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Therapeutic Advances in Urology 2019More than a million men worldwide are diagnosed with prostate cancer every year. After androgen deprivation therapy (ADT), chemotherapy has been the only subsequent... (Review)
Review
More than a million men worldwide are diagnosed with prostate cancer every year. After androgen deprivation therapy (ADT), chemotherapy has been the only subsequent intervention to improve survival in the metastatic setting but has limitations for patients who may not tolerate its toxicity profile or are not candidates on the basis of comorbidities. Novel anti-androgens such as abiraterone acetate have shown promise for such patients. This review draws on clinical evidence and experience to identify abiraterone as a well-tolerated, effective alternative to docetaxel. In the castration-resistant setting, studies demonstrated a survival benefit over placebo, prompting further trials in the hormone-naïve population. More recently the STAMPEDE and LATITUDE studies suggest abiraterone has comparable survival outcomes to docetaxel in the castration-sensitive setting, with evidence in favour of its quality of life profile. Available comparisons with docetaxel are limited, but those available suggest they have comparable efficacy. However, the significant cost compared with docetaxel is a major barrier in resource-rationed healthcare settings. Overall, abiraterone is an effective alternative to chemotherapy for men with castration-sensitive prostate cancer, but this should be balanced with the significantly greater cost.
PubMed: 30671143
DOI: 10.1177/1756287218820804 -
European Journal of Endocrinology Apr 2020The human adrenal is the dominant source of androgens in castration-resistant prostate cancer (CRPC) and classic 21-hydroxylase deficiency (21OHD). Abiraterone, derived...
CONTEXT
The human adrenal is the dominant source of androgens in castration-resistant prostate cancer (CRPC) and classic 21-hydroxylase deficiency (21OHD). Abiraterone, derived from the prodrug abiraterone acetate (AA), inhibits the activity of cytochrome P450 17-hydroxylase/17,20-lyase (CYP17A1), the enzyme required for all androgen biosynthesis. AA treatment effectively lowers testosterone and androstenedione in 21OHD and CRPC patients. The 11-oxygenated androgens are major adrenal-derived androgens, yet little is known regarding the effects of AA administration on 11-oxygenated androgens.
OBJECTIVE
To test the hypothesis that AA therapy decreases 11-oxygenated androgens.
DESIGN
Samples were obtained from 21OHD or CRPC participants in AA or AA plus prednisone (AAP)-treatment studies, respectively.
METHODS
We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the 11-oxygenated androgens, 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone, in plasma or serum samples from six 21OHD and six CRPC patients before and after treatment with AA or AAP, respectively.
RESULTS
In CRPC patients, administration of AAP (1000 mg/day AA with prednisone and medical castration) lowered all four 11-oxygenated androgens to below the lower limits of quantitation (<0.1-0.3 nmol/L), equivalent to 64-94% reductions from baseline. In 21OHD patients, administration of AA (100-250 mg/day for 6 days) reduced all 11-oxygenated androgens by on average 56-77% from baseline.
CONCLUSIONS
We conclude that AA and AAP therapies markedly reduce the production of the adrenal-derived 11-oxygenated androgens, both in patients with high (21OHD) or normal (CRPC) 11-oxygenated androgens at baseline, respectively. Reduction of 11-oxygenated androgens is an important aspect of AA and AAP pharmacology.
Topics: Abiraterone Acetate; Adrenal Hyperplasia, Congenital; Adult; Androgens; Androstenes; Chromatography, Liquid; Cytochrome P-450 Enzyme Inhibitors; Drug Therapy, Combination; Humans; Male; Prednisone; Prostatic Neoplasms; Tandem Mass Spectrometry; Testosterone
PubMed: 32045360
DOI: 10.1530/EJE-19-0905 -
The Oncologist May 2023Niraparib (NIRA) is a highly selective inhibitor of poly (adenosine diphosphate-ribose) polymerase, PARP1 and PARP2, which play a role in DNA repair. The phase II QUEST...
