Previous Docetaxel Research Articles

Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial

Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases. In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751. Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5-18·0] vs 9·8 months [7·3-23·7]; hazard ratio [HR]=0·66, 95% CI 0·52-0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53-0·85) and spinal cord compression (HR=0·52, 95% CI 0·29-0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35-1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28-1·82). Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases. Algeta and Bayer HealthCare Pharmaceuticals.

Metronomic Oral Cyclophosphamide Chemotherapy Possibly Contributes to Stabilization of Disease in Patients With Metastatic Castration-Resistant Prostate Cancer: A Prospective Analysis of Consecutive Cases

Introduction/BackgroundCastration-resistant prostate cancer remains a therapeutic challenge, even after establishing the survival benefits of docetaxel chemotherapy. Metronomic chemotherapy stabilizes various cancers through antiangiogenic and immunomodulatory effects. We evaluate the activity of metronomic oral cyclophosphamide chemotherapy in metastatic CRPC patients, and assess predictive factors for clinical outcomes. Patients and MethodsTwenty-four patients with metastatic CRPC received an oral cyclophosphamide and dexamethasone regimen. Of those, 11 patients (45.8%) had been exposed and resistant to previous docetaxel chemotherapy. Six patients had refused to receive docetaxel chemotherapy, and 7 patients could not receive the therapy because of deteriorated performance status. All patients had already shown resistance to continuous dexamethasone therapy. Demographic and clinical data were collected prospectively. ResultsA total of 16 patients (66.7%) experienced a reduction in PSA levels, and PSA decrease ≥ 50% was observed in 8 patients (33.3%). The median PSA progression-free and overall survival were 5.0 months and 19.0 months, respectively. The favorable PSA decrease had no associations with the progression-free and overall survival, but 7 patients (29.2%) in whom response had exceeded 8 months achieved long overall survival of 28 months in median. None of the patients discontinued therapy because of the presence of toxicities. ConclusionMetronomic cyclophosphamide is an active and well tolerated chemotherapy and can be an option for metastatic CRPC patients. The benefit of this regimen could not always be evaluated according to a favorable PSA decrease; thus, we must identify the predictive factors of response other than known clinical factors.

Enzalutamide in men with prostate cancer resistant to docetaxel and abiraterone.

247 Background: Since FDA approval in 2011, abiraterone (Zytiga) has supplanted docetaxel as preferred first-line treatment for metastatic castrate-resistant prostate cancer. In August 2012 enzalutamide (Xtandi) was FDA-approved for the treatment of castrate-resistant prostate cancer after docetaxel (Taxotere). We performed a retrospective chart review at a large medical oncology clinic specializing in prostate cancer to determine the PSA response rates of enzalutamide administered to men who had previously progressed on both abiraterone and docetaxel. This report includes some patients who participated in the Astellas/Medivation-sponsored Early Access Program; however, it represents the author’s independent clinical experience. Methods: Enzalutamide was administered at a dose of 160 mg daily. Patients were subsequently followed with monthly physical examination, PSA and routine blood tests. No hepatotoxicity or seizures occurred. Men were considered evaluable for PSA response if they received enzalutamide for twelve weeks. A PSA decline of 30% from baseline after 12 weeks was defined as a response. A PSA increase of 30% from baseline within 12 weeks was defined as disease progression. Men with neither a 30% increase nor a 30% decline were classified as having stable disease. Results: 66 men were treated and 63 were evaluable for PSA response. Median age was 67. Median baseline PSA was 68.5. All participants had disease that had progressed on abiraterone. 55 men received previous docetaxel. 38 had received previous Provenge. Two men stopped before 12 weeks because of intolerable fatigue. One man died of progressive disease before 12 weeks. After a median follow up of 12.5 weeks, 18(29%) men met criteria for PSA response. 13(21%) men had stable disease and 32(51%) men had PSA progression. Conclusions: Enzalutamide has activity in a heavily pretreated population of men resistant to abiraterone and docetaxel.

Safety of cabazitaxel in elderly patients with metastatic castrate resistant prostate cancer (mCRPC) previously treated with docetaxel therapy.

