abiraterone-acetate and Bone-Neoplasms

Most men with advanced prostate cancer will develop bone metastases, which have a substantial impact on quality of life. Bone metastases can lead to skeletal-related events (SREs), which place a burden on patients and healthcare systems. For men with castration-resistant prostate cancer (CRPC) and bone metastases, the treatment landscape has evolved rapidly over the past few years. The relatively recent approvals of the hormonal agents abiraterone acetate and enzalutamide, second-line chemotherapy cabazitaxel, and the radiopharmaceutical radium-223 dichloride (radium-223), have provided clinicians with a greater choice of treatments. These compounds have benefits in terms of overall survival based on the results of pivotal phase 3 studies. The bisphosphonate zoledronic acid and the RANK ligand inhibitor denosumab are indicated for the prevention of SREs in men with metastatic CRPC but studies of these compounds have not demonstrated a survival benefit. The important question of the role of bisphosphonates or denosumab in combination with these new agents has thus materialised. Current and emerging evidence from clinical studies of abiraterone acetate, enzalutamide and radium-223, suggest that addition of bisphosphonates or denosumab to these new therapies may provide further clinical benefits for patients with prostate cancer and bone metastases. This evidence may help to shape clinical practice but are based largely on post hoc analyses of clinical trial data. It is therefore apparent that further data are required from both clinical studies and real-world settings to enable physicians to understand the efficacy and safety of combination therapy with the new agents plus bisphosphonates or denosumab.

Topics: Abiraterone Acetate; Benzamides; Bone Density Conservation Agents; Bone Neoplasms; Clinical Trials, Phase III as Topic; Denosumab; Diphosphonates; Humans; Imidazoles; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radium; Randomized Controlled Trials as Topic; Taxoids; Zoledronic Acid

When advanced prostate cancer recurred during hormonal therapy and became the castration-resistant prostate cancer, "vintage hormonal therapy," such as antiandrogen alternating therapy or estrogen-related hormonal therapy, was widely carried out in Japan until 2013. This vintage hormonal therapy controlled the progression of castration-resistant prostate cancer. When castration-resistant prostate cancer relapses during these therapies, chemotherapy using docetaxel has been carried out subsequently. Since new hormonal therapies using abiraterone acetate and enzalutamide, which improve the prognosis of castration-resistant prostate cancer, became available in Japan from 2014, therapeutic options for castration-resistant prostate cancer have increased. Furthermore, the improvement of the further prognosis is promising by using cabazitaxel for docetaxel-resistant castration-resistant prostate cancer and radium-223 for castration-resistant prostate cancer with bone metastasis. An increase in therapeutic options gives rise to many questions, including best timing to use them and the indication. Furthermore, physicians have to consider the treatment for the recurrence after having carried out chemotherapy. We want to argue the difference in hormonal therapy between Japan and Western countries, and problems when carrying out new treatments, and the importance of imaging in the present review article.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Neoplasms; Disease Progression; Docetaxel; Humans; Japan; Male; Neoplasm Recurrence, Local; Nitriles; Phenylthiohydantoin; Prognosis; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Radium; Taxoids

Health-related quality of life (HRQoL) deteriorates rapidly in patients with advanced-stage cancer, with patients seriously disturbed by fatigue, sleep disorders, bone pain, constipation and other disease related symptoms. As treatment and prognosis continues to improve, reducing symptoms and improving quality of life with minimum of toxicities have become important therapeutic goals. The effectiveness of abiraterone acetate and enzalutamide in both prolonging life and improving quality of life in asymptomatic or mildly symptomatic patients with metastatic castrations-resistant prostate cancer (mCRPC) has been clinically proven.. Mit dem Auftreten von Metastasen verschlechtert sich zusehends auch die gesundheitsbezogene Lebensqualität von Karzinom-Patienten. Vor allem Fatigue, Schlafstörungen, Knochenschmerzen, Obstipation und andere krankheitsassoziierte Symptome belasten die Betroffenen sehr. Infolge der verbesserten Behandlungsmöglichkeiten und längeren Überlebenszeiten stellen auch Symptomkontrolle und Verbesserung der Lebensqualität wichtige Ziele der Tumortherapie dar. Bei Patienten mit metastasiertem kastrationsresistentem Prostatakarzinom (mCRPC) konnte für Abirateronacetat und Enzalutamid neben der signifikanten Überlebensverlängerung auch ein signifikanter Nutzen hinsichtlich mehrerer Parameter der Lebensqualität gezeigt werden.

Topics: Abiraterone Acetate; Benzamides; Bone Neoplasms; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Survival Rate; Treatment Outcome

Two new drugs, the CYP17 inhibitor abiraterone acetate and the androgen receptor (AR) antagonist enzalutamide, have recently shown to prolong OS prior chemotherapy or in docetaxel treated mCRPC patients, using steroidal therapy or placebo as control group. Updated analyses underlined the role of these new agents on two prostate-specific endpoints as radiographic progression-free survival (rPFS) and time to first skeletal-related event (tSRE). On the basis of these reports, we made an indirect comparison between abiraterone and enzalutamide. We obtained a clinically but not significant difference favouring enzalutamide over abiraterone in terms of rPFS (HR 0.48, 95% CI 0.22-1.02). No significant difference was shown in term of tSRE (HR 0.99, 95% CI 0.83-1.17). In conclusion, abiraterone and enzalutamide have both demonstrated to significantly delay the bone progression resulting in similar improvements in bone-related endpoints in patients with mCRPC.

Topics: Abiraterone Acetate; Androgen Receptor Antagonists; Benzamides; Bone Neoplasms; Cytochrome P-450 Enzyme Inhibitors; Disease Progression; Disease-Free Survival; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Chemoradiotherapy; Clinical Trials, Phase II as Topic; Humans; Male; Prednisone; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Radioisotopes; Radium; Treatment Outcome

Despite castrate levels of androgens, the androgen receptor (AR) remains active and continues to drive prostate cancer progression. Since the approval of docetaxel, four additional agents that show a survival benefit have been registered on the basis of randomized phase 3 trials. These have included enzalutamide and abiraterone, two agents designed specifically to affect the androgen axis, sipuleucel-T, which stimulates the immune system and cabazitaxel, a chemotherapeutic agent. Denosumab was shown to significantly delay skeletal-related events. Clinicians are challenged with a multitude of treatment options and potential sequencing of these agents that, consequently, make clinical decision making more complex. The induction of constitutively-active AR splice variants (AR-Vs) driving clonal proliferation of AR-negative and AR-independent metastases may be one major potential mechanism of resistance to new hormone therapies.