Niraparib (NIRA) is a highly selective inhibitor of poly (adenosine diphosphate-ribose) polymerase, PARP1 and PARP2, which play a role in DNA repair. The phase II QUEST study evaluated NIRA combinations in patients with metastatic castration-resistant prostate cancer who were positive for homologous recombination repair gene alterations and had progressed on 1 prior line of novel androgen receptor-targeted therapy. Results from the combination of NIRA with abiraterone acetate plus prednisone, which disrupts androgen axis signaling through inhibition of CYP17, showed promising efficacy and a manageable safety profile in this patient population.
Topics: Male; Humans; Abiraterone Acetate; Prednisone; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36994854
DOI: 10.1093/oncolo/oyad008 -
European Urology Oncology Jun 2024Limited responses have been observed in patients treated with enzalutamide after disease progression on abiraterone for metastatic castration-resistant prostate cancer...
Pembrolizumab and Enzalutamide in Patients with Abiraterone Acetate-Pretreated Metastatic Castration-Resistant Prostate Cancer: Cohort C of the Phase 1b/2 KEYNOTE-365 Study.
BACKGROUND
Limited responses have been observed in patients treated with enzalutamide after disease progression on abiraterone for metastatic castration-resistant prostate cancer (mCRPC), but androgen receptor signaling impacts T-cell function.
OBJECTIVE
To evaluate the efficacy and safety of pembrolizumab plus enzalutamide in mCRPC.
DESIGN, SETTING, AND PARTICIPANTS
Patients in cohort C of the phase 1b/2 KEYNOTE-365 study, who received ≥4 wk of treatment with abiraterone acetate in the prechemotherapy mCRPC state and experienced treatment failure or became drug-intolerant, were included.
INTERVENTION
Pembrolizumab 200 mg intravenously every 3 wk plus enzalutamide 160 mg orally once daily.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
The primary endpoints were safety, the confirmed prostate-specific antigen (PSA) response rate, and the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 on blinded independent central review (BICR). Secondary endpoints included radiographic progression-free survival (rPFS) on BICR and overall survival (OS).
RESULTS AND LIMITATIONS
A total of 102 patients received pembrolizumab plus enzalutamide. Median follow-up was 51 mo (interquartile range 37-56). The confirmed PSA response rate was 24% (95% confidence interval [CI] 16-33%). The confirmed ORR was 11% (95% CI 2.9-25%; 4/38 patients; two complete responses). Median rPFS was 6.0 mo (95% CI 4.1-6.3). Median OS was 20 mo (95% CI 17-24). Treatment-related adverse events (TRAEs) occurred in 94 patients (92%); grade 3-5 TRAEs occurred in 44 patients (43%). The incidence of treatment-related rash was higher with combination therapy than expected from the safety profile of each drug. One patient (1.0%) died of a TRAE (cause unknown). Study limitations include the single-arm design.
CONCLUSIONS
Pembrolizumab plus enzalutamide had limited antitumor activity in patients who received prior abiraterone treatment without previous chemotherapy for mCRPC, with a safety profile consistent with the individual profiles of each agent.
PATIENT SUMMARY
Pembrolizumab plus enzalutamide showed limited antitumor activity and manageable safety in patients with metastatic castration-resistant prostate cancer. The KEYNOTE-365 trial is registered on ClinicalTrials.gov as NCT02861573.
Topics: Humans; Male; Benzamides; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Nitriles; Aged; Antibodies, Monoclonal, Humanized; Abiraterone Acetate; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Aged, 80 and over; Cohort Studies; Neoplasm Metastasis
PubMed: 37940446
DOI: 10.1016/j.euo.2023.10.008 -
European Urology Open Science Jun 2023The PROpel trial assessed the combination of olaparib + abiraterone acetate (AA) plus prednisone and androgen deprivation therapy (ADT) versus AA plus prednisone and...
