Cabozantinib for Progressive Metastatic Castration-resistant Prostate Cancer Following Docetaxel: Combined Analysis of Two Phase 3 Trials

Two phase 3 trials, COMET-1 and COMET-2, have reported that cabozantinib did not significantly extend overall survival (OS) compared to prednisone and prednisone plus mitoxantrone, respectively, in post-docetaxel patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted a retrospective analysis of a combined data set from these trials to identify a benefit in subsets of patients according to prognostic risk factors. The prognostic ability of factors to predict survival was evaluated using Cox proportional hazards regression models. Evaluation of potential beneficial subsets was performed using interaction terms between factors and cabozantinib. All tests were two-sided and p≤0.05 was considered statistically significant. A total of 1147 post-docetaxel patients with mCRPC were available (1028 from COMET-1 and 119 from COMET-2). The following factors were prognostic for OS: age, disease-free interval, hemoglobin, prostate-specific antigen, alkaline phosphatase, albumin, bone scan lesion area, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, and pain (all p<0.05). There was no interaction effect on survival between cabozantinib versus comparator arms and any prognostic group. After adjusting for prognostic factors, cabozantinib was associated with better OS (hazard ratio 0.80, 95% confidence interval 0.67-0.95; p=0.012). Further investigation of cabozantinib in a better-powered trial or a rational patient population based on a molecular biomarker may be warranted. PATIENT SUMMARY: Two phase 3 trials have reported no survival benefit for cabozantinib, a multitarget oral drug, in metastatic castration-resistant prostate cancer. This analysis pooled 1147 patients from these trials to identify a survival benefit for cabozantinib. This study suggests that further rational development may be justified

A CD24‐p53 axis contributes to African American prostate cancer disparities

Background: Using a functional analysis of prostate cancer cells, we found a CD24-dependent inactivation of mutant p53, but the clinical significance of this observation remained uncertain. Here, we validated these results with samples of human prostate cancer and explored the role of a CD24-p53 axis in racial disparities of prostate cancer. Methods: Samples of formalin-fixed, paraffin-embedded prostate cancer from 141 European Americans (EAs) and 147 African Americans (AAs) in two independent sample cohorts were assessed for protein expression of CD24, mutant p53, mouse double minute 2 human homolog (MDM2), and cyclin dependent kinase inhibitor 2A (ARF) using immunohistochemical analyses. All samples were analyzed for TP53R175H and TP53R273H. Results: CD24, mutant p53, MDM2, and ARF proteins were expressed in 55%, 24%, 39%, and 68% of prostate cancer samples, respectively. CD24 and mutant p53 were present more frequently in late-stage and metastatic prostate cancer. The presence of CD24 was associated with a greater than fourfold risk of metastasis, which included lymph node and distant metastases. H score analysis showed positive correlations of CD24 expression with mutant p53 (r =.308, P &lt;.001) and MDM2 (r =.227, P =.004). There was a negative correlation for CD24 with ARF (r = −.280, P &lt;.001). A racial disparity was evident for CD24 (AAs/EAs: 64% vs 47%; P =.004) but not for mutant p53 (AA/EA: 28% vs 21%; P =.152). In 32 CD24+/mutant p53+ cases, a TP53R273H mutation was found in five cases, but no TP53R175H mutation was found. Conclusion: The CD24-p53 axis may contribute to aggressive and metastatic prostate cancers, especially those of AAs. This observation enhances understanding of the pathogenesis of prostate cancer and its associated racial disparities

EV-301 long-term outcomes : 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma

Abstract: Introduction: This exploratory analysis evaluated efficacy and safety data for enfortumab vedotin versus chemotherapy over a median follow-up of

Impact of the Number of Cycles of Platinum Based First Line Chemotherapy for Advanced Urothelial Carcinoma.

