Docetaxel-refractory Castration-resistant Prostate Cancer Research Articles

Comprehensive analysis of the associations between clinical factors and outcomes by machine learning, using post marketing surveillance data of cabazitaxel in patients with castration-resistant prostate cancer

BackgroundWe aimed to evaluate relationships between clinical outcomes and explanatory variables by network clustering analysis using data from a post marketing surveillance (PMS) study of castration-resistant prostate cancer (CRPC) patients.MethodsThe PMS was a prospective, multicenter, observational study of patients with metastatic, docetaxel-refractory CRPC treated with cabazitaxel in Japan after its launch in 2014. Graphical Markov (GM) model-based simulations and network clustering in ‘R’ package were conducted to identify correlations between clinical factors and outcomes. Factors shown to be associated with overall survival (OS) in the machine learning analysis were confirmed according to the clinical outcomes observed in the PMS.ResultsAmong the 660 patients analyzed, median patient age was 70.0 years, and median OS and time-to-treatment failure (TTF) were 319 and 116 days, respectively. In GM-based simulations, factors associated with OS were liver metastases, performance status (PS), TTF, and neutropenia (threshold 0.05), and liver metastases, PS, and TTF (threshold 0.01). Factors associated with TTF were OS and relative dose intensity (threshold 0.05), and OS (threshold 0.01). In network clustering in ‘R’ package, factors associated with OS were number of treatment cycles, discontinuation due to disease progression, and TTF (threshold 0.05), and liver and lung metastases, PS, discontinuation due to adverse events, and febrile neutropenia (threshold 0.01). Kaplan–Meier analysis of patient subgroups demonstrated that visceral metastases and poor PS at baseline were associated with worse OS, while neutropenia or febrile neutropenia and higher number of cabazitaxel cycles were associated with better OS.ConclusionsNeutropenia may be a predictive factor for treatment efficacy in terms of survival. Poor PS and distant metastases to the liver and lungs were shown to be associated with worse outcomes, while factors related to treatment duration were shown to positively correlate with better OS.

Real-world efficacy and safety of two doses of cabazitaxel (20 or 25\u2009mg/m2) in patients with castration-resistant prostate cancer: results of a Japanese post-marketing surveillance study

BackgroundThe recommended starting dose of cabazitaxel for castration-resistant prostate cancer (CRPC) is 25 mg/m2 in Japan and Europe. Although lower doses are established alternatives based on randomized controlled trials, the safety and efficacy of 25 and 20 mg/m2 in real-world settings are not well established. Therefore, we investigated the safety and efficacy of cabazitaxel at the recommended starting dose or a lower dose (20 mg/m2) in real-world clinical practice.MethodsWe compared the safety and efficacy of cabazitaxel between patients who received cabazitaxel at starting doses of 25 and 20 mg/m2 (C25 and C20, respectively) in a Japanese post-marketing surveillance study of 662 patients with docetaxel-refractory CRPC. Safety was assessed in terms of adverse drug reactions (ADRs). Prostate-specific antigen (PSA) response rate, overall survival (OS), and time-to-treatment failure (TTF) were compared between the C25 and C20 groups in unmatched patients and after applying propensity score matching.ResultsThe C20 and C25 groups comprised 190 and 159 patients without matching and 112 patients per group after matching. In unmatched patients, any-grade (C25 vs C20: 89.3% vs 78.4%, Fisher’s p < 0.01) and grade ≥ 3 (81.1% vs 61.1%) ADRs were more frequent in the C25 group. Neutropenia (any grade: 61.6% vs 54.2%; grade ≥ 3: 55.3% vs 42.6%) and febrile neutropenia (grade ≥ 3: 30.2% vs 14.7%) were more frequent in the C25 group. In matched patients, the PSA response rate (reduction in PSA ≥30% from a baseline ≥5 ng/mL) was 26.4 and 32.0% in the C20 and C25 groups, respectively, median OS was 291 days (95% CI 230–not reached) versus not reached (hazard ratio 0.73, 95% CI 0.50–1.08), and TTF favored C25 (hazard ratio 0.75, 95% CI 0.57–0.99).ConclusionsClinicians should consider the patient’s risk of clinically significant ADRs and prophylactic granulocyte colony stimulating factor when selecting the starting dose of cabazitaxel for CRPC. Some patients at high risk of ADRs or unfit patients may benefit from a lower starting dose of 20 mg/m2, whereas fit patients may be candidates for a starting dose of 25 mg/m2.Trial registrationNot applicable.