UNLABELLED
The PROpel trial assessed the combination of olaparib + abiraterone acetate (AA) plus prednisone and androgen deprivation therapy (ADT) versus AA plus prednisone and ADT alone as first-line treatment for metastatic castration-resistant prostate cancer (mCPRP). To contextualize the progression free survival (PFS) benefit in PROpel, we performed a systematic review and quasi-individual patient data network meta-analysis on randomized controlled trials of first-line hormonal treatments for mCPRC. Meta-analysis was performed for the PROpel control arm and PREVAIL (enzalutamide) and COU-AA-302 (AA) treatment arms. Kaplan-Meier PFS curves were digitally reconstructed and differences in restricted mean survival time (ΔRMST) were computed. Combination therapy yielded longer PFS (24-mo ΔRMST 1.5 mo, 95% confidence interval 0.6-2.4) in comparison to novel hormonal treatments alone. However, the lack of mature overall survival data, higher complication rates, and higher health care costs are limitations of combination therapy. Ultimately, combining treatments, rather than molecularly targeted sequencing in cases of failure, might not be justified in unselected patients with mCRPC.
PATIENT SUMMARY
A recent trial showed that for metastatic prostate cancer that does not respond to hormone treatment, combined therapy with two drugs (olaparib and abiraterone) may prolong survival free from cancer progression. We included these data in an analysis of three trials that confirmed a small benefit. This combination approach has higher complication rates and is more expensive, and longer-term results for overall survival are needed.
PubMed: 37182120
DOI: 10.1016/j.euros.2023.03.009 -
BMC Cancer Jun 2023To investigate the survival outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients receiving first-line novel androgen receptor axis-targeted...
PURPOSE
To investigate the survival outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients receiving first-line novel androgen receptor axis-targeted therapies (ARATs) and prognostic factors for patient survival.
METHODS
This retrospective study obtained data from 202 patients who started abiraterone acetate or enzalutamide as first-line therapy for mCRPC between 2016 and 2021 from a single academic center. The primary endpoint was overall survival (OS) defined as the interval from the start of ARAT to death, loss to follow-up, or the end of the study period. The secondary endpoints were PSA decline, PSA nadir, and time to nadir (TTN) after ARATs. Kaplan-Meier survival analyses were applied for depicting OS. Cox proportional hazards model with inversed probability of treatment weighing-adjustment was used to validate the effect of patient, disease, and treatment response factors on OS.
RESULTS
Among 202 patients, 164 patients were treated with first-line ARATs alone and 38 patients received second-line chemotherapy. The median OS was not reached in patients with first-line ARATs alone and was 38.8 months in those with subsequent chemotherapy after failure from ARATs. OS was not different between the use of abiraterone and enzalutamide, though enzalutamide showed a higher rate of PSA decline ≧ 90% (56% versus 40%, p = 0.021) and longer TTN (5.5 versus 4.7 months, p = 0.019). Multivariable analysis showed that PSA nadir > 2 ng/mL [hazard ratio (HR) 7.04, p < 0.001] and TTN<7 months (HR 2.18, p = 0.012) were independently associated with shorter OS. Patients with both of these poor prognostic factors had worse OS compared to those who had 0-1 factors (HR 9.21, p < 0.001).
CONCLUSIONS
Patients with mCRPC who received first-line ARATs had better survival if they had a PSA nadir[Formula: see text]2 ng/mL or a TTN[Formula: see text]7 months. Further study is needed to determine if an early switch in therapy for those in whom neither is achieved may impact OS.
