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Cancer Medicine Oct 2023There is little evidence of abiraterone acetate (AA) plus prednisone for patients with non-metastatic castration-resistant prostate cancer (nmCRPC). In this study, we...
BACKGROUND
There is little evidence of abiraterone acetate (AA) plus prednisone for patients with non-metastatic castration-resistant prostate cancer (nmCRPC). In this study, we conducted a comparative analysis of real-world survival outcomes between AA plus prednisone and enzalutamide (Enz) in patients with nmCRPC, utilizing our consortium dataset.
MATERIALS AND METHODS
The clinical records of 133 nmCRPC patients treated with first-line Enz or AA plus prednisone were analyzed. The primary endpoints of the study were overall survival (OS) and cancer-specific survival (CSS). Cumulative incidence function (CIF) using Fine and Gray models was also utilized to assess non-cancer-caused death considering the competing risk of cancer-caused death.
RESULTS
During a median follow-up of 36 months, 34 patients (25.6%) had deceased, with a median OS of 99 months in the entire cohort. There were no significant differences in comorbidities between the Enz and AA groups. Time to PSA progression (TTPP: HR 0.81, 95% CI 0.51-1.30, P = 0.375) and CSS (HR 1.32, 95% CI 0.55-3.44, P = 0.5141) were comparable between the two groups. However, intriguingly, there was a trend towards shorter OS in patients treated with AA plus prednisone compared to Enz (HR 0.57, 95% CI 0.29-1.12, P = 0.0978, median of 99 and 69 months in Enz and AA groups, respectively). CIF analysis revealed that nmCRPC patients treated with AA plus prednisone were more likely to result in non-cancer-caused death than those treated with Enz (HR 5.22, 95% CI 1.88-14.50, P = 0.0014).
CONCLUSIONS
Our real-world survival analysis suggests that while AA plus prednisone may demonstrate comparable treatment efficacy to Enz in the context of nmCRPC, there may be an increased risk of non-cancer-caused death. Physicians should take into consideration this information when making treatment decisions for patients with nmCRPC.
Topics: Male; Humans; Abiraterone Acetate; Prednisone; Prostatic Neoplasms, Castration-Resistant; Phenylthiohydantoin; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37706578
DOI: 10.1002/cam4.6536 -
Drugs in R&D 2010Abiraterone acetate (CB 7630; CB7630; JNJ-212082), the 3β-acetate prodrug of abiraterone, is structurally related to ketoconazole and is being developed by Cougar... (Review)
Review
Abiraterone acetate (CB 7630; CB7630; JNJ-212082), the 3β-acetate prodrug of abiraterone, is structurally related to ketoconazole and is being developed by Cougar Biotechnology as a hormonal therapy for advanced prostate and breast cancers. As a selective inhibitor of adrenal androgens, it is thought to be a safer product than existing second-line hormonal therapies. This review discusses the key development milestones and therapeutic trials of this drug.
Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Animals; Antineoplastic Agents, Hormonal; Drug Evaluation, Preclinical; Drugs, Investigational; Humans; Neoplasms; Prodrugs
PubMed: 21171672
DOI: 10.2165/11587960-000000000-00000 -
The Lancet. Oncology May 2023Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for...
Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol.
BACKGROUND
Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival.
METHODS
We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0-2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544).
FINDINGS
Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86-107) in the abiraterone trial and 72 months (61-74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8-86·9) in the abiraterone group versus 45·7 months (41·6-52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53-0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9-81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3-59·0) in the standard of care group (HR 0·65 [0·55-0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83-1·32]; p=0·71) or between-trial heterogeneity (I p=0·70). In the first 5 years of treatment, grade 3-5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial).
INTERPRETATION
Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years.
FUNDING
Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.
Topics: Male; Humans; Abiraterone Acetate; Prostatic Neoplasms; Androgen Antagonists; Androgens; Prednisolone; Docetaxel; Antineoplastic Combined Chemotherapy Protocols; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Clinical Trials, Phase III as Topic; Meta-Analysis as Topic
PubMed: 37142371
DOI: 10.1016/S1470-2045(23)00148-1 -
The Journal of Steroid Biochemistry and... Feb 2020The formation of steroid hormones in peripheral target tissues is referred to as their intracrine formation. This process occurs in hormone dependent malignancies such... (Review)
Review
The formation of steroid hormones in peripheral target tissues is referred to as their intracrine formation. This process occurs in hormone dependent malignancies such as prostate and breast cancer in which the disease can be either castrate resistant or occur post-menopausally, respectively. In these instances, the major precursor steroid of androgens and estrogens is dehydroepiandrosterone (DHEA) and DHEA-SO. This article reviews the major pathways by which adrenal steroids are converted to the potent male sex hormones, testosterone (T) and 5α-dihydrotestosterone (5α-DHT) and the discrete enzyme isoforms involved in castration resistant prostate cancer. Previous studies have mainly utilized radiotracers to investigate these pathways but have not used prevailing concentrations of precursors found in castrate male human serum. In addition, the full power of stable-isotope dilution liquid chromatography tandem mass spectrometry has not been applied routinely. Furthermore, it is clear that adaptive responses occur in the transporters and enzyme isoforms involved in response to androgen deprivation therapy that need to be considered.