e16081 Background: Cabazitaxel (Cab) is a novel taxane for treatment of mCRPC in progression during or after Docetaxel therapy. However, the management of elderly pts also depends on comorbidities that may impact the performance status and influence the treatment decisions. This study was aimed to assess both activity and safety of Cab in a cohort of ≥ 65 yrs aged patients with mCRPC unresponsive to Docetaxel. Methods: Between 11/2011 and 01/2013, 26 pts with mCRPC relapsing after Docetaxel as first line treatment were enrolled following their comprehensive geriatric assessment for eligibility to the study also extended as EAP. The Cab schedule included 25 mg/m2 every three weeks plus 10 mg Prednisone (P) daily. Comorbidities were assessed using the cumulative illness rating geriatric scale (CIRS-G) with 0-4 score. Median age was 73 yrs (65-89), ECOG PS 0-2, median baseline PSA was 107 ng/ml, whereas comorbidities included pneumonia, arterial hypertension, arrhythmias and diabetes. Pts were managed every 3 months by CT, whereas both response rate (RR) and correlations between comorbidities and toxicity were the endpoints of the study. Results: Pts received the CabP schedule with none dose reduction. Minimal adverse effects were recorded as grade 3-4 anemia whereas no episodes of neutropenic fever were observed. Sexteen/26 pts entered in EAP study. Comorbidities were recorded as GIRS-G1-2 in 17 pts, G3 in 7, and G4 in 2. 9/26 pts received total previous docetaxel dose < 1200 mg/tot and 17/26 pts received ≥ 1200 mg/toto. Among the CabP-treated pts, 3 of them showed partial response with one year of median duration and PSA response ≥ 50%, whereas 8 maintained a stable disease with 9 months of median duration and PSA response < 50%. Conversely, 15 pts underwent progression after 5 months of CabP treatment. Conclusions: Our data suggest that comorbidities in mCRPC ≥ 65 yrs aged pts do not interfere with the toxicity of CabP thus supporting its efficacy and safety in older pts unresponsive to previous Docetaxel therapy. Therefore, CabP does not impact the quality of life and emphasizes a proper disease control (PR+SD) in 11/26 pts.

Landmarks in non‐hormonal pharmacological therapies for castration‐resistant prostate cancer

• The treatment of metastatic and castration-resistant prostate cancer (CRPC) has advanced considerably from the era where it was considered that the disease was resistant to chemotherapy. • Cytotoxic chemotherapy involving docetaxel is now used routinely as a first-line therapy after failed first- and second-line androgen deprivation in advanced disease, improving quality of life and to a limited extent, survival in patients with advanced prostate cancer. • The cytotoxic taxane, cabazitaxel has also become a second-line treatment option for patients with CRPC failing previous docetaxel therapy. • Additionally, a broad range of agents are now available or under development including immune-based therapies (cellular therapies and vaccines), bone-targeting agents (anti-osteolytic and anti-tumour therapies) and molecular-based agents targeting cellular control mechanisms. • Most of these remain experimental but on-going pharmacological development will inevitably provide urologists and urological oncologists with a broader range of therapeutic options for better cancer management in the future.

953 - Cabazitaxel in Patients with Advanced CRPC after Docetaxel-Failure. Results of Expanded Program Access (EAP) in Spain: Safety and Efficacy

ABSTRACT Background Cabazitaxel is the new chemotherapy standard in second line treatment of metastatic castrate resistant prostate cancer (CPRC) [TROPIC Trial, Lancet 2010]. The aim of this study was to analyze the baseline characteristics and outcomes of a cohort of patients from six Spanish hospitals enrolled in a EAP. (total no of pts: 138) Methods Between 3-2011 and 12-2012, 65 mCRPC pts who have progressed on or after docetaxel-based chemotherapy were treated with Cabazitaxel (25 mg/m2 IV q3wks plus oral prednisone 10mg daily. All pts had proven histology confirmation of prostate adenocarcinoma and progressive disease (radiologic and/or rising PSA) at the beginning of the treatment. Results Median age was 63 years (range 45-83) and ECOG 0-1 in 25%-68% respectively. Median PSA at baseline was 864 ng/ml. Seventy-eight percent had bone metastases, 33% lymph nodes metastases and 14% visceral metastases. Previous therapy was: hormonal, (median 2 lines) and chemotherapy (median 1.6 lines). Thirty percent (20 pts) had received ketoconazole. Median previous docetaxel dose was 1029 mg/m2(50-3750). Seventy percent of pts received G-CSF as primary prophylaxis in any cycle, 24% (16pts) had grade >3 neutropenia and 9% (6 pts) had febrile neutropenia. Other grade 3 toxicities were: anemia 3pts (4,6%), asthenia 5pts (7,7%), diarrhea 1 pt (1,5%). No toxic death was reported. The PSA decrease ≥50% was observed in 64% (31pts) and the median number of cycles administered was 6 at last check. Median progression free survival was 4.4 months (2.7-6.1). Conclusions Results of this Spanish EAP confirm the efficacy and manageable safety of Cabazitaxel in daily practice. (CGR I would not comment on GCSF as many countries do not use prophylactic GCSF) Disclosure All authors have declared no conflicts of interest.