Topics: Male; Humans; Abiraterone Acetate; Prostatic Neoplasms, Castration-Resistant; Prostate-Specific Antigen; Prognosis; Retrospective Studies; Androgen Antagonists; Nitriles; Treatment Outcome
PubMed: 37340337
DOI: 10.1186/s12885-023-10885-4 -
International Journal of Clinical... Feb 2020Abiraterone acetate plus prednisone is approved in metastatic castration-resistant prostate cancer. There is some evidence in favour of the steroid switch from... (Review)
Review
INTRODUCTION
Abiraterone acetate plus prednisone is approved in metastatic castration-resistant prostate cancer. There is some evidence in favour of the steroid switch from prednisone to dexamethasone in patients who progressed whilst on abiraterone acetate plus prednisone or prednisolone.
MATERIALS AND METHODS
The aim of this review is to discuss the results from the clinical studies available, examining potential mechanisms of action and patient selection criteria for this treatment option.
RESULTS
A total of four studies were evaluated. Among possible eligibility criteria for steroid switch, we found: PSA progression without any radiological or clinical progression during abiraterone acetate + prednisone; no high-grade adverse events related to CYP-17 inhibition; and unfitness for chemotherapy or radium-223.
CONCLUSION
Although large randomized prospective trials are warranted, steroid switch seems to offer a good option for certain patients treated with abiraterone acetate plus prednisone or prednisolone.
Topics: Abiraterone Acetate; Adrenal Cortex Hormones; Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Male; Middle Aged; Patient Selection; Prednisolone; Prednisone; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome
PubMed: 31705219
DOI: 10.1007/s10147-019-01577-w -
Prostate Cancer and Prostatic Diseases Dec 2020The combination of abiraterone acetate and prednisone (AA/P) is used to treat metastatic prostate cancer, but molecular predictors of treatment response are not well...
BACKGROUND
The combination of abiraterone acetate and prednisone (AA/P) is used to treat metastatic prostate cancer, but molecular predictors of treatment response are not well elucidated. We evaluated plasma circulating tumor DNA- (ctDNA-) based copy number alterations (CNAs) to determine treatment-related predictive and prognostic biomarkers for metastatic castration-resistant prostate cancer (mCRPC).
METHODS
Serial plasma specimens were prospectively collected from 88 chemotherapy-naive mCRPC patients before and after 12 weeks of AA/P treatment. Sequencing-based CNA analyses were performed on 174 specimens. We evaluated CNA-associated 12-week responses for primary resistance, time to treatment change (TTTC) for secondary resistance, and overall survival for prognosis (P < 0.05). Associations with primary resistance were analyzed using the Fisher exact test. Kaplan-Meier survival curves and Cox regression analyses were used to determine the associations of CNAs with acquired resistance and overall survival.
RESULTS
ctDNA reduced by 3.89% in responders and increased by 0.94% in nonresponders (P = 0.0043). Thirty-one prostate cancer-related genes from whole genome CNAs were tested. AR and AR enhancer amplification were associated with primary resistance (P = 0.0039) and shorter TTTC (P = 0.0003). ZFHX3 deletion and PIK3CA amplification were associated with primary resistance (P = 0.026 and P = 0.017, respectively), shorter TTTC (P = 0.0008 and P = 0.0016, respectively), and poor survival (P = 0.0025 and P = 0.0022, respectively). CNA-based risk scores combining selected significant associations (AR, NKX3.1, and PIK3CA) at the univariate level with TTTC were predictive of secondary resistance (P = 0.0002). and established prognoses for survival based on CNAs in ZFHX3, RB1, PIK3CA, and OPHN1 (P = 0.002). Multigene risk scores were more predictive than individual genes or clinical risk factors (P < 0.05).
CONCLUSION
Plasma ctDNA CNAs and risk scores can predict mCRPC-state treatment and survival outcomes.
