Cabazitaxel versus abiraterone or enzalutamide in poor prognosis metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase II trial.

BACKGROUND: Treatment of poor prognosis metastatic castration-resistant prostate cancer (mCRPC) includes taxane chemotherapy and androgen receptor pathway inhibitors (ARPI). We sought to determine optimal treatment in this setting. PATIENTS AND METHODS: This multicentre, randomised, open-label, phase II trial recruited patients with ARPI-naive mCRPC and poor prognosis features (presence of liver metastases, progression to mCRPC after <12 months of androgen deprivation therapy, or ≥4 of 6 clinical criteria). Patients were randomly assigned 1 : 1 to receive cabazitaxel plus prednisone (group A) or physician's choice of enzalutamide or abiraterone plus prednisone (group B) at standard doses. Patients could cross over at progression. The primary endpoint was clinical benefit rate for first-line treatment (defined as prostate-specific antigen response ≥50%, radiographic response, or stable disease ≥12 weeks). RESULTS: Ninety-five patients were accrued (median follow-up 21.9 months). First-line clinical benefit rate was greater in group A versus group B (80% versus 62%, P = 0.039). Overall survival was not different between groups A and B (median 37.0 versus 15.5 months, hazard ratio (HR) = 0.58, P = 0.073) nor was time to progression (median 5.3 versus 2.8 months, HR = 0.87, P = 0.52). The most common first-line treatment-related grade ≥3 adverse events were neutropenia (cabazitaxel 32% versus ARPI 0%), diarrhoea (9% versus 0%), infection (9% versus 0%), and fatigue (7% versus 5%). Baseline circulating tumour DNA (ctDNA) fraction above the cohort median and on-treatment ctDNA increase were associated with shorter time to progression (HR = 2.38, P < 0.001; HR = 4.03, P < 0.001). Patients with >30% ctDNA fraction at baseline had markedly shorter overall survival than those with undetectable ctDNA (HR = 38.22, P < 0.001). CONCLUSIONS: Cabazitaxel was associated with a higher clinical benefit rate in patients with ARPI-naive poor prognosis mCRPC. ctDNA abundance was prognostic independent of clinical features, and holds promise as a stratification biomarker.

Anti-VEGF therapy in mRCC: differences between Asian and non-Asian patients.

BACKGROUND: Several reports suggest that vascular endothelial growth factor (VEGF)-targeted therapy in metastatic renal cell carcinoma (mRCC) may be more toxic in Asian vs non-Asian populations. Comparative efficacy of these agents with respect to ethnicity is not well characterised. METHODS: A multicentre, retrospective, cohort study using Asian and non-Asian centres which collected data on ethnicity, dose reductions and outcomes using the International mRCC Database Consortium. RESULTS: This study included 1024 (464 Asian, 560 non-Asian) patients with a 29.4 months median follow-up. The percentage of dose modifications/reductions between non-Asians and Asians was similar (55% vs 61% P=0.1197). When adjusted for risk groups, there was no difference in overall or progression-free survival between non-Asians and Asians. Patients with dose reductions due to toxicity had longer treatment durations and overall survival than those who did not in both non-Asian (10.6 vs 5.0 months, P<0.0001; 22.6 vs 16.1 months, P=0.0016, respectively) and Asian populations (8.9 vs 5.4 months, P=0.0028; 28.0 vs 18.7 months, P=0.0069, respectively). CONCLUSIONS: Adjusting for risk groups, there appears to be no difference in outcome between Asian vs non-Asian patients with mRCC treated with VEGF-targeted therapy. Judicious dose reductions may allow for better outcomes in both populations due to longer treatment durations, but direct comparisons are needed.

The importance of the dose of etoposide in the initial treatment of metastatic germ cell tumors and advances in management of patients that relapse.

OBJECTIVE: The primary objective was to evaluate the effect of etoposide dose in a 3-day cisplatin/etoposide/bleomycin (PEB) regimen on progression free survival (PFS) and overall survival (OS). Secondary objectives were to determine the impact of a paclitaxel-based salvage regimen on OS and to compare the risk distribution of germ cell patients seen at a tertiary care center to that quoted in the International Germ Cell Consensus Classification (IGCCC). METHODS: A retrospective chart review of all 302 metastatic germ cell patients requiring cisplatin-based chemotherapy between January 1980 and December 2004 was conducted. Data collected on initial treatment included the dose of etoposide: 500 mg/m2/cycle (E500) or 360 mg/m2/cycle (E360) and whether the salvage treatment contained paclitaxel or not. PFS and OS were calculated. Patients were risk stratified as per IGCCC variables. RESULTS: The relapse rate and overall survival for E500 was 3% and 97% respectively compared to a relapse rate and OS rate of 29% and 80% respectively for E360. The addition of paclitaxel to salvage chemotherapy regimens for patients that relapsed results were 1/5 (20%) of patients dying compared to 26/39 (67%) for those who received a non-paclitaxel based salvage regimen. Ninety percent of seminoma patients were good risk and 10% were intermediate risk. Non-seminoma (NSGCT) patients were skewed to the good-risk category: 71% good risk, 10% intermediate risk and 18% poor risk as compared to 56%, 28% and 16% respectively as reported by the IGCCC. Five-year PFS and OS were comparable to those documented by the IGCCC with the exception of the intermediate risk NSGCT patients. CONCLUSION: This review demonstrated that PEB treatment containing higher dose etoposide was superior in terms of PFS and OS. Although the sample size was small, it appeared that paclitaxel containing salvage regimens resulted in superior outcomes compared to previously used salvage regimens. Our center had a similar risk distribution of patients as that quoted by the IGCCC.