Topics: Abiraterone Acetate; Androstenes; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Benzamides; Bone Neoplasms; Clinical Trials, Phase III as Topic; Denosumab; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids; Tissue Extracts

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Denosumab; Docetaxel; Humans; Male; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms; Taxoids

Improved understanding of mechanisms underlying metastatic castration-resistant prostate cancer (mCRPC) progression has led to the recognition of multiple molecular targets and advances in the therapeutic landscape. The addition of abiraterone acetate, sipuleucel-T, cabazitaxel, and denosumab to the therapeutic armamentarium and the impending addition of MDV-3100 and radium-223 underscore the importance of androgen pathway inhibition, immunotherapy, tubulin antagonism, and pathophysiology of bone metastasis.. Review the next generation of molecular targets in mCRPC.. Medline databases were searched for >100 original articles published as of October 18, 2011, with the search terms metastatic castration-resistant prostate cancer, targeted therapy, biologic agents, and immunotherapy. Proceedings from the last 5 yr of conferences of the American Society of Clinical Oncology, American Urological Association, European Society of Medical Oncology, and the European Association of Urology were also searched. We included novel and promising drugs that have reached clinical trial evaluation.. The major findings were addressed in an evidence-based fashion. Prospective trials and important preclinical data were analyzed.. mCRPC is a disease with multiple molecular drivers. Molecular pathways being targeted in ongoing phase 3 trials are androgen signaling (MDV3100, TAK700), immunoregulatory pathways (ipilimumab, Prostvac-VF-TRICOM), Src (dasatinib), Met (cabozantinib), clusterin (custirsen), and angiogenesis (aflibercept, tasquinimod). The strides made in identifying multiple other novel molecular targets offer potential opportunities for further improving outcomes.

Topics: Abiraterone Acetate; Androstadienes; Anilides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Bone Neoplasms; Cancer Vaccines; Carcinoma; Clinical Trials, Phase III as Topic; Clusterin; Dasatinib; Denosumab; Humans; Ipilimumab; Male; Nitriles; Orchiectomy; Phenylthiohydantoin; Prostatic Neoplasms; Pyridines; Pyrimidines; Quinolines; Quinolones; Radium; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Taxoids; Thiazoles; Tissue Extracts; Treatment Outcome; Vaccines, Synthetic

If androgen deprivation, chemical with LH-RH analogs or surgical with bilateral orchiectomy, still remains the stone edge of treatment of prostate cancer, in the metastatic setting, this hormonosensitivity, most of the time long, finally move on in hormonal-failure. If rare changes in the therapeutic strategy have been achieved in this setting since 2004 and the arrival of docetaxel, it is the global perception of the disease that has been modified and the definition of one specific entity: the castrate-resistant prostate cancer. This new definition and the changes of design and end-points of clinical trials testing new agents with strong recruitment during the past years have conducted to a real revolution in the management of castrate-refractory prostate cancer. The place of secondary hormonal manipulations, such as withdrawal of the anti-androgen, oestrogen or ketoconazole, still exists for a selected group of patients. In case of aggressive disease and symptoms, chemotherapy should be selected, docetaxel, in a three weeks schedule, and may be combined with Estracyt. It is time to consider the revolution of the post-chemotherapy setting with the arrival of two new drugs ; a cytotoxic one, the cabazitaxel and hormonal for the second one, the abiraterone acetate. The place of the immunotherapy with the sipuleucel-T may be more difficult to precise, especially in Europe, even if it has been finally indicated in the United States in the metastatic setting. Concerning bone metastasis, zoledronic acid was during a long time the only bone-targeted agent, effective in reducing the incidence of skeletal related events, and was recently exceeded by the denosumab, an anti-RANK ligand. Finally, let us hope that other changes will be achieved in the near future, with the cabazitaxel-docetaxel confrontation in the first-line setting, and the introduction of the abiraterone acetate before chemotherapy with docetaxel, already tested in ongoing trials.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bone Density Conservation Agents; Bone Neoplasms; Cancer Vaccines; Denosumab; Diphosphonates; Docetaxel; Estramustine; Humans; Imidazoles; Male; Orchiectomy; Prostatic Neoplasms; Taxoids; Tissue Extracts; Zoledronic Acid

The paper aims to evaluate the efficacy and safety of. Median rPFS was 5.5 months (95% CI 5.3-5.5). Median rPFS of patients with AR-V7(-) CTCs was longer than that of patients with AR-V7(+) CTCs (5.5 versus 2.2 months, respectively; P = 0.056). Median overall survival was 14.8 months (95% CI 11.2-not reached) and was significantly greater for AR-V7(-) patients than for AR-V7(+) patients (14.8 months versus 3.5 months, respectively; P < 0.01).

Topics: Abiraterone Acetate; Androgen Antagonists; Benzamides; Bone Neoplasms; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radium; Receptors, Androgen

Radium-223, abiraterone, and enzalutamide have each been shown to significantly improve survival as monotherapy in patients with metastatic castration-resistant prostate cancer. However, effects of combination radium-223 plus abiraterone or enzalutamide on survival and safety remain unclear.. This single-center retrospective cohort study used electronic health record data of patients with metastatic castration-resistant prostate cancer and bone metastases who were treated with radium-223 between April 1, 2014 and February 19, 2019. Patients who received radium-223 monotherapy were compared to patients who received a combination of radium-223 plus either abiraterone or enzalutamide. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, time to symptomatic skeletal event, symptomatic skeletal event-free survival, and incidence of drug-related adverse events. Time-to-event analyses were estimated by log rank tests using Kaplan-Meier curves. Hazard ratios and 95% confidence intervals were derived from Cox proportional hazards models. Chi-square tests evaluated difference in serious adverse events between the two arms.. A total of 60 patients met inclusion criteria (n = 41 in the monotherapy arm, n = 19 in the combination arm). Differences in median overall survival were not observed (12.7 vs. 12.8 months; HR 1.15, 95% CI 0.59-2.23; P = 0.68), but median progression-free survival was significantly longer in the combination arm (7.6 vs. 4.9 months; HR 1.94, 95% CI 1.11-3.40; P = 0.02). Significant differences were not observed in time to first SSE (P = 0.97), SSE-free survival (P = 0.16), or in the overall incidence of serious adverse events (P = 0.45).. Combination radium-223 plus abiraterone or enzalutamide did not improve overall survival, but prolonged progression-free survival without increasing the incidence of serious adverse events in metastatic castration-resistant prostate cancer patients with bone metastases. However, these results are limited by small numbers and patient selection inherent in retrospective analysis.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Neoplasms; Chemoradiotherapy; Follow-Up Studies; Humans; Male; Nitriles; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms, Castration-Resistant; Radium; Retrospective Studies; Survival Rate

ERA 223 compared concurrent abiraterone acetate/prednisolone (AAP) plus radium-223 with AAP plus placebo in men with chemotherapy-naïve asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. We report data from a subgroup of Japanese patients in ERA 223.. Patients were randomized to radium-223 (55 kBq/kg) or placebo once every 4 weeks (max. 6 cycles), and also received oral abiraterone acetate 1000 mg once daily plus prednisone/prednisolone 5 mg twice daily during and after radium-223/placebo treatment, until a symptomatic skeletal event (SSE). The primary endpoint was SSE-free survival (SSE-FS); overall survival (OS) was a secondary endpoint.. Of 806 patients randomized in ERA 223, 114 patients (57 per arm) were enrolled in Japan. SSE-FS was not improved significantly in the radium-223 arm [25.5 months, 95% CI 20.6-not estimated (NE)] compared with the placebo arm (28.7 months, 95% CI 19.7-NE) (HR = 0.907, 95% CI 0.501-1.642). OS and other secondary endpoints were not improved significantly in the radium-223 arm. The incidence of fracture was 23% and 11% in the radium-223 and placebo arms, respectively. The incidence of death was 32% and 36%, respectively.. In the Japanese ERA 223 subgroup, concurrent treatment with AAP and radium-223 did not significantly improve SSE-FS and increased the incidence of fracture, similar to outcomes achieved in the overall population, while an increased incidence of death was not evident. The combination of radium-223 with AAP is not recommended in Japanese patients with asymptomatic or mildly symptomatic mCRPC and bone metastases.. Clinical trial registration no: NCT02043678.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Asian People; Bone Neoplasms; Disease-Free Survival; Double-Blind Method; Fractures, Bone; Humans; Male; Middle Aged; Placebos; Prednisolone; Prednisone; Prostatic Neoplasms, Castration-Resistant; Radium; Treatment Outcome