Topics: Abiraterone Acetate; Adult; Aged; Anti-Inflammatory Agents; Biomarkers, Tumor; Cell-Free Nucleic Acids; DNA Copy Number Variations; Humans; Kallikreins; Male; Middle Aged; Neoplasm Metastasis; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Steroid Synthesis Inhibitors; Survival Rate; Treatment Outcome
PubMed: 32203070
DOI: 10.1038/s41391-020-0224-4 -
Current Urology Oct 2019The treatment landscape for advanced prostate cancer is evolving rapidly, with new agents and strategies, and more optimal use of existing therapies under constant... (Review)
Review
The treatment landscape for advanced prostate cancer is evolving rapidly, with new agents and strategies, and more optimal use of existing therapies under constant development. Efforts were focused on better understanding of the biology of the disease. This effort has paved the way for a more contemporary and effective therapies to be developed. There are now 6 FDA-approved therapies that increase overall survival. These include the immunotherapy sipuleucel-T; the 2 androgen pathway inhibitors: abiraterone acetate and enzalutamide; 2 chemotherapy drugs: docetaxel and cabazitaxel; and the radionuclide: radium-223. Advanced prostate cancer may be one of the few cancers for which multiple chemotherapy and nonchemotherapy regimens are considered as standard. Several recently published clinical trials have demonstrated the suprising activity of chemotherapy-free strategies, and we should not be too eager to discount these "old-fashioned" treatments. Optimal sequencing is still unclear because new therapies have proliferated so quickly that comparative data are limited. In this short communication, we identify current challenges and unmet needs in advanced prostate cancer and provide an overview of their respective clinical activity, while highlighting distinctions between therapies.
PubMed: 31768170
DOI: 10.1159/000499292 -
Japanese Journal of Clinical Oncology Aug 2021Abiraterone acetate plus prednisolone is approved to treat patients with castration-resistant prostate cancer. This study evaluated the safety and efficacy of... (Observational Study)
Observational Study
Safety and efficacy of abiraterone acetate plus prednisolone in patients with castration-resistant prostate cancer: a prospective, observational, post-marketing surveillance study.
BACKGROUND
Abiraterone acetate plus prednisolone is approved to treat patients with castration-resistant prostate cancer. This study evaluated the safety and efficacy of abiraterone acetate plus prednisolone in castration-resistant prostate cancer patients with or without previous chemotherapy in a real-world setting in Japan.
METHODS
This study was an observational, prospective, post-marketing surveillance. Castration-resistant prostate cancer patients, who initiated abiraterone acetate after its approval in Japan, were enrolled. Data were collected during an observation period of 12 months and a follow-up period of another 12 months. Adverse events and adverse drug reactions were evaluated for safety. Prostate-specific antigen levels and overall survival were evaluated for efficacy.
RESULTS
From 141 participating institutions, 497 patients were registered: 492 patients including 180 chemotherapy-naïve, 311 chemotherapy-experienced and one off-label-use patient received abiraterone and were evaluated for safety. Adverse events were observed in 225/492 patients (45.7%), adverse drug reactions in 131/492 patients (26.6%) and serious adverse drug reactions in 61/492 patients (12.4%). The most commonly observed adverse drug reaction was abnormal hepatic function (6.5%), followed by hypokalemia (3.0%) and decreased appetite (2.0%). At week 12, 110/432 patients (25.5%) achieved ≥50% decrease from baseline in prostate-specific antigen, and the proportion was higher in chemotherapy-naïve patients (56/161 patients; 34.8%) compared with chemotherapy-experienced patients (54/271 patients; 19.9%, P < 0.001). Survival rates at 24 months were 68.3% (295/432 patients), 73.9% (119/161 chemotherapy-naïve patients) and 64.9% (176/271 chemotherapy-experienced patients).
CONCLUSIONS
This large-scale, real-world, post-marketing surveillance study confirmed the safety and efficacy of abiraterone acetate plus prednisolone in Japanese castration-resistant prostate cancer patients with or without previous chemotherapy.
Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Prednisolone; Product Surveillance, Postmarketing; Prospective Studies; Prostatic Neoplasms, Castration-Resistant
PubMed: 34050660
DOI: 10.1093/jjco/hyab077