Potential predictive and prognostic factors for sequential treatment with abiraterone acetate and cabazitaxel in metastatic docetaxel-refractory castration-resistant prostate cancer (mDR-CRPC).

e16093 Background: in recent years Abiraterone Acetate (AA) andCabazitaxel (Cbz) were shown to be efficacious agents in patients with mDR-CRPC. However, no data exist for patients treated with both these drugs in terms of best sequencing evaluation and potential predictive and prognostic factors for different treatment sequencies. Aim of our study was to analyze these data in a real world scenario. Methods: intention-to-treat (ITT) analysis of activity data deriving from all consecutive patients with mDR-CRPC treated in our unit with prednisone plus Cbz, AA or both drugs. Data analyzed were, median Progression Free Survival (mPFS) for the two single agents and their sequencies (evaluated according to PCWG2, Prostate Cancer Working Group 2, criteria) and their possible correlations with median age, Gleason score, baseline PSA, ECOG PS, visceral metastases and number of previous chemotherapy lines. Results: here we report characteristics and activity data of the initial 62 patients, 7 treated with Cbz, 32 with AA and 16 with both drugs. The median age of our study population was 71.5 years (range, 55-87), median Gleason Score 8 (4-9) and median ECOG PS 0 (0–3); visceral disease was present in 37 cases (59.7%). The mPFS, according to Kaplan Meier method (KM), was 4.7 months (m) for patients treated with Cbz, 8.6 months for cases treated with AA and 8.2 m for cases treated with both agents. Of the 16 patients treated with both drugs, 12 received a sequence Cbz-AA and 4 a sequence AA-Cbz for an overall median PFS of, respectively, 5.6 and 4.0 m. Any of the analyzed prognostic or predictive factor was found to be significant. Conclusions: in our experience AA and Cbz were showed to be effective agents in the mDR-CRPC setting also when used sequentially. No clear indication of a preferred treatment sequence was identified such as eventual prognostic/predictive factors, also because of the limited number of treated patients. These data should be analyzed in large size prospective trials.

Recent advances in second-line treatment of castration-resistant prostate cancer

Patients with metastatic castration-resistant prostate cancer (CRPC) no longer responsive to docetaxel have a poor prognosis, worsened quality-of-life, and traditionally few options for treatment. This review addresses promising and practice-changing developments for the treatment of CRPC in the second-line setting. Recent data for cabazitaxel, a novel taxane chemotherapy, and abiraterone acetate, a novel inhibitor of androgen synthesis, demonstrate significant improvements in the survival of patients with docetaxel-refractory CRPC. We review the mechanisms of action of these agents and data from phase III clinical trials, contextualizing their place in therapy. We also update other areas of investigation, including oral platinum analogues, vascular-endothelial growth factor receptor targeted therapy, inhibitors of chaperone proteins, and androgen receptor antagonists. Upon disease progression after first-line docetaxel chemotherapy, cabazitaxel and abiraterone improve survival of patients with CRPC and are important novel treatment options. Potential toxicity from cabazitaxel necessitates careful patient selection and supportive care. Both abiraterone and cabazitaxel are also being evaluated in the first-line setting, and therefore the optimal sequencing of therapies remains uncertain. Many other novel agents continue to be evaluated and promising classes of agents include antisense oligonucleotides against clusterin (custirsen) and androgen receptor antagonists (MDV3100).