Abiraterone acetate plus prednisone or prednisolone improves progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. Radium-223 improves overall survival and delays the onset of symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases. We assessed concurrent treatment with abiraterone acetate plus prednisone or prednisolone and radium-223 in such patients.. We did a randomised, double-blind, placebo-controlled, phase 3 trial at 165 oncology and urology centres in 19 countries. Eligible patients were aged 18 years or older, and had histologically confirmed, progressive, chemotherapy-naive, asymptomatic or mildly symptomatic castration-resistant prostate cancer and bone metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 6 months, and adequate haematological, renal, and liver function. Participants were randomly assigned (1:1) according to a permuted block design (block size 4) via interactive response technology to receive up to six intravenous injections of radium-223 (55 kBq/kg) or matching placebo once every 4 weeks. All patients were also scheduled to receive oral abiraterone acetate 1000 mg once daily plus oral prednisone or prednisolone 5 mg twice daily during and after radium-223 or placebo treatment. The primary endpoint was symptomatic skeletal event-free survival, which was assessed in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of any study drug. This trial is registered with ClinicalTrials.gov, number NCT02043678. Enrolment has been completed, and follow-up is ongoing.. Between March 30, 2014, and Aug 12, 2016, 806 patients were randomly assigned to receive radium-223 (n=401) or placebo (n=405) in addition to abiraterone acetate plus prednisone or prednisolone. The study was unblinded prematurely, on Nov 17, 2017, after more fractures and deaths were noted in the radium-223 group than in the placebo group (in an unplanned ad-hoc analysis), but all patients had completed radium-223 or placebo before this date. At the primary analysis (data cutoff Feb 15, 2018), 196 (49%) of 401 patients in radium-223 group had had at least one symptomatic skeletal event or died, compared with 190 (47%) of 405 patients in the placebo group (median follow-up 21·2 months [IQR 17·0-25·8]). Median symptomatic skeletal event-free survival was 22·3 months (95% CI 20·4-24·8) in the radium-223 group and 26·0 months (21·8-28·3) in the placebo group (hazard ratio 1·122 [95% CI 0·917-1·374]; p=0·2636). Fractures (any grade) occurred in 112 (29%) of 392 patients in the radium-223 group and 45 (11%) of 394 patients in the placebo group. The most common grade 3-4 treatment-emergent adverse events were hypertension (43 [11%] patients in the radium-223 group vs 52 [13%] patients in the placebo group), fractures (36 [9%] vs 12 [3%]) and increased alanine aminotransferase concentrations (34 [9%] vs 28 [7%]). Serious treatment-emergent adverse events occurred in 160 (41%) patients in the radium-223 group and 155 (39%) in the placebo group. Treatment-related deaths occurred in two (1%) patients in the radium-223 group (acute myocardial infarction and interstitial lung disease) and one (<1%) in the placebo group (arrhythmia).. The addition of radium-223 to abiraterone acetate plus prednisone or prednisolone did not improve symptomatic skeletal event-free survival in patients with castration-resistant prostate cancer and bone metastases, and was associated with an increased frequency of bone fractures compared with placebo. Thus, we do not recommend use of this combination.. Bayer.

Topics: Abiraterone Acetate; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Double-Blind Method; Fractures, Bone; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Prednisolone; Prednisone; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Radium

We evaluated the use of abiraterone acetate (1,000 mg) plus prednisone (5 mg) in patients with high risk, nonmetastatic, castration resistant prostate cancer.. Patients considered at high risk for progression to metastatic disease (prostate specific antigen 10 ng/ml or greater, or prostate specific antigen doubling time 10 months or less) received abiraterone acetate plus prednisone daily in 28-day cycles. The primary study end point was the proportion of patients in whom a 50% or greater prostate specific antigen reduction was achieved during cycles 1 to 6. Secondary end points included time to prostate specific antigen progression, time to radiographic evidence of disease progression and safety.. Of the 131 enrolled patients 44 (34%) remained on treatment with a median followup of 40.0 months. Median age was 72 years (range 48 to 90). Of the patients 82.4% were white and 14.5% were black. Median screening prostate specific antigen was 11.9 ng/dl and median prostate specific antigen doubling time was 3.4 months. Prostate specific antigen was significantly reduced (p <0.0001) with a 50% or greater prostate specific antigen reduction in 86.9% of cases and a 90% or greater reduction in 59.8%. Median time to prostate specific antigen progression was 28.7 months (95% CI 21.2-38.2). Median time to radiographic evidence of disease progression was not reached but on sensitivity analysis in 15 patients it was estimated to be 41.4 months (95% CI 27.6-not estimable). Baseline testosterone 12.5 ng/dl or greater and a 90% or greater prostate specific antigen reduction at cycle 3 were associated with longer time to prostate specific antigen progression and radiographic evidence of disease progression. Outcomes in black patients were similar to those in other patients. Adverse events, grade 3 or greater adverse events and serious adverse events were reported in 96.2%, 61.1% and 43.5% of patients, respectively.. In patients with high risk, nonmetastatic, castration resistant prostate cancer treatment with abiraterone acetate plus prednisone demonstrated a significant 50% or greater prostate specific antigen reduction with encouraging results for the secondary end points, including the safety of 5 mg prednisone.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Humans; Kallikreins; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Middle Aged; Prednisone; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant

Androgen receptor (AR) signaling and incomplete inhibition of estrogen signaling may contribute to metastatic breast cancer (MBC) resistance to a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole). We assessed whether combined inhibition of androgen biosynthesis with abiraterone acetate plus prednisone and estradiol synthesis with exemestane (E) may be of clinical benefit to postmenopausal patients with NSAI-pretreated estrogen receptor-positive (ER+) MBC.. Patients (N = 297) were stratified by the number of prior therapies for metastatic disease (0-1 versus 2) and by prior NSAI use (adjuvant versus metastatic), and randomized (1 : 1 : 1) to receive oral once daily 1000 mg abiraterone acetate plus 5 mg prednisone (AA) versus AA with 25 mg E (AAE) versus 25 mg E alone (E). Each treatment arm was well balanced with regard to the proportion of patients with AR-positive breast cancer. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, clinical benefit rate, duration of response, and overall response rate.. There was no significant difference in PFS with AA versus E (3.7 versus 3.7 months; hazard ratio [HR] = 1.1; 95% confidence interval [CI] 0.82-1.60; P = 0.437) or AAE versus E (4.5 versus 3.7 months; HR = 0.96; 95% CI 0.70-1.32; P = 0.794). Increased serum progesterone concentrations were observed in both arms receiving AA, but not with E. Grade 3 or 4 treatment-emergent adverse events associated with AA, including hypokalemia and hypertension, were less common in patients in the E (2.0% and 2.9%, respectively) and AA arms (3.4% and 1.1%, respectively) than in the AAE arm (5.8% for both).. Adding AA to E in NSAI-pretreated ER+ MBC patients did not improve PFS compared with treatment with E. An AA-induced progesterone increase may have contributed to this lack of clinical activity.. NCT01381874.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Lymphatic Metastasis; Middle Aged; Postmenopause; Proportional Hazards Models; Receptors, Estrogen; Treatment Outcome