We evaluated the impact of the number of cycles of platinum based, first line chemotherapy (fewer than 6 cycles vs the conventional 6 cycles or more) on the survival of patients with metastatic urothelial carcinoma. We used the RISC (Retrospective International Study of Invasive/Advanced Cancer of the Urothelium) database. The association of the number of cycles of chemotherapy with overall survival was investigated by Cox multiple regression analysis after controlling for recognized prognostic factors. We excluded patients who received fewer than 3 or more than 9 platinum chemotherapy cycles to reduce confounding factors. The primary analysis was a comparison of overall survival for 3 to 5 vs 6 to 9 cycles using 6-month landmark analysis when 281 death events were observed. Of the 1,020 patients in the RISC 472 received cisplatin or carboplatin, of whom 338 and 134, respectively, were evaluable. A total of 157 patients received 3 to 5 cycles (median 4) and 315 received 6 to 9 cycles (median 6). There was no significant difference in overall survival between 3 to 5 and 6 to 9 cycles (HR 1.02, 95% CI 0.78-1.33, p = 0.91). No significant interactions were observed for the type of platinum (p = 0.09) and completed planned chemotherapy (p = 0.56). The limitations of a hypothesis generating, retrospective analysis applied. Four cycles of platinum based, first line chemotherapy appeared adequate and did not significantly compromise the survival of patients with advanced urothelial carcinoma. The omission of excessive cycles may avoid unnecessary cumulative toxicity and facilitate a better transition to second line therapy and investigational switch maintenance therapy strategies. These results require prospective validation but they may impact practice in select patients

Impact of the Number of Cycles of Platinum Based First Line Chemotherapy for Advanced Urothelial Carcinoma

Purpose: We evaluated the impact of the number of cycles of platinum based, first line chemotherapy (fewer than 6 cycles vs the conventional 6 cycles or more) on the survival of patients with metastatic urothelial carcinoma. Materials and Methods: We used the RISC (Retrospective International Study of Invasive/Advanced Cancer of the Urothelium) database. The association of the number of cycles of chemotherapy with overall survival was investigated by Cox multiple regression analysis after controlling for recognized prognostic factors. We excluded patients who received fewer than 3 or more than 9 platinum chemotherapy cycles to reduce confounding factors. The primary analysis was a comparison of overall survival for 3 to 5 vs 6 to 9 cycles using 6-month landmark analysis when 281 death events were observed. Results: Of the 1,020 patients in the RISC 472 received cisplatin or carboplatin, of whom 338 and 134, respectively, were evaluable. A total of 157 patients received 3 to 5 cycles (median 4) and 315 received 6 to 9 cycles (median 6). There was no significant difference in overall survival between 3 to 5 and 6 to 9 cycles (HR 1.02, 95% CI 0.78–1.33, p = 0.91). No significant interactions were observed for the type of platinum (p = 0.09) and completed planned chemotherapy (p = 0.56). The limitations of a hypothesis generating, retrospective analysis applied. Conclusions: Four cycles of platinum based, first line chemotherapy appeared adequate and did not significantly compromise the survival of patients with advanced urothelial carcinoma. The omission of excessive cycles may avoid unnecessary cumulative toxicity and facilitate a better transition to second line therapy and investigational switch maintenance therapy strategies. These results require prospective validation but they may impact practice in select patients. © 2018 American Urological Association Education and Research, Inc

Impact of the number of cycles of platinum-based first-line chemotherapy for advanced urothelial carcinoma

PURPOSE: To evaluate the impact of number of cycles of platinum-based first-line chemotherapy &lt;6 versus the conventional ≥6 on survival of metastatic urothelial carcinoma (UC).MATERIALS AND METHODS: The Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC) database was employed. The association of the number of cycles of chemotherapy with overall survival (OS) was investigated by Cox multiple regression analysis after controlling for recognized prognostic factors. We excluded patients receiving &lt;3 or &gt;9 cycles of platinum chemotherapy to reduce confounding factors. The primary analysis was a comparison of OS with 3-5 cycles versus 6-9 cycles using 6-month landmark analysis when 281 death events were observed.RESULTS: Of 1,020 patients in RISC, 472 who received cisplatin (n=338) or carboplatin (n=134) were evaluable. A total of 157 patients received 3-5 cycles (median 4) and 315 received 6-9 cycles (median 6). There was no significant difference in OS between 3-5 and 6-9 cycles (HR 1.02, 95%CI: 0.78-1.33, p=0.91). No significant interactions were observed with type of platinum (p=0.09) and completed planned chemotherapy (p=0.56). Limitations of a hypothesis-generating retrospective analysis apply.CONCLUSIONS: Four cycles of platinum based first-line chemotherapy appear adequate and do not significantly compromise survival of patients with advanced UC. The omission of excessive cycles may avoid unnecessary cumulative toxicities and facilitate better transition to second-line therapy and investigational switch maintenance therapy strategies. These results require prospective validation, but may impact practice in selected patients.</p