Experience in the use of sunitinib given as a single agent in metastatic chemoresistant and castration-resistant prostate cancer patients

Objective: Vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) correlate with poor prognosis in castration-resistant prostate cancer (CRPC). Sunitinib has shown activity in CRPC and at the time of this analysis there was no standard therapy for docetaxel-refractory CRPC.Methods: We present a case series data collection of 19 patients with a median age of 73 years, CRPC and rising prostate-specific antigen (PSA). Patients received sunitinib 37.5 mg continuous daily dose. One cycle comprised a 4-week period. Patients were evaluated by CT scan every 8 weeks and PSA was monitored every 4 weeks.Results: Median Eastern Cooperative Oncology Group (ECOG) performance status score was 2. Patients received a median of two previous treatment lines for the hormone-refractory setting. Baseline median PSA was 280 ng/ml. Patients received a median of 16 weeks of therapy (4 – 48+). One patient achieved a partial response (5%) and 12 (66.7%) achieved stable disease for at least 3 months according to RECIST criteria. Median progression-free survival was 4 months. PSA declined > 50% in 5/19 (26.3%) and stabilized in 7/19 (37%) patients. Frequent adverse events were grade 3 asthenia (21%), grade 3 diarrhea (10%) and grade 3 hand-foot syndrome (15.7%).Conclusions: Activity with sunitinib was observed in highly pretreated docetaxel-refractory CRPC with acceptable tolerability. Additional studies should confirm the role of antiangiogenic agents in this setting.

Phase II trial of cisplatin plus prednisone in docetaxel-refractory castration-resistant prostate cancer patients

Docetaxel represents the first-line treatment for castration-resistant prostate cancer (CRPC). New therapeutic options are needed for subsequent lines of therapy in CRPC patients. Patients with progressive CRPC, pretreated with docetaxel, were enrolled at the Department of Molecular and Clinical Oncology and Endocrinology of University 'Federico II of Naples' from April 2007 to January 2010. Accrued patients received cisplatin at the dose of 75 mg/m(2) every 3 weeks with daily 10 mg prednisone. Measures of response and progression were defined according to the Prostate Cancer Working Group (PCWG1) criteria. Toxicity was graded according to the Common Toxicity Criteria of the National Cancer Institute, version 3.0. Twenty-five patients were recruited. Median age was 65 years (interquartile range 55-74 years). All patients were evaluable for PSA response and toxicity and thirteen patients (52%) were evaluable for measurable disease. A total of 170 cycles of cisplatin chemotherapy were administered. Median dose intensity corresponded to 96% (range 83.8-98.3%) of the maximum dose intensity that could be delivered. Three patients (12%) presented grade 3-4 neuropathy and ten (40%) presented grade 3-4 neutropenia. Five patients (20%) showed a greater than 50% PSA decline, and three of thirteen patients with measurable disease presented a partial response. Median progression-free survival was 5.6 months (24 weeks; range 15-24). Median survival was 55 weeks (range 46-64; see Fig. 1). Cisplatin plus prednisone appears to represent an active regimen in docetaxel-refractory CRPC with an acceptable toxicity profile. Further investigations in this setting are warranted to confirm these early encouraging findings.

Abiraterone Acetate, A Novel Adrenal Inhibitor in Metastatic Castration-Resistant Prostate Cancer

The androgen receptor remains the key player in patients with castration-resistant prostate cancer (CRPC). Available agents capable of blocking early adrenal androgen production have limited activity and can lead to significant toxicities. Abiraterone acetate, a pregnenolone analog, is a small molecule that irreversibly inhibits CYP17, a rate-limiting enzyme in androgen biosynthesis. Several clinical trials have demonstrated the safety and efficacy of this compound in men with metastatic CRPC. Recently, a randomized phase 3 trial evaluating abiraterone acetate in docetaxel-refractory CRPC patients demonstrated a survival improvement over placebo-treated patients (14.8 vs 10.9months; HR 0.646; P < 0.0001). A similar trial in the pre-chemotherapy setting has completed accrual and is undergoing analysis. Here we review the rationale and clinical development of abiraterone acetate in men with CRPC.