Progression-free survival (PFS) in metastatic castration-resistant prostate cancer (mCRPC) trials has been inconsistently defined and poorly associated with overall survival (OS). A reproducible quantitative definition of radiographic PFS (rPFS) was tested for association with a coprimary end point of OS in a randomized trial of abiraterone in patients with mCRPC.. rPFS was defined as ≥ two new lesions on an 8-week bone scan plus two additional lesions on a confirmatory scan, ≥ two new confirmed lesions on any scan ≥ 12 weeks after random assignment, and/or progression in nodes or viscera on cross-sectional imaging, or death. rPFS was assessed by independent review at 15% of deaths and by investigator review at 15% and 40% of deaths. rPFS and OS association was evaluated by Spearman's correlation.. A total of 1,088 patients were randomly assigned to abiraterone plus prednisone or prednisone alone. At first interim analysis, the hazard ratio (HR) by independent review was 0.43 (95% CI, 0.35 to 0.52; P < .001; abiraterone plus prednisone: median rPFS, not estimable; prednisone: median rPFS, 8.3 months). Similar HRs were obtained by investigator review at the first two interim analyses (HR, 0.49; 95% CI, 0.41 to 0.60; P < .001 and HR, 0.53; 95% CI, 0.45 to 0.62; P < .001, respectively), validating the imaging data assay used. Spearman's correlation coefficient between rPFS and OS was 0.72.. rPFS was highly consistent and highly associated with OS, providing initial prospective evidence on further developing rPFS as an intermediate end point in mCRPC trials.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Neoplasms; Disease-Free Survival; Double-Blind Method; Humans; Male; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant; Radiography; Survival Rate; Treatment Outcome

The aim of this paper was to evaluate the activity and tolerability of weekly docetaxel (D) combined with weekly epirubicin (EPI) in patients with advanced castrate-resistant prostate cancer (CRPC) previously exposed to D and abiraterone acetate (AA). Locally advanced or metastatic CRPC patients with 0-2 performance status, who had progressed after D and AA therapy, were included in the study. Previous treatment with chemotherapy agent cabazitaxel was also admitted. Treatment consisted of D 30 mg/m(2) intravenously (i.v.) and EPI 30 mg/m(2) i.v., every week (D/EPI). Chemotherapy was administered until disease progression or unacceptable toxicity. In our institution, twenty-six patients received D/EPI: their median age was 72 years (range 59-83 years). Twenty-three (88.5%) patients had bone metastases. A decrease in PSA levels ≥50% was observed in seven patients (26.9%, 95% CI: 0.11-0.47); of these, five had achieved a ≥50% PSA response during prior first-line D and six had achieved a PSA response during prior AA Among the subjects who were symptomatic at baseline, pain was reduced in nine patients (38.1%) with a significant decrease in analgesic use. Median progression-free survival was 4.4 months (95% CI, 3-5.2), and median overall survival was 10.7 months (95% CI, 8.9-18.4). Treatment was well tolerated and no grade 4 toxicities were observed. Our findings suggest that weekly D/EPI is feasible and active in heavily pretreated advanced CRPC patients and seem to support the hypothesis that the addition of EPI to D may lead to overcome the resistance to D in a subgroup of patients.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Docetaxel; Drug Administration Schedule; Drug Resistance, Neoplasm; Epirubicin; Humans; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Survival Analysis; Taxoids; Treatment Outcome

Bone metastases are a major cause of morbidity in metastatic castration-resistant prostate cancer. Abiraterone acetate potently disrupts intracrine androgen receptor signalling pathways implicated in the progression of the disease, including bone metastases. We assessed data for pain control and skeletal-related events prospectively collected as part of the randomised, phase 3 COU-AA-301 trial of abiraterone acetate plus prednisone versus placebo plus prednisone in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy.. The COU-AA-301 trial enrolled patients with metastatic castration-resistant prostate cancer in whom one or two lines of chemotherapy (one docetaxel based) had been unsuccessful and who had Eastern Cooperative Oncology Group performance statuses of 2 or less. Pain intensity and interference of pain with daily activities were assessed with the Brief Pain Inventory-Short Form questionnaire at baseline, day 15 of cycle 1, and day 1 of each treatment cycle thereafter until discontinuation. We assessed, with prospectively defined response criteria that incorporated analgesic use, clinically meaningful changes in pain intensity and interference with daily living. We measured time to first occurrence of skeletal-related events, which we defined as pathological fracture, spinal cord compression, palliative radiation to bone, or bone surgery, and regularly assessed them throughout the study. Pain palliation was assessed in patients who had clinically significant baseline pain, whereas all other analyses were done in the overall intention-to-treat population. COU-AA-301 is registered with ClinicalTrials.gov, number NCT00638690.. Median follow-up was 20·2 months (IQR 18·4-22·1). In patients with clinically significant pain at baseline, abiraterone acetate and prednisone resulted in significantly more palliation (157 of 349 [45·0%] patients vs 47 of 163 [28·8%]; p=0·0005) and faster palliation (median time to palliation 5·6 months [95% CI 3·7-9·2] vs 13·7 months [5·4-not estimable]; p=0·0018) of pain intensity than did prednisone only. Palliation of pain interference (134 of 223 [60·1%] vs 38 of 100 [38·0%], p=0·0002; median time to palliation of pain interference 1·0 months [95% CI 0·9-1·9] vs 3·7 months [2·7-not estimable], p=0·0004) and median duration of palliation of pain intensity (4·2 months [95% CI 3·0-4·9] vs 2·1 months [1·4-3·7]; p=0·0056) were significantly better with abiraterone acetate and prednisone than with prednisone only. In the overall population, median time to occurrence of first skeletal-related event was significantly longer with abiraterone acetate and prednisone than with prednisone only (25·0 months [95% CI 25·0-not estimable] vs 20·3 months [16·9-not estimable]; p=0·0001).. In patients with metastatic castration-resistant prostate cancer previously treated with docetaxel, abiraterone acetate and prednisone offer significant benefits compared with prednisone alone in terms of pain relief, delayed pain progression, and prevention of skeletal-related events.. Janssen Research & Development and Janssen Global Services.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Androstadienes; Bone Neoplasms; Double-Blind Method; Drug Therapy, Combination; Fractures, Spontaneous; Glucocorticoids; Humans; Male; Middle Aged; Pain Management; Pain Measurement; Palliative Care; Prednisone; Prostatic Neoplasms; Spinal Cord Compression; Steroid 17-alpha-Hydroxylase