Topics: Humans; Intracellular Space; Male; Paracrine Communication; Prostate; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Steroids; Tumor Microenvironment
PubMed: 31614208
DOI: 10.1016/j.jsbmb.2019.105499 -
Urologic Oncology May 2023Deep prostate-specific antigen (PSA) response (≥90% reduction in PSA [PSA90]) is an important early response indicator of radiographic progression-free survival and...
Comparison of prostate-specific antigen response in patients with metastatic castration-sensitive prostate cancer initiated on apalutamide or abiraterone acetate: A retrospective cohort study.
BACKGROUND
Deep prostate-specific antigen (PSA) response (≥90% reduction in PSA [PSA90]) is an important early response indicator of radiographic progression-free survival and overall survival in patients with metastatic castration-sensitive prostate cancer (mCSPC). This study compared PSA90 responses by 6 months between patients with mCSPC at first use of apalutamide or abiraterone acetate, both androgen receptor signaling inhibitors.
METHODS
Clinical data from 77 community urology practices in the United States were analyzed. Patients with mCSPC were classified into treatment cohorts based on their first filled prescription (index date) for apalutamide or abiraterone acetate on or after September 17, 2019 (approval date of apalutamide for mCSPC). Patients were followed from the index date until the earliest of index treatment discontinuation, treatment switch, end of clinical activity, or end of data availability (September 17, 2021). Inverse probability of treatment weighting (IPTW) was used to ensure similarity in distribution of baseline characteristics between cohorts. PSA90 was defined as the earliest attainment of ≥90% reduction in PSA relative to baseline (most recent value within 13 weeks pre-index). Time to PSA90 between cohorts was compared by weighted Kaplan-Meier analysis and with Cox proportional hazards models.
RESULTS
A total of 364 patients treated with apalutamide and 147 treated with abiraterone acetate met the study criteria. Patient characteristics were well balanced after IPTW. By 6 months post-index, patients initiated on apalutamide were 53% more likely to achieve PSA90 than those initiated on abiraterone acetate (P = 0.016). Similar results were observed by 9 and 12 months post-index (both P ≤ 0.019). The median time to PSA90 was 3.5 months for the apalutamide cohort and not reached for the abiraterone acetate cohort.
CONCLUSIONS
In real-world patients with mCSPC, significantly more patients achieved PSA90 with apalutamide than with abiraterone acetate, and this response was achieved earlier with apalutamide.
Topics: Humans; Male; Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Castration; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome
PubMed: 37080833
DOI: 10.1016/j.urolonc.2023.03.013 -
The Oncologist May 2015Dexamethasone combined with abiraterone acetate might result in improved survival in the treatment of castration-resistant prostate cancer compared with the Food and...
Dexamethasone combined with abiraterone acetate might result in improved survival in the treatment of castration-resistant prostate cancer compared with the Food and Drug Administration-approved prednisone combination, but the hypothesis must be confirmed with with clinical studies comparing the two combinations.
Topics: Androstenes; Antineoplastic Agents, Hormonal; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant
PubMed: 25888269
DOI: 10.1634/theoncologist.2015-0010 -
Therapeutic Advances in Medical Oncology May 2017Abiraterone acetate 1000 mg/day, combined with prednisone 5 mg PO twice daily, is indicated for the treatment of metastatic castration-resistant prostate cancer (mCRPC).... (Review)
Review
Abiraterone acetate 1000 mg/day, combined with prednisone 5 mg PO twice daily, is indicated for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Abiraterone acetate is the oral prodrug of abiraterone, a specific CYP17 inhibitor that blocks androgen biosynthesis within the adrenal glands, testes and tumor microenvironment. In a phase III trial of men with asymptomatic or minimally symptomatic, chemotherapy-naïve mCRPC, treatment with oral abiraterone acetate plus prednisone led to a statistically significant improvement in the co-primary endpoints of overall survival and radiographic progression-free survival when compared with placebo plus prednisone. In long-term follow-up of phase III trials, the incidence of corticosteroid-associated adverse events was 25.5% in the abiraterone acetate plus prednisone arm compared with 23.3% in the placebo plus prednisone arm. The need for regular patient monitoring and appropriate management of symptoms during long-term use of prednisone must be placed in context with the improvement in survival seen with abiraterone plus prednisone. Within the multidisciplinary environment that is emerging to meet quality and cost imperatives, abiraterone acetate plus prednisone is suitable for use in the chemotherapy-naïve population with minimal symptoms as well as in patients who have been treated with docetaxel and may have symptomatic disease. Ongoing trials are evaluating the role of abiraterone acetate plus prednisone in patients with nonmetastatic CRPC and metastatic hormone-sensitive prostate cancer, while further trials in the mCRPC setting are evaluating its use in combination regimens.
