Critical appraisal of cabazitaxel in the management of advanced prostate cancer

Docetaxel remains a cornerstone of therapy for the patient with metastatic castration-resistant prostate cancer (CRPC). However, the landscape of CRPC therapy is changing rapidly – recently, data from the phase III TROPIC study revealed a survival advantage with the novel taxane cabazitaxel/prednisone (compared with mitoxantrone/prednisone) in a cohort of 755 men with docetaxel-refractory metastatic CRPC. Interestingly, cabazitaxel bears substantial structural similiarity to docetaxel but appears to be mechanistically distinct. In preclinical studies, the agent has antitumor activity in a variety of docetaxel-refractory in vitro and in vivo models. Subsequent to phase I testing in advanced solid tumors (where neutropenia was identified as a dose-limiting toxicity), the agent was assessed in a phase II trial in advanced, taxane-refractory breast cancer and in the aforementioned phase III TROPIC study. This review describes in detail the preclinical and clinical development of cabazitaxel

Cryopreserved placental tissue allograft accelerates time to continence following robot-assisted radical prostatectomy.

Intra-operatively placed cryopreserved placental tissue allograft (CPTA) has shown promise in expediting the recovery urinary continence (UC) following robot-assisted radical prostatectomy (RARP). In this retrospective review of a prospectively maintained single-surgeon, single-institution RARP database, we compare three groups of patients: historical controls (C; N = 183 men) that received no allograft versus two different CPTA products (total CPTA N = 162 [A1 N = 81; A2 N = 81]). The CPTA product was intra-operatively placed as an onlay over the area of the neurovascular bundles during RARP. CPTA cases had significantly faster median time to UC (A1 = 1.4 months; A2 = 1.45 months) versus controls (1.64 months), p = 0.01. On multivariable analysis, use of A1 (HR 1.55, 95% CI [1.14-2.09], p = 0.005) and use of A2 (HR 1.53, CI [1.11-2.11], p = 0.01) were significantly associated with quicker return of UC. Older age (HR 0.97, CI [0.96-0.99], p = 0.001) and non-organ-confined clinical stage (HR 0.51, CI [0.26-1.0] p = 0.05), were significantly associated with slower return of UC. In a propensity score-matched analysis of 77 CPTA patients with sufficient follow-up versus controls, there was significantly less biochemical recurrence (BCR; p = 0.01). Our study indicates that CPTA use appears to accelerate time to UC in age- and performance status-matched men undergoing RARP without increased risk of BCR

A phase II trial of the Src-kinase inhibitor AZD0530 in patients with advanced castration-resistant prostate cancer: a California Cancer Consortium study.

Prostate cancer cells undergo neuroendocrine differentiation during androgen deprivation and secrete neuropeptides, hence activating androgen receptor-regulated genes. Src-family protein kinases are involved in neuropeptide-induced prostate cancer growth and migration. A phase II trial of AZD0530, an oral Src-family kinase inhibitor, in patients with advanced castration resistant prostate cancer was conducted. The primary endpoint was prostate cancer-specific antigen (PSA) response rate, defined as a 30% or greater decrease. A two-stage Simon design was used. Eligibility criteria included documentation of castration resistance (including antiandrogen withdrawal), adequate end-organ function, and performance status, and not more than one prior taxane-based chemotherapy regimen. AZD0530 was given at 175 mg orally once daily continuously. Rapid accrual led to 28 patients registering in the first stage. Median age was 67 years. Sixteen patients had performance status (PS) 0, eight patients had PS 1, and four patients had PS 2. Nine patients (32%) had prior docetaxel-based chemotherapy. Five patients had transient PSA reductions not meeting PSA response criteria. Median progression-free survival time was 8 weeks. Treatment was generally well tolerated. AZD0530, a potent oral Src kinase inhibitor, is feasible and tolerable in this pretreated patient population but possessed little clinical efficacy as monotherapy. Strong preclinical evidence warrants further investigation of AZD0530 in earlier-stage prostate cancer or as combination therapy

Long-Term Outcomes of Patients on a Phase II Prospective Trial of Oligometastatic Hormone-Sensitive Prostate Cancer Treated with Androgen Deprivation and External Beam Radiation.

PURPOSE: External beam radiation therapy (EBRT) to oligometastases may improve outcomes in patients with oligometastatic hormone-sensitive prostate cancer (oHSPC). Follow-up on this cohort has been limited to(ADT) on a prospective trial. MATERIALS AND METHODS: From 2006 to 2011, oHSPC patients with 1-5 metastases (mts) received 36 weeks of ADT (LHRH agonist + bicalutamide) and up to 53 Gy to all visible mts. When indicated, the primary tumor or prostate bed was treated with EBRT up to 78 Gy or 66 Gy, respectively. RESULTS: 29 patients were treated: 15 de novo, 14 oligorecurrent. 21 patients (72.4%) had bone mts. Median number of mts per patient was 1 (range 1-5). EBRT was administered to 52 lesions (38 bone, 12 pelvic lymph nodes [LNs], 2 non-pelvic LNs) up to 53 Gy (range 47-66). Median follow-up was 9.9 years (yrs, range 0.2-14.4). Median overall survival (OS) was 9.7 yrs (95% Confidence Interval [CI]:5.8-Not Reached [NR]). Median progression-free survival (PFS) was 1.9 yrs (95%CI: 1.6-2.2). Patients who presented with prostate cancer-defined de novo mts had significantly improved (p=0.04) median PFS (2.0 yrs, 95%CI: 1.3-6.0) compared to oligorecurrent pts (1.8 yrs, 95%CI: 1.0-2.0). Patients who presented with LN-only mts had numerically improved (p=0.13) median PFS (5.8 yrs, 95%CI: 1.2-NR) compared to patients with bony mts (1.8 yrs, 95%CI: 1.3-2.0). At last follow-up, 17 patients (58.6%) had local control of all EBRT treated mts. The mts that locally progressed had previously been controlled for median 3.5 yrs (range 1.7-10.5). CONCLUSION: Our results compare favorably with other reported studies of oHSPC and provide new insights into their long-term outcomes