Abiraterone is an oral inhibitor of CYP17, which is essential for androgen biosynthesis. This multicenter study assessed its efficacy in patients with castration-resistant prostate cancer (CRPC), without prior chemotherapy or CYP17-targeted therapy, and frequency of bone scans discordant with prostate-specific antigen (PSA) and clinical response.. Thirty-three patients received abiraterone acetate 1,000 mg daily with prednisone 5 mg twice daily in continuous 28-day cycles. Patients were evaluated monthly for efficacy and safety. Bone scan flare was defined as the combination, after 3 months of therapy, of an interpreting radiologist's report indicating "disease progression" in context of a 50% or more decline in PSA level, with scan improvement or stability 3 months later.. A 50% or more decline in PSA level at week 12 was confirmed in 22 of 33 (67%) patients. Declines in PSA level of 50% or more were seen in 26 of 33 (79%) patients. Undetectable PSA levels (≤0.1 ng/mL) occurred in 2 patients. Median time on therapy and time to PSA progression were 63 weeks and 16.3 months, respectively. Twenty-three patients were evaluable for bone scan flare. Progression was indicated in radiologist's report in 12 of 23 (52%), and 11 of 12 subsequently showed improvement or stability. As prospectively defined, bone scan flare was observed in 11 of 23 (48%) evaluable patients or 11 of 33 (33%) enrolled patients. Adverse events were typically grade 1/2 and consistent with prior published abiraterone reports.. Clinical responses to abiraterone plus prednisone were frequent and durable in men with metastatic CRPC. Further investigation is needed to clarify the confounding effect of bone scan flare on patient management and interpretation of results. Clin Cancer Res; 17(14); 4854-61. ©2011 AACR.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androstadienes; Antineoplastic Agents, Hormonal; Bone and Bones; Bone Neoplasms; Humans; Male; Middle Aged; Neoplasm Metastasis; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms; Radiography; Treatment Outcome

Lay abstract Patients with metastatic castration-resistant prostate cancer are often first treated with novel hormonal therapy (NHT) using abiraterone or enzalutamide. To aid decisions about what treatment to use next, we reviewed information about patients who were treated with an alternative NHT (226 patients) or the nuclear medicine radium-223 (120 patients) after the first NHT. Most patients given radium-223 had cancer that had spread to their bones only, whereas many patients given an alternative NHT had cancer in their bones and other parts of their body. Around one in four patients given radium-223 and one in five given an alternative NHT had symptoms related to their bone metastases after starting treatment. Five in every ten patients given radium-223 received further therapy, including chemotherapy in 50% of these patients, while four in every ten patients given an alternative NHT received further therapy, including chemotherapy in 75%. On average, patients lived for almost a year after starting radium-223 or an alternative NHT.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Benzamides; Bone Neoplasms; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Radium; Retrospective Studies

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Neoplasms; Combined Modality Therapy; Docetaxel; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radiopharmaceuticals; Radium; Retrospective Studies; Survival Rate; Taxoids

Bone resorption inhibitors (BRIs) are recommended by international guidelines to prevent skeletal-related events (SREs) among patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. Abiraterone acetate with prednisone is currently the most common first-line therapy for the treatment of patients with mCRPC; however, the clinical impact of the addition of BRIs to abiraterone acetate with prednisone in this disease setting is unknown.. To evaluate the association of the use of concomitant BRIs with overall survival (OS) and time to first SRE among patients with mCRPC and bone metastases receiving abiraterone acetate with prednisone as first-line therapy.. This retrospective cohort study collected data from 745 consecutive patients who began receiving abiraterone acetate with prednisone as first-line therapy for mCRPC with bone metastases between January 1, 2013, and December 31, 2016. Data were collected from 8 hospitals in Canada, Europe, and the US from June 15 to September 15, 2019.. Patients were classified by receipt vs nonreceipt of concomitant BRIs and subclassified by volume of disease (high volume or low volume, using definitions from the Chemohormonal Therapy Vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer [CHAARTED] E3805 study) at the initiation of abiraterone acetate with prednisone therapy.. The primary end point was OS. The secondary end point was time to first SRE. The Kaplan-Meier method and Cox proportional hazards models were used.. Of the 745 men (median age, 77.6 years [interquartile range, 68.1-83.6 years]; 699 White individuals [93.8%]) included in the analysis, 529 men (71.0%) received abiraterone acetate with prednisone alone (abiraterone acetate cohort), and 216 men (29.0%) received abiraterone acetate with prednisone plus BRIs (BRI cohort). A total of 420 men (56.4%) had high-volume disease, and 276 men (37.0%) had low-volume disease. The median follow-up was 23.5 months (95% CI, 19.8-24.9 months). Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone acetate cohort (31.8 vs 23.0 months; hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; P < .001). The OS benefit in the BRI cohort was greater for patients with high-volume vs low-volume disease (33.6 vs 19.7 months; HR, 0.51; 95% CI, 0.38-0.68; P < .001). The BRI cohort also had a significantly shorter time to first SRE compared with the abiraterone acetate cohort (32.4 vs 42.7 months; HR, 1.27; 95% CI, 1.00-1.60; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; 95% CI, 1.57-3.35; P < .001). In the multivariable analysis, concomitant BRIs use was independently associated with longer OS (HR, 0.64; 95% CI, 0.52-0.79; P < .001).. In this study, the addition of BRIs to abiraterone acetate with prednisone as first-line therapy for the treatment of patients with mCRPC and bone metastases was associated with longer OS, particularly in patients with high-volume disease. These results suggest that the use of BRIs in combination with abiraterone acetate with prednisone as first-line therapy for the treatment of mCRPC with bone metastases could be beneficial.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Bone Density Conservation Agents; Bone Neoplasms; Cohort Studies; Humans; Kaplan-Meier Estimate; Male; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant; Registries; Retrospective Studies

It is hypothesised that cotargeting the androgen receptor (AR) and paracrine androgen biosynthesis with enzalutamide and abiraterone acetate in metastatic castration-resistant prostate cancer (mCRPC) will dissipate adaptive feedback loops observed with either agent alone.. To assess the safety, efficacy, androgen signalling/metabolome, and drug-drug interactions (DDIs) of enzalutamide with abiraterone acetate in progressive bone mCRPC (bmCRPC).. This open-label, single-centre interventional study was conducted in bmCRPC patients.. Enzalutamide 160mg and abiraterone acetate 1000mg once daily; prednisone 5mg twice daily.. Adverse events (AEs), prostate-specific antigen (PSA) response, progression-free survival (PFS), tumour biomarker/metabolite expression, and C. Enzalutamide combined with abiraterone acetate has a manageable safety profile, without a meaningful DDI. Both agents are pharmacodynamically active with no feedback. Efficacy findings do not support significant benefit of combined treatment for unselected bmCRPC.. This is the first study combining enzalutamide plus abiraterone in bone metastatic castration-resistant prostate cancer. Results show that this combination is safe.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Neoplasms; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant

Abiraterone acetate (abiraterone) combined with prednisone is a standard of care in metastatic castration-resistant prostate cancer. Recently, benefit in overall survival was reported in metastatic castration-sensitive prostate cancer also, and an extension of indication has been granted. Abiraterone is seldom associated with liver toxicity. The clinical management and the outcome of patients with transaminase increase while on abiraterone have not been described.. We identified 25 men with metastatic prostate cancer and liver function test disorders occurring while on abiraterone treatment from December 2009 to September 2017 in three oncology centres in France.. Forty-six liver disorder events occurred in 25 patients while on abiraterone treatment. The median age at liver function test increase was 67 (55-85) years. The incidence of aspartate aminotransférase (AST) (24 events) and that of alanine aminotransférase (ALT) (22 events) increases were similar. Liver toxicity was of grade 1, 2 and 3 (Common Terminology Criteria for Adverse Events. version 4) in 7 (32%), 6 (27%) and 9 (41%) patients for ALT, and in 12 (50%), 6 (25%) and 6 (25%) for AST, respectively. The median time from abiraterone initiation to the detection of liver toxicity was 7.1 (4-95) weeks. The median time from highest ALT/AST increase to normalisation was 6.2 [2-14] weeks. In 13 patients (52%), liver tests spontaneously returned to baseline values, while abiraterone was continued at full dose.. Liver function test increase is a rare event that typically occurs within the first two months on abiraterone. Most patients experience normalisation of the tests, either spontaneously or after dose reduction/discontinuation.

Topics: Abiraterone Acetate; Administration, Oral; Aged; Aged, 80 and over; Alanine Transaminase; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Bone Neoplasms; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Incidence; Liver Function Tests; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Prednisone; Prostatic Neoplasms, Castration-Resistant; Remission, Spontaneous

To evaluate the fracture risk and survival outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) who received sequentially abiraterone acetate (AA) and radium 223 [223Ra]RaCl. We retrospectively reviewed the records of mCRPC patients who received [223Ra]RaCl. We reviewed data of a consecutive series of 94 mCRPC patients. Most of the patients (85.1%) received [223Ra]RaCl. The findings of this study show that the treatment with [223Ra]RaCl

Topics: Abiraterone Acetate; Bone Neoplasms; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Radium; Retrospective Studies; Treatment Outcome

Prostate cancer care in the Middle East is highly variable and access to specialist multidisciplinary management is limited. Academic tertiary referral centers offer cutting-edge diagnosis and treatment; however, in many parts of the region, patients are managed by non-specialists with limited resources. Due to many factors including lack of awareness and lack of prostate-specific antigen (PSA) screening, a high percentage of men present with locally advanced and metastatic prostate cancer at diagnosis. The aim of these recommendations is to assist clinicians in managing patients with different levels of access to diagnostic and treatment modalities.. The first Advanced Prostate Cancer Consensus Conference (APCCC) satellite meeting for the Middle East was held in Beirut, Lebanon, November 2017. During this meeting a consortium of urologists, medical oncologists, radiation oncologist and imaging specialists practicing in Lebanon, Syria, Iraq, Kuwait and Saudi Arabia voted on a selection of consensus questions. An additional workshop to formulate resource-stratified consensus recommendations was held in March 2019.. Variations in practice based on available resources have been proposed to form resource-stratified recommendations for imaging at diagnosis, initial management of localized prostate cancer requiring therapy, treatment of castration-sensitive/naïve advanced prostate cancer and treatment of castration-resistant prostate cancer.. This is the first regional consensus on prostate cancer management from the Middle East. The following recommendations will be useful to urologists and oncologists practicing in all areas with limited access to specialist multi-disciplinary teams, diagnostic modalities and treatment resources.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Benzamides; Biopsy, Large-Core Needle; Bone Neoplasms; Docetaxel; Endosonography; Health Resources; Health Services Accessibility; Humans; Iraq; Kallikreins; Kuwait; Lebanon; Lymph Node Excision; Magnetic Resonance Imaging; Male; Margins of Excision; Middle East; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Radiotherapy, Adjuvant; Risk; Salvage Therapy; Saudi Arabia; Syria

Topics: Abiraterone Acetate; Absorptiometry, Photon; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Neoplasms; Docetaxel; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prednisolone; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Zoledronic Acid

Topics: Abiraterone Acetate; Bone Density; Bone Neoplasms; Double-Blind Method; Humans; Male; Prednisolone; Prednisone; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Radium

Topics: Abiraterone Acetate; Aged, 80 and over; Antineoplastic Agents; Bone Neoplasms; Contraindications, Drug; Disease Progression; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Mineralocorticoid Receptor Antagonists; Neoplasm Staging; Prostatic Neoplasms, Castration-Resistant; Spironolactone; Treatment Outcome; Withholding Treatment

This study aimed to evaluate the therapeutic effect of enzalutamide (ENZ) or abiraterone acetate (ABI) on bone metastasis in castration-resistant prostate cancer (CRPC), using bone scan index (BSI).. Treatment outcomes for 31 patients who had undergone ENZ or ABI treatment were examined for CRPC with bone metastases. Cox proportional-hazards regression models were used to investigate the association between overall survival (OS) and clinical characteristics.. Median OS after ENZ or ABI treatment was 29 months. Considering the flare phenomenon, BSI in 17 (55%) patients decreased following treatment. In multivariate analysis, low baseline BSI value and a decrease in BSI following treatment were associated with longer OS (hazard ratio [HR]=8.009; p=0.35 and HR=7.025; p=0.045*, respectively).. Low BSI value before ENZ/ABI treatment and a decrease in BSI following ENZ or ABI treatment are independent predictors of longer OS. BSI could be useful for risk assessment of CRPC patients with bone metastases.

Topics: Abiraterone Acetate; Aged; Benzamides; Bone and Bones; Bone Neoplasms; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radionuclide Imaging

Topics: Abiraterone Acetate; Bone Neoplasms; Double-Blind Method; Humans; Male; Prednisolone; Prednisone; Prostatic Neoplasms, Castration-Resistant; Radium

Topics: Abiraterone Acetate; Adenocarcinoma; Adrenal Cortex Hormones; Aged; Antineoplastic Agents, Hormonal; Bone Neoplasms; Chlorpheniramine; Desensitization, Immunologic; Dexamethasone; Drug Administration Schedule; Histamine Antagonists; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Urticaria