PubMed: 28529549
DOI: 10.1177/1758834017698644 -
Cancer Drug Resistance (Alhambra,... 2020Castration-resistant prostate cancer is the lethal form of prostate cancer and most commonly remains dependent on androgen receptor (AR) signaling. Current therapies use... (Review)
Review
Castration-resistant prostate cancer is the lethal form of prostate cancer and most commonly remains dependent on androgen receptor (AR) signaling. Current therapies use AR signaling inhibitors (ARSI) exemplified by abiraterone acetate, a P450c17 inhibitor, and enzalutamide, a potent AR antagonist. However, drug resistance to these agents occurs within 12-18 months and they only prolong overall survival by 3-4 months. Multiple mechanisms can contribute to ARSI drug resistance. These mechanisms can include but are not limited to germline mutations in the AR, post-transcriptional alterations in AR structure, and adaptive expression of genes involved in the intracrine biosynthesis and metabolism of androgens within the tumor. This review focuses on intracrine androgen biosynthesis, how this can contribute to ARSI drug resistance, and therapeutic strategies that can be used to surmount these resistance mechanisms.
PubMed: 35582223
DOI: 10.20517/cdr.2020.60 -
Frontiers in Endocrinology 2023This research work was aimed at evaluating the incidence and risk factors of adverse events (AEs) occurring in patients treated with abiraterone acetate (AA) and...
BACKGROUND
This research work was aimed at evaluating the incidence and risk factors of adverse events (AEs) occurring in patients treated with abiraterone acetate (AA) and prednisone (PDN) outside clinical trials. These associations were assessed regarding the survival outcomes.
METHODS
The study included 191 patients aged ≥18 years of confirmed metastatic castration-resistant prostate cancer (mCRPC) between March 2017 and April 2022. AE incidences were descriptively summarized from the whole cohort. Baseline characteristics, safety (treatment-emergent AEs and severe AEs), and efficacy [progression-free survival (PFS)] were analyzed. Multi-variable Cox proportional hazards models were employed to assess the factors linked with PFS.
RESULTS
Overall, the median PFS was 17.16 months (range, 0.5-57.58). Patient baseline prostate-specific antigen (PSA) ≧̸10 ng/ml ( = 0.000), multiple organ metastasis ( = 0.007), hypertension ( = 0.004), and coronary heart disease ( = 0.004) were associated with worse PFS; however, radiotherapy ( = 0.028) was linked to better PFS at univariate analysis in the overall cohort. Baseline multiple organ metastasis, hypertension, and radiotherapy remained statistically significant in multivariable models ( = 0.007, = 0.005, and = 0.011, respectively).Incidence of AEs showed increased bilirubin (BIL) (55/191 patients, 28.8%) followed by increased alanine aminotransferase/aspartate aminotransferase (ALT/AST) (48/191 patients, 25.09%). The most common grade 3 AEs were increased ALT (3/191, 1.57%) followed by elevated BIL, hypercholesterolemia, and hypokalemia. Anemia had shorter PFS. There were no unexpected AEs in any patient.
CONCLUSION
AA is effective and tolerated in asymptomatic or slightly symptomatic mCRPC in "real-life" setting. The survival outcomes are influenced by multiple organ metastasis, hypertension, and radiotherapy.
Topics: Male; Humans; Adolescent; Adult; Abiraterone Acetate; Prednisone; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Hypertension
PubMed: 37251681
DOI: 10.3389/fendo.2023.1158949 -
World Journal of Clinical Oncology Feb 2021The number of treatment options for metastatic hormone-sensitive prostate cancer has increased substantially in recent years. The classic treatment approach for these...
The number of treatment options for metastatic hormone-sensitive prostate cancer has increased substantially in recent years. The classic treatment approach for these patients-androgen-deprivation therapy alone-is now considered suboptimal. Several randomized phase III clinical trials have demonstrated significant clinical benefits-including significantly better overall survival and quality of life-for treatments that combine androgen-deprivation therapy with docetaxel, abiraterone acetate, enzalutamide, apalutamide, and/or radiotherapy to the primary tumour. As a result, these approaches are now included in treatment guidelines and considered standard of care. However, the different treatment strategies have not been directly compared, and thus treatment selection remains at the discretion of the individual physician or, ideally, a multidisciplinary team. Given the range of available treatment approaches with varying toxicity profiles, treatment selection should be individualized based on the patient's clinical characteristics and preferences, which implies active patient participation in the decision-making process. In the present document, we discuss the changing landscape of the management of patients with metastatic hormone-sensitive prostate cancer in the context of several recently-published landmark randomized trials. In addition, we discuss several unresolved issues, including the optimal sequencing of systemic treatments and the incorporation of local treatment of the primary tumour and metastases.
PubMed: 33680871
DOI: 10.5306/wjco.v12.i2.43