Cabazitaxel in patients with advanced CRPC after docetaxel failure: Results of expanded program access (EAP) in Spain: Safety and efficacy.

e15149 Background: Cabazitaxel is the new chemotherapy standard as second line in castrate resistant prostate cancer (CPRC) [Tropic Trial, Lancet 2010]. The aim of this study was to analyze the baseline characteristics and outcomes in a different cohort of patients (pts) from six hospitals in Spain within to EAP. Methods: We report a cohort of 65 pts including in EAP trial, who have progressed on or after docetaxel-based chemotherapy. Cabazitaxel was administered a standard dose of 25 mg/m2 IV q3wks. All pts had proven histology confirmation of prostate adenocarcinoma and progressive disease (radiologic and/or rising PSA) at the beginning of the treatment. Results: We collected data of 65 pts between 3-2011 to 12-2012. Median age was 63 years (range 45-83) and ECOG 0-1-2 in 26%-58%-16% respectively. Median basal PSA was 864 and Gleason grade was 7. Seventy-eight percent had bone metastases, 33% ganglionar metastases and 14% visceral metastases. Previous therapy was: hormonal, median 2 lines and chemotherapy was median of 1.6 lines. Thirty percent (20 pts) had received ketoconazole. Median of previous docetaxel dose was 1029 mg/m2(50-3750). Seventy percent of pts received G-CSF as primary prophylaxis in any cycle, 24% (16pts) had grade >3 neutropenia and 6 pts (9%) had febrile neutropenia. Other toxicities were: g3 anemia 3pts (4,6%), g3 asthenia 5pts (7,7%), g3 diarrhea 1 pt (1,5%). No toxic death was reported. The PSA response rate to cabazitaxel was 64% (31pts) and the median of cabazitaxel cycles administered was 6 at last follow-up. Median progression free survival was 4.4 months (2.7-6.1). Conclusions: These results confirm the efficacy and safety of cabazitaxel in this setting. Similar baselines parameters to Tropic trial were observed. This data reflex that Cabazitaxel in CRPC pts after docetaxel failure require the use of G-CSF in daily clinical practice.

Cicatricial Entropion Following Docetaxel (Taxotere) Therapy

We report eyelid margin changes in 3 patients after docetaxel treatment for breast cancer. These patients were referred to Cincinnati Eye Institute for eyelash abnormalities and/or epiphora and all had been treated with docetaxel in the near past. The ophthalmic complaints started soon after chemotherapy. All 3 cases showed varying degrees of palpebral mucosal inflammation and cicatricial changes leading to marginal entropion. The first patient exhibited very prominent eyelid margin inflammation and diffuse trichiasis without madarosis. The second patient had extensive madarosis and abnormally curved, thin eyelashes with punctal and canalicular obstruction. Her marginal entropion was most prominent at the medial lower eyelids. The last patient showed significant lash misdirection in a scattered distribution and patchy madarosis along with pseudomembranes blocking the puncta. All of these eyelid abnormalities occurred soon after docetaxel treatment for advanced breast cancer. Such changes in the absence of questioning for previous docetaxel use in history taking.

Predictive factors of response to docetaxel (DOC) rechallenge (ReC) in castration-resistant prostate cancer (CRPC) patients (pts).

e15126 Background: ReC with DOC is an option for CRPC pts, who have responded to first-line DOC and have stopped the treatment without progression. The possibility of obtaining a new response by a DOC ReC is usually considered on the basis of the response to the previous treatment. We attempt to identify if there are additional factors able to predict ReC response. Methods: From March, 2002 to December, 2010, a consecutive series of 45 CRPC pts received at least one ReC after first-line DOC, for a total of 91 ReC courses (median 2, range 1-7). ReCs consisted of 4-6 DOC cycles and were proposed until the appearance of a true resistance to DOC: we consider as DOC-resistant pts showing a clinical and/or biochemical progression during DOC treatment. For each ReC course, we recorded the following parameters: treatment schedule (3 wks vs weekly), estramustine use (yes vs no), PSA response (↓ > 50%) at the previous DOC course, baseline parameters (hemoglobin, alkaline phosphatase, pain presence, ECOG), number of previous DOC courses, PSA parameters (slope LOG, doubling time, velocity) during both previous DOC course and treatment holiday, duration of treatment holiday before ReC. A binary logistic regression analysis was applied. Continuous variables were categorized by quartiles and chosen for the initial model after a univariate chi-square analysis. Results: In 67% of 91 ReCs we observed a PSA reduction > 50%. After a median follow-up of 25 mos, the median survival is 32 mos and the projected 2-years overall survival is 77.5%. ReC was well tolerated with no more than grade 1-2 hematological and non-hematological toxicities. Having an interval log-PSA equal to or more than 0.62 [(exp(beta) 8.965; p= 0.020], an interval from the previous cycle equal to or more than 23 weeks [(exp(beta) 8.212; p= 0.002], a response to the previous cycle [(exp(beta) 7.658; p= 0.014], resulted to be independently predictive of a response to ReC. Conclusions: In our experience, for CRPC pts sensitive to DOC, ReC appears to be a good option to obtain further response. Response to the previous cycle, interval log-PSA and interval from the previous cycle are factors able to identify the pts having more probabilities to respond to ReC.