We examined whether androgen receptor splice variant 7 (AR-V7) in circulating tumor cell(CTC)clusters can be used to predict survival in patients with bone metastatic castration resistant-prostate cancer (mCRPC) treated with abiraterone or enzalutamide.. We retrospectively enrolled 98 patients with CRPC on abiraterone or enzalutamide, and investigated the prognostic value of CTC cluster detection (+ v -) and AR-V7 detection (+ v -) using a CTC cluster detection - based AR-V7 mRNA assay. We examined ≤50% prostate-specific antigen (PSA) responses, PSA progression-free survival (PSA-PFS), clinical and radiological progression-free survival (radiologic PSF), and overall survival (OS). We then assessed whether AR-V7 expression in CTC clusters identified after On-chip multi-imaging flow cytometry was related to disease progression and survival after first-line systemic therapy.. All abiraterone-treated or enzalutamide-treated patients received prior docetaxel. The median follow-up was 20.7 (range: 3.0-37.0) months in the abiraterone and enzalutamide cohorts, respectively. Forty-nine of the 98 men (50.0%) were CTC cluster (-), 23 of the 98 men (23.5%) were CTC cluster(+)/AR-V7(-), and 26 of the 98 men (26.5%) were CTC cluster(+)/AR-V7(+). CTC cluster(+)/AR-V7(+) patients were more likely to have EOD ≥3 at diagnosis (P = 0.003), pain (P = 0.023), higher alkaline phosphatase levels (P < 0.001), and visceral metastases (P < 0.001). On multivariable analysis, pretherapy CTC cluster(+), CTC cluster(+)/AR-V7(-), and ALP >UNL were independently associated with a poor PSA-PFS, radiographic PFS, and OS in abiraterone-treated patients and enzalutamide-treated patients.. The CTC clusters and AR-V7-positive CTC clusters detected were important for assessing the response to abiraterone or enzalutamide therapy and for predicting disease outcome.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Benzamides; Biomarkers, Tumor; Bone Neoplasms; Drug Resistance, Neoplasm; Humans; Male; Neoplastic Cells, Circulating; Nitriles; Phenylthiohydantoin; Predictive Value of Tests; Prognosis; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen

Over the last decade, significant advances have been made in the development of therapies for patients with metastatic castration-resistant prostate cancer. Abiraterone and enzalutamide were approved as treatments based on data supporting improved overall survival compared to placebo. Radium-223 became the first approved radiopharmaceutical which decreased skeletal-related events, palliated pain, and showed improved overall survival in symptomatic patients with castration-resistant prostate cancer and bone metastasis only.. We present the case of an eighty-two year old man with metastatic castration-resistant prostate cancer who was treated with sequential therapy (abiraterone - enzalutamide - radium 223). The sequencing and treatment used for our patient was viable because of his clinical characteristics, which have allowed for longer survival time with an acceptable quality of life. These actions must be agreed on by the Multidisciplinary Tumour Board, in order to optimize the use of available courses of treatment.. The treatment of these patients is changing rapidly, but many questions remain regarding the optimal sequencing of the available drugs. Sequential or concomitant use of the next generation hormonal agents - abiraterone and enzalutamide - cannot currently be recommended. Data regarding the safety of concomitant abiraterone, enzalutamide or denosumab with radium-223 is reassuring and timely. However, we cannot advocate the general use of combined radium-223 therapy at this time, irrespective of prior therapy.. A better understanding of active mechanisms, the genetic characteristics of each metastatic castration-resistant prostate cancer and the development of new prognostic and predictive biomarkers will help determine sequencing or different combination treatments for each individual patient.

Topics: Abiraterone Acetate; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biomarkers, Tumor; Bone Neoplasms; Combined Modality Therapy; Humans; Male; Neoplasm Metastasis; Neoplasm Staging; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Radium; Tomography, X-Ray Computed; Treatment Outcome

There is much interest in confirming whether the efficacy of abiraterone acetate (AA) demonstrated within the trial setting is reproducible in routine clinical practice. We report the clinical outcome of metastatic castration-resistant prostate cancer (mCRPC) patients treated with AA in real-life clinical practice.. The clinical records of mCRPC patients treated with AA from all 6 public oncology centers in Hong Kong between August 2011 and December 2014 were reviewed. The treatment efficacy and its determinants, and toxicities were determined.. A total of 110 patients with mCRPC were treated with AA in the review period, of whom 58 were chemo-naive and 52 had received prior chemotherapy (post-chemo). The median follow-up time was 7.5/11.4 months for chemo-naive/post-chemo patients. 6.9/15.4 % of chemo-naive/post-chemo patients had visceral metastases. The median overall survival (OS) and progression-free survival (PFS) were 18.1/15.5 months and 6.7/6.4 months for chemo-naive/post-chemo patients, respectively. Among chemo-naive patients, those with visceral diseases had significantly inferior OS (2.8 vs 18.0 p = 0.0007) and PFS (2.8 vs 6.8 months, p = 0.0088) than those without. Pain control was comparable in both groups of patients. The most common grade 3 or above toxicities were hypertension (6.9/5.8 %) and hypokalemia (3.4/3.8 %) in chemo-naive/post-chemo patients. In multivariate analysis, the presence of prostate-specific antigen (PSA) response (≥50 % drop of PSA from baseline) within the first 3 months of therapy was associated with favorable OS and PFS in both chemo-naive and post-chemo group.. In clinical practice outside the trial setting, OS after AA in our chemo-naive patient cohort (18.1 months) was considerably shorter than that reported in the COU-AA-302 trial (34.7 months), and the OS was particularly short in those with visceral metastases (2.8 months). Conversely, AA was efficacious in post-chemo patients. AA resulted in comparable pain control in both groups of patients. The presence of PSA response within the first 3 months of treatment was a significant determinant of survival.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Bone Neoplasms; Disease-Free Survival; Humans; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

To evaluate the efficacy of enzalutamide (Enz) as fourth- or fifth-line treatment in men with metastasized castration-resistant prostate cancer (mCRPC), by analyzing a retrospective cohort of heavily pretreated patients.. We evaluated toxicity, overall survival (OS), progression-free survival (PFS) and time to prostate-specific antigen (PSA) progression data from 47 CRPC patients treated with fourth- or fifth-line Enz.. All patients were treated with docetaxel and abiraterone acetate and 42 patients (89%) with cabazitaxel. The median age of the patients was 69 years (IQR, 63-73.5), 79% had bone metastases, 55% had lymph node metastases, and 17% had visceral metastases. The median duration of Enz treatment was 12.0 weeks (IQR, 8.3-20.4), and 11 patients (23%) responded to Enz (maximum PSA decline ≥50%). In general, Enz was well tolerated, with the most frequently reported adverse events being fatigue and nausea. The median OS was 40.1 weeks (95% CI, 25.4-61.4), the median PFS was 12.1 weeks (95% CI, 9.9-14.0) and the median time to PSA progression was 15.7 weeks (95% CI, 14.0-28.7).. Analysis of this retrospective cohort suggests that Enz is well tolerated and that there is a 23% response rate in heavily pretreated CRPC patients, which is comparable with third-line treatment outcomes.

