LHRH sparing therapy in patients with chemotherapy-naïve, mCRPC treated with abiraterone acetate plus prednisone: results of the randomized phase II SPARE trial

Background Although the benefit of androgen deprivation therapy (ADT) continuation in metastatic castration-resistant prostate cancer (mCRPC) remains controversial, clinical evidence is lacking. Recent results indicated that treatment with abiraterone acetate (AA) plus prednisone (P) further suppresses serum testosterone levels over ADT alone, suggesting that continuation of ADT in the treatment of mCRPC may not be necessary. Methods In this exploratory phase 2 study, mCRPC patients were randomized with a 1:1 ratio to receive either continued ADT plus AA + P (Arm A) or AA + P alone (Arm B). The primary endpoint was the rate of radiographic progression-free survival (rPFS) at month 12. Secondary endpoints included PSA-response rate, objective response, time to PSA progression and safety. Results A total of 68 patients were equally randomized between the two study arms. Median testosterone-levels remained below castrate-levels throughout treatment in all patients. According to the intention-to-treat analysis the rPFS rate was 0.84 in Arm A and 0.89 in Arm B. Moderate and severe treatment-emergent adverse events were reported for 72% of the patients in Arm A and for 85% of the patients in Arm B. Conclusions AA + P treatment without ADT may be effective in mCRPC patients and ADT may not be necessary in patients receiving AA + P

Antimicrobial peptides of the Cecropin-family show potent antitumor activity against bladder cancer cells

<p>Abstract</p> <p>Background</p> <p>This study evaluated the cytotoxic and antiproliferative efficacy of two well-characterized members of the Cecropin-family of antimicrobial peptides against bladder tumor cells and benign fibroblasts.</p> <p>Methods</p> <p>The antiproliferative and cytotoxic potential of the Cecropins A and B was quantified by colorimetric WST-1-, BrdU- and LDH-assays in four bladder cancer cell lines as well as in murine and human fibroblast cell lines. IC₅₀values were assessed by logarithmic extrapolation, representing the concentration at which cell viability was reduced by 50%. Scanning electron microscopy (SEM) was performed to visualize the morphological changes induced by Cecropin A and B in bladder tumor cells and fibroblasts.</p> <p>Results</p> <p>Cecropin A and B inhibit bladder cancer cell proliferation and viability in a dose-dependent fashion. The average IC₅₀values of Cecropin A and B against all bladder cancer cell lines ranged between 73.29 μg/ml and 220.05 μg/ml. In contrast, benign fibroblasts were significantly less or not at all susceptible to Cecropin A and B. Both Cecropins induced an increase in LDH release from bladder tumor cells whereas benign fibroblasts were not affected. SEM demonstrated lethal membrane disruption in bladder cancer cells as opposed to fibroblasts.</p> <p>Conclusion</p> <p>Cecropin A and B exert selective cytotoxic and antiproliferative efficacy in bladder cancer cells while sparing targets of benign murine or human fibroblast origin. Both peptides may offer novel therapeutic strategies for the treatment of bladder cancer with limited cytotoxic effects on benign cells.</p

Adherence Measures for Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone Acetate plus Prednisone: Results of a Prospective, Cluster-Randomized Trial

Residual androgen production causes tumor progression in metastatic, castration-resistant prostate cancer (mCRPC) patients. Abiraterone acetate (AA), a prodrug of abiraterone, is an oral CYP-17 inhibitor that blocks androgen production. It was hypothesized that adherence-enhancing measures (AEM) might be beneficial for mCRPC patients receiving abiraterone acetate plus prednisone (AA + P). This multicenter, prospective, 2-arm trial allocated mCRPC patients who were progressive after docetaxel-based chemotherapy or asymptomatic/mildly symptomatic after failure of an androgen deprivation therapy to Arm A (with AEM) or Arm B (without AEM) by center-based cluster-randomization. The primary objective was to assess the influence of AEM on discontinuation rates and medication adherence in mCRPC patients treated with AA + P. A total of 360 patients were allocated to Arm A, and 315 patients to Arm B. At month 3, the rate of treatment discontinuation, not due to disease progression or the start of new cancer therapy, was low in both arms (A: 9.0% vs. B: 7.3%, OR = 1.230). Few patients had a medium/low Morisky Medication Adherence Scale (MMAS-4) score (A: 6.4% vs. B: 9.1%, OR = 0.685). The results obtained did not suggest any clear adherence difference between Arm A and Arm B. In patients with mCRPC taking AA + P medication, adherence seemed to be generally high

No measurable effect of systemically induced PPD-response on treatment success.

<p>(<b>A</b>) Recurrence-free survival depending on PPD-status before therapy. (<b>B</b>) The increase of percentages of IFN-γ producing CD4 T cells among all specific T cells after stimulation with PPD between baseline and maximum value was compared in non-responders (white circles, n=8) and responders (black circles, n=10).</p

Bladder cancer patients before BCG-therapy and healthy controls do not differ in their baseline PPD-reactivity.

<p>(<b>A</b>) The percentage of individuals with pre-existing immunity towards PPD (≥0.05% CD69 positive interferon-γ (IFN-γ) or interleukin 2 (IL-2) producing CD4 T cells) and (<b>B</b>) PPD-reactive T cell frequencies of IFN-γ or IL-2 producing CD4 T cells were quantified in bladder cancer patients before BCG-therapy (n=18) and in age-matched healthy controls (n=54). In one patient, the baseline value was not available. However, as this patient did not have any specific immunity one week after start of therapy, baseline immunity was considered below detection limit. T cell frequencies of each individual (circles) as well as the median value and interquartile range (IQR) are shown, and the detection limit (0.05% reactive CD4 T cells) is represented by a dotted line.</p

Higher increase in PPD-reactive T cell frequencies in patients without pre-existing immunity before therapy.

<p>The increase of PPD and SEB-reactive CD69 positive IFN-γ producing T cells between baseline and the maximum value during BCG-instillations was quantified for all patients and results were stratified for patients with negative and positive PPD-status before therapy. Medians and interquartile ranges are indicated.</p