A pilot study of the liposomal MUC1 vaccine BLP25 in prostate specific antigen failures after radical prostatectomy.

PURPOSE: Men with biochemical failure after radical prostatectomy have few therapeutic options other than androgen deprivation therapy. Targeted therapies in this group are appropriate because the optimal timing of the initiation of hormonal therapy in this patient population is unknown. A single institution pilot trial was performed using BLP25 liposome vaccine in hormone naïve patients with prostate specific antigen failure after radical prostatectomy to determine if prostate specific antigen progression could be halted. MATERIALS AND METHODS: Men with biochemical failure after radical prostatectomy were enrolled. Primary end points were efficacy and safety of the MUC1 BLP25 liposomal vaccine. Changes in prostate specific antigen doubling time were also evaluated. Patients received a single intravenous dose of cyclophosphamide, followed by vaccinations with BLP25 liposome vaccine for up to 1 year. Prostate specific antigen was measured at baseline and during treatment, and prostate specific antigen doubling time was calculated for these intervals. RESULTS: A total of 16 patients with a median age of 60 years were enrolled. All patients received cyclophosphamide and 15 of 16 completed the primary treatment period. Ten patients completed the maintenance period. After the 8-week primary treatment period 8 of 16 patients had stable or decreased prostate specific antigen. At the last on-study prostate specific antigen measurement 1 patient maintained stable prostate specific antigen but all others had progression. However, 6 of the 16 patients had greater than 50% prolongation of prostate specific antigen doubling time compared to pre-study prostate specific antigen doubling time. CONCLUSIONS: BLP25 liposome vaccine shows promise for prolonging prostate specific antigen doubling time in hormone naïve men with biochemical failure after prostatectomy and little morbidity. This could potentially translate into the deferral of hormonal therapy. Further testing in this population of patients is warranted.

Outcome of advanced stage low grade follicular lymphomas in a population-based retrospective cohort.

BACKGROUND: To the authors' knowledge previous reports of patient outcome for advanced stage low grade follicular lymphomas (LGFL) have not been population-based. This is the first report describing the outcome of these patients based on a population-based cohort. METHODS: A retrospective chart review was performed for all patients diagnosed with advanced stage LGFL between 1987-1995 for the adult population of central and northern Alberta, Canada. RESULTS: One hundred and fifty-seven patients were diagnosed with advanced stage LGFL. Approximately 45% of patients had died at last follow-up. Treatment was initiated at the time of diagnosis in 87 patients (55%), with alkylating agents used in 66% of them. Of the 70 patients not treated at the initial diagnosis, 69% had been treated at a median of 16.3 months. The overall median survival was 5.9 years. On univariate analysis, significant variables (P < 0.20) included age, B symptoms, symptomatic lymphadenopathy, symptomatic splenomegaly, splenomegaly, Eastern Cooperative Oncology Group performance status, baseline lactate dehydrogenase (LDH), diffuse component on histology, and treatment at the time of diagnosis. By multivariate analysis, the only factors that influenced survival significantly and independently were baseline LDH and B symptoms. An elevated baseline LDH had a hazard ratio of 2.80 (95% confidence interval [CI], 1.65, 4.74) and a median survival of 8.0 years versus 3.6 years (P < 0.0001). B symptoms had a hazard ratio of 2.30 (95% CI, 1.23, 4.30) and a median survival of 6.5 years versus 3.1 years (P < 0.0067). CONCLUSIONS: Although some patients with advanced stage LGFL enjoy a prolonged survival, 80% of deaths in this cohort were attributable to lymphoma. The median overall survival of 5.9 years offers a less positive perspective on the outcome of these patients than in previous nonpopulation-based reports. This emphasizes the need for further population-based studies as well as new therapeutic approaches, especially those directed toward patients with poor prognostic features such as elevated baseline LDH and B symptoms.