Ixabepilone, mitoxantrone, and prednisone for metastatic castration‐resistant prostate cancer after docetaxel‐based therapy

Mitoxantrone plus prednisone and ixabepilone each have modest activity as monotherapy for second-line chemotherapy in patients with docetaxel-refractory castration-resistant prostate cancer. Clinical noncross- resistance was previously observed. Phase 1 testing determined the maximum tolerated dose and dose-limiting toxicities with the combination regimen; a phase 2 study was conducted to evaluate the activity of the combination. Patients with metastatic progressive castration-resistant prostate cancer during or after 3 or more cycles of taxane-based chemotherapy enrolled in a phase 2 multicenter study of ixabepilone 35 mg/m(2) and mitoxantrone 12 mg/m(2) administered on Day 1 every 21 days with pegfilgrastim support, along with prednisone 5 mg twice daily. Patients were evaluated for disease response and toxicity. Results are reported for the 56 evaluable patients. Twenty-five (45%; 95% confidence interval [CI], 31%-59%) experienced confirmed ≥ 50% prostate-specific antigen (PSA) declines, 33 (59%; 95% CI, 45%-72%) experienced confirmed ≥ 30% PSA declines, and 8 of 36 patients (22%; 95% CI, 10%-39%) with measurable disease experienced objective responses. Median time to PSA or objective progression was 4.4 months (95% CI, 3.5-5.6), and median progression-free survival was also 4.4 months (95% CI, 3.0-6.0). Median overall survival was 12.5 months (95% CI, 10.2-15.9). Thirty-two percent of patients experienced grade 3 of 4 neutropenia, and 11% experienced grade 3 or higher neutropenic infections, including 1 treatment-related death. Grade 2 and 3 neuropathy occurred in 11% and 12.5% of patients, respectively. These results suggest that the combination of ixabepilone and mitoxantrone is both feasible and active in castration-resistant prostate cancer and requires dosing with pegfilgrastim.

Phase I Study of Ixabepilone, Mitoxantrone, and Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Therapy: A Study of the Department of Defense Prostate Cancer Clinical Trials Consortium

Mitoxantrone plus prednisone and ixabepilone each have modest activity as second-line chemotherapy in docetaxel-refractory castration-resistant prostate cancer (CRPC) patients. Clinical noncrossresistance was previously observed. Metastatic CRPC patients progressing during or after taxane-based chemotherapy enrolled in a phase I multicenter study of ixabepilone and mitoxantrone administered every 21 days along with prednisone. Ixabepilone and mitoxantrone doses were alternately escalated in a standard 3 + 3 design. Patients were evaluated for toxicity and disease response. Dose-limiting toxicities (DLTs) were defined as treatment related, occurring during cycle 1, and included grade 4 prolonged or febrile neutropenia, thrombocytopenia (grade 4 or grade 3 with bleeding), or > or = grade 3 nonhematologic toxicity. Thirty-six patients were treated; 59% of patients experienced grade 3/4 neutropenia. DLTs included grade 3 diarrhea (n = 1), prolonged grade 4 neutropenia (n = 4), and grade 5 neutropenic infection (n = 1). Due to prolonged neutropenia, the highest dose levels were repeated with pegfilgrastim on day 2 of each cycle. The maximum tolerated dose in combination with pegfilgrastim was not exceeded. The recommended phase II dose is mitoxantrone 12 mg/m2 and ixabepilone 35 mg/m2 every 21 days, pegfilgrastim 6 mg subcutaneously day 2, and continuous prednisone 5 mg twice per day. Thirty-one percent of patients have experienced > or = 50% prostate-specific antigen (PSA) declines, and two experienced objective responses. Of 21 patients treated with mitoxantrone 12 mg/m2 plus ixabepilone > or = 30 mg/m2, nine (43%) experienced > or = 50% PSA declines (95% CI, 22% to 66%). These results suggest that the combination of ixabepilone and mitoxantrone is feasible and active in CRPC and requires dosing with pegfilgrastim.