Phase II trial of paclitaxel and uracil–tegafur in metastatic breast cancer. TEGATAX trial

This Phase II trial investigated the combination paclitaxel (P) and uracil–tegafur (UFT) in patients with metastatic breast cancer (MBC). Methods Main eligibility criteria included HER-2 negative MBC, ECOG performance status of 0–2, exposure to 1–2 prior chemotherapy regimen in the metastatic setting, previous exposure to an anthracycline containing regimen either at metastatic or adjuvant setting. Each 35-day cycle consisted of P at 80 mg/m 2 by intravenous infusion on days 1, 8, 15, 22 and 29 and oral UFT at 300 mg/m 2 TID (three time a day) from days 1–28 and oral folinic acid at 90 mg QD (one a day). Results Between March 2003 and December 2007, 31 patients were enrolled. Median age was 66 years (range 44–78). All tumours were HER-2 negative and 7% were triple negative (ER, PgR, HER-2). The majority of patients had visceral disease (81%). All patients had received an anthracycline containing regimen and 74% had a previous docetaxel containing treatment. Median of 4 and 3 cycles of P and UFT were administered with a relative dose intensity of 85.3% and 94.3%, respectively. Twelve (40%)(95% CI: 22.5–57.5) confirmed ORR were observed. Stable and progression disease were reported in 43% and 17% of cases. Median Response duration was 8.4 month (95% CI: 4.9–11.7), median Time to progression was 9.5 months (95% CI: 6.6–13.8) and median Overall Survival was 23.5 months (95% CI: 16.8–37.2). Thirteen pts (43%) experienced a grade 3 or 4 adverse events (AEs): One death occurred related to the study drugs (febrile neutropenia). Chemotherapy was discontinued due to toxicity in 30% of pts Conclusions Accrual was closed in January 2008 due to concerns regarding the degree and accumulative nature of AEs. Nonetheless, the ORR is encouraging and warranted further studies with adapted doses and schedules.

Comparison of Survival in Advanced Non-Small Cell Lung Cancer Patients in the Pre- and Post-Gefitinib Eras

Background: The aim of this study was to analyze the survival difference between advanced non-small cell lung cancer (NSCLC) patients in the pre-gefitinib and post-gefitinib eras in Korea. Patients and Methods: 830 patients with advanced/metastatic or recurrent NSCLC who received palliative chemotherapy were retrospectively reviewed. Using a matched-pair case-control study design, 334 pairs from the pre-gefitinib era (January 1999 to December 2001) and the post-gefitinib era (January 2002 to December 2005) were matched by age, sex and histology. Results: The median overall survival from the date of first administration of palliative chemotherapy was significantly longer in the post-gefitinib era (11.5 vs. 19.3 months, p< 0.001). Multivariate analysis showed that gefitinib was associated with longer overall survival (hazard ratio 0.58, p< 0.001) as were never having been a smoker, adenocarcinoma histology, good performance, stage IIIB, ≥3 prior episodes of chemotherapy, platinum-based chemotherapy and previous docetaxel or pemetrexed treatment. Patients in the post-gefitinib era showed significantly longer overall survival in almost all subgroups. Gefitinib treatment was of significantly greater benefit in patients with adenocarcinoma than in those with non-adenocarcinoma (test for interaction p< 0.001). Conclusion: These results indicate a significant improvement of survival in advanced NSCLC patients treated with gefitinib in Korea.

Phase II Trial of Sunitinib for the Therapy of Progressive Metastatic Castration-Refractory Prostate Cancer After Previous Docetaxel Chemotherapy

Effective options are lacking for progressive castration-refractory prostate cancer (CRPC) after conventional chemotherapy. Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor that is approved multinationally for renal cell carcinoma and gastrointestinal stromal tumors. A phase II trial was conducted to examine the efficacy and toxicities of sunitinib in metastatic CRPC progressing after 1-2 previous chemotherapy regimens including docetaxel. The primary objective was clinical progression-free survival (PFS) with a 12-week PFS ≤ 30% assumed to be of interest. Secondary objectives included prostate-specific antigen (PSA) response, modulation of PSA kinetics, objective response, quality of life, pain, survival, and toxicities. Sunitinib 50 mg daily was administered orally on days 1-28 of each 6-week cycle. Patients were treated to a maximum of 8 cycles or until clinically progressive disease or intolerable toxicity.