Topics: Abdominal Neoplasms; Abiraterone Acetate; Aged; Antineoplastic Agents; Benzamides; Bone Neoplasms; Disease Progression; Disease-Free Survival; Docetaxel; Humans; Lymphatic Metastasis; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radium; Retreatment; Retrospective Studies; Survival Rate; Taxoids

The activity of enzalutamide after prior treatment with both abiraterone acetate (abiraterone) and docetaxel has been examined in several retrospective studies. However, limited data are available on the efficacy of enzalutamide following abiraterone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC).. To compare the activity of enzalutamide after abiraterone in docetaxel-experienced and docetaxel-naive mCRPC patients.. The British Columbia Cancer Agency Cancer Registry was searched for mCRPC patients who received enzalutamide after prior abiraterone. Clinicopathologic characteristics, confirmed prostate-specific antigen (PSA) response rates (PSA decline ≥ 50% confirmed ≥ 3 wk later), and survival data were collected.. Outcomes on enzalutamide were compared between docetaxel-experienced and docetaxel-naive patients using chi-square for PSA response and log-rank test for time to PSA progression and overall survival (OS). Univariate analysis was performed to identify variables associated with confirmed PSA response on enzalutamide, using either chi-square for categorical variables or logistic regression for continuous variables.. A total of 115 patients received enzalutamide after abiraterone: 68 had received prior docetaxel and 47 were docetaxel naive. Median time on enzalutamide was 4.1 mo. Confirmed PSA response rates (22% vs 26%; p=0.8), median time to radiologic/clinical progression (4.6 mo vs 6.6 mo; p=0.6), and median OS (10.6 mo vs 8.6 mo; p=0.2) did not differ significantly between docetaxel-experienced and docetaxel-naive patients. No clinical variables (including prior response to abiraterone) were found to associate significantly with confirmed PSA response to enzalutamide.. Antitumour activity of enzalutamide following abiraterone was limited in mCRPC patients irrespective of prior docetaxel use. Identifying clinical and molecular factors predictive of response to enzalutamide remains a high priority for future research.. We looked at the effectiveness of enzalutamide after abiraterone acetate for treatment of advanced prostate cancer. We found that patients who had received docetaxel chemotherapy before abiraterone gained similar benefit from enzalutamide compared with patients who had not received docetaxel. These results suggest that earlier treatment with docetaxel does not have a large impact on the activity of enzalutamide after abiraterone.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Neoplasms; Disease Progression; Docetaxel; Humans; Lymphatic Metastasis; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Survival Rate; Taxoids

Optimal sequencing of cabazitaxel (C) and abiraterone acetate (A) after docetaxel (D) for metastatic castration-resistant prostate cancer (mCRPC) is unclear. We assessed treatment patterns and outcomes in patients with mCRPC receiving different sequences of A or C, or both, after administration of D.. Retrospective analysis was conducted of US Oncology Network iKnowMed (iKM) electronic health record (EHR) data to assess patients with mCRPC who received treatment with D and were subsequently treated with C or A, or both, between April 2011 and May 2012. Patients received 2 or 3 drugs: DA, DC, DAC, or DCA. Overall survival (OS) and time to treatment failure (TTF) were analyzed by the Kaplan-Meier method from the start to the end of second-line therapy after administration of D (TTF1) and to the end of combined second- and third-line therapy (TTF2) for 3-drug sequences. Multivariable Cox proportional hazard models evaluated the impact of baseline clinical prognostic factors and treatment sequence on OS and TTF.. Of 350 patients who were treated with D and subsequent therapies, 183 (52.3%) received DA, 54 (15.4%) received DC, 77 (22.0%) received DCA, and 36 (10.3%) received DAC. In a multivariable analysis, adjusted comparisons suggested that 3-drug sequences were associated with improved OS versus 2-drug sequences (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.092-0.476; P = .0002). There were no statistically significant differences in OS and TTF for DC versus DA, and OS was significantly greater for DCA versus DAC (HR, 0.13; 95% CI, 0.022-0.733; P = .0210). More cycles of C were administered in DCA than in DAC (median 6 vs. 4; t test P < .0001), whereas the duration of A treatment was similar.. Administration of 3 agents in the DCA sequence was more optimal for treating mCRPC in this hypothesis-generating study.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Disease-Free Survival; Docetaxel; Drug Administration Schedule; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

Metastatic castration-resistant prostate cancer (mCRPC) often involves bone, and bone-targeted therapy (BTT) has become part of the overall treatment strategy.. Investigation of outcomes for concomitant BTT in a post hoc analysis of the COU-AA-302 trial, which demonstrated an overall clinical benefit of abiraterone acetate (AA) plus prednisone over placebo plus prednisone in asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients.. This report describes the third interim analysis (prespecified at 55% overall survival [OS] events) for the COU-AA-302 trial.. Patients were grouped by concomitant BTT use or no BTT use.. Radiographic progression-free survival and OS were coprimary end points. This report describes the third interim analysis (prespecified at 55% OS events) and involves patients treated with or without concomitant BTT during the COU-AA-302 study. Median follow-up for OS was 27.1 mo. Median time-to-event variables with 95% confidence intervals (CIs) were estimated using the Kaplan-Meier method. Adjusted hazard ratios (HRs), 95% CIs, and p values for concomitant BTT versus no BTT were obtained via Cox models.. While the post hoc nature of the analysis is a limitation, superiority of AA and prednisone versus prednisone alone was demonstrated for clinical outcomes with or without BTT use. Compared with no BTT use, concomitant BTT significantly improved OS (HR 0.75; p=0.01) and increased the time to ECOG deterioration (HR 0.75; p<0.001) and time to opiate use for cancer-related pain (HR 0.80; p=0.036). The safety profile of concomitant BTT with AA was similar to that reported for AA in the overall intent-to-treat population. Osteonecrosis of the jaw (all grade 1/2) with concomitant BTT use was reported in <3% of patients.. AA with concomitant BTT was safe and well tolerated in men with chemotherapy-naïve mCRPC. The benefits of AA on clinical outcomes were increased with concomitant BTT.. Treatment of advanced prostate cancer often includes bone-targeted therapy. This post hoc analysis showed that in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone in combination with bone-targeted therapy, there was a continued trend in prolongation of life when compared with patients treated with prednisone alone.. ClinicalTrials.gov NCT00887198.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Bone Neoplasms; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Multicenter Studies as Topic; Odds Ratio; Prednisone; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Steroid Synthesis Inhibitors; Time Factors; Treatment Outcome

Topics: Abiraterone Acetate; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Density Conservation Agents; Bone Neoplasms; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Steroid Synthesis Inhibitors

Abiraterone acetate (AA) is a selective oral inhibitor of Steroid-17α-Hydroxylase, for patients with castration-resistant prostate cancer. Not all patients respond to therapy, however, there are no biomarkers predicting response to AA therapy. The aim of the present study was the identification of a biomarker for patients who are likely to respond to AA therapy.. We measured thyroid parameters in a collective of 30 patients before and during AA therapy. For statistical analyses, paired and unpaired t-tests were used.. During AA therapy, responders developed a significant increase in thyroid stimulating hormone (TSH) compared to non-responders (p=0.03). In the subgroup of responders, 16 out of 21 patients (76.1%) had a significant increase in TSH level (p=0.001), suggesting that TSH increase is predictive of therapy response. Non-responders showed no change in TSH level during AA therapy.. Hypothyreosis may serve as a simple predictive biomarker for therapy response under AA therapy.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androstadienes; Biomarkers, Pharmacological; Bone Neoplasms; Follow-Up Studies; Humans; Hypothyroidism; Male; Middle Aged; Neoplasm Staging; Prognosis; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase; Thyrotropin

Topics: Abiraterone Acetate; Aged; Androstadienes; Antineoplastic Agents; Bone Neoplasms; Humans; Lymphatic Metastasis; Male; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retreatment

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Bone Neoplasms; Glucocorticoids; Humans; Male; Pain Management; Prednisone; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase