin was significantly decreased in the OGX-011 arm suggesting a biologic effect of treatment. Although this study was not powered for survival, the OGX-011 arm demonstrated a median overall survival benefit of 10.6 months with an unadjusted hazard ratio of 0.60 (patients treated with OGX-011 plus docetaxel had a 40% reduction in their death rate versus docetaxel alone). Phase III exploration is currently under development.

The final abstract presented today was mature data from the phase 2 randomized, placebo-controlled trial of a poxviral-based PSA targeted immunotherapy in 122 patients with metastatic CRPC. PROSTVAC VF-TRICOM is a recombinant poxvirus which expresses tumor-associated antigens and a triad of immune costimulatory molecules (B7.1, ICAM-1, and LFA-3: TRICOM). Although the study did not meet its primary endpoint of PFS, the vaccine was generally well-tolerated and associated with an 8.5-month improvement in median overall survival compared to placebo. (Abstract #5013)