abiraterone-acetate and bicalutamide

A subgroup of androgen receptor-expressing tumors represents approximately 30 % of all triple negative tumors. The androgen receptor and its signaling pathways have a central biological role in this tumor entity. These triple negative androgen receptor-positive tumors occur in older patients and do not appear to have a better prognosis compared to other triple negative tumors. In addition to androgen receptor-expression, these tumors are genomically characterized by a high frequency of PIK3CA activating mutation. Three clinical trials reported efficacy data for anti-androgens (bicalutamide, abiraterone acetate and enzalutamide) based on strong preclinical rationale. These trials report clinical benefit rates in about one in five patients. These encouraging but still limited results make a case for the identification of predictive response factors and therapeutic combinations to improve response rates. This review will provide an update on the biological and clinical knowledge of this tumoral subgroup that opens the way to non-cytotoxic anti-androgen therapies.

Topics: Abiraterone Acetate; Age Factors; Aged; Androgen Antagonists; Anilides; Benzamides; Class I Phosphatidylinositol 3-Kinases; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Female; Forecasting; Humans; Mutation; Nitriles; Phenylthiohydantoin; Prognosis; Rare Diseases; Receptors, Androgen; Signal Transduction; Tosyl Compounds; Triple Negative Breast Neoplasms

A high incidence of fall and fracture in a subset of patients treated with androgen receptor inhibitors (ARIs) has been reported, although the relative risk (RR) of fall and fracture for patients who receive ARI treatment is unknown.. To evaluate whether treatment with ARIs is associated with an elevated relative risk for fall and fracture in patients with prostate cancer.. Cochrane, Scopus, and MedlinePlus databases were searched from inception through August 2019.. Randomized clinical trials comparing patients with prostate cancer treated with any ARI or placebo were included.. Two independent reviewers used a standardized data extraction and quality assessment form. A mixed effects model was used to estimate the effects of ARI on relative risk, with included studies treated as random effects and study groups treated as fixed effects in the pooled analysis. Sample size for each study was used to weight the mixed model. Statistical analysis was performed from August to October 2019.. The primary outcome was RR of fall and fractures for patients receiving ARI treatment.. Eleven studies met this study's inclusion criteria. The total population was 11 382 men (median [range] age: 72 [43-97] years), with 6536 in the ARI group and 4846 in the control group. Participants in the ARI group could have received enzalutamide, apalutamide, or darolutamide in combination with androgen deprivation therapy or other enzalutamide combinations; patients in the control group could have received placebo, bicalutamide, or abiraterone. The reported incidence of fall was 525 falls (8%) in the ARI group and 221 falls (5%) in the control group. The incidence of fracture was 242 fractures (4%) in the ARI group and 107 fractures (2%) in the control group. Use of an ARI was associated with an increased risk of falls and fractures: all-grade falls (RR, 1.8; 95% CI, 1.42-2.24; P < .001); grade 3 or greater fall (RR, 1.6; 95% CI, 1.27-2.08; P < .001); all-grade fracture (RR, 1.59; 95% CI, 1.35-1.89; P < .001), and likely grade 3 or greater fracture (RR, 1.71; 95% CI, 1.12-2.63; P = .01).. Use of ARI was associated with an increase in falls and fractures in patients with prostate cancer as assessed by a retrospective systematic review and meta-analysis. Further studies are warranted to identify and understand potential mechanisms and develop strategies to decrease falls and fractures associated with ARI use.

Topics: Abiraterone Acetate; Accidental Falls; Androgen Receptor Antagonists; Anilides; Antineoplastic Agents, Hormonal; Benzamides; Case-Control Studies; Fractures, Bone; Humans; Incidence; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Pyrazoles; Risk Factors; Thiohydantoins; Tosyl Compounds; Trauma Severity Indices

Breast cancer (BC) is traditionally viewed as an oestrogen-dependent disease in which the androgen receptor (AR) is inhibitory, counteracting the oncogenic activity of oestrogen receptor α (ERα (ESR1)). Most probably as a result of this crosstalk, the AR has prognostic value in ER-positive disease, with AR positivity reported to correlate with a better prognosis. Activation of the AR pathway has been previously used as a therapeutic strategy to treat BC, but its usage declined following the introduction of the anti-oestrogen tamoxifen. More recently, it has been demonstrated that a subset of triple-negative BCs (molecular apocrine) are dependent upon androgen signalling for growth and therapies that inhibit androgen signalling, currently used for the treatment of prostate cancer, e.g. the antiandrogen bicalutamide and the CYP17 inhibitor abiraterone acetate are undergoing clinical trials to investigate their efficacy in this BC subtype. This review summarises the current knowledge of AR activity in BC.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Androstadienes; Anilides; Estrogen Antagonists; Female; Humans; Nitriles; Receptors, Androgen; Receptors, Estrogen; Signal Transduction; Steroid 17-alpha-Hydroxylase; Tamoxifen; Tosyl Compounds; Triple Negative Breast Neoplasms

Although prostate cancer is a very common form of malignancy in men, the clinical significance of androgen deprivation therapy (ADT) with abiraterone acetate versus the nonsteroidal antiandrogen bicalutamide has not yet been verified in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). The present study was designed to initiate this verification in real-world Japanese clinical practice.. We retrospectively analyzed the records of 312 patients with high-risk mHSPC based on LATITUDE criteria and had received ADT with bicalutamide (n = 212) or abiraterone acetate (n = 100) between September 2015 and December 2020. Bicalutamide was given at 80 mg daily and abiraterone was given at 1000 mg daily as four 250-mg tablets plus prednisolone (5-10 mg daily). Overall survival (OS), cancer-specific survival (CSS), and time to castration-resistant prostate cancer (CRPC) were compared. The prognostic factor for time to CRPC was analyzed by Cox proportional hazard model.. Patients in the bicalutamide group were older, and more of them had poor performance status (≧2), than in the abiraterone group. Impaired liver function was noted in 2% of the bicalutamide group and 16% of the abiraterone group (p < 0.001). Median follow-up was 22.5 months for bicalutamide and 17 months for abiraterone (p < 0.001). Two-year OS and CSS for bicalutamide versus abiraterone was 77.8% versus 79.5% (p = 0.793) and 81.1% versus 82.5% (p = 0.698), respectively. Median time to CRPC was significantly longer in the abiraterone group than in the bicalutamide group (NA vs. 13 months, p < 0.001). In multivariate analysis, Gleason score ≧9, high alkaline phosphatase, high lactate dehydrogenase, liver metastasis, and bicalutamide were independent prognostic risk factors for time to CRPC. Abiraterone prolonged the time to CRPC in patients with each of these prognostic factors.. Despite limitations regarding the time-dependent bias, ADT with abiraterone acetate significantly prolonged the time to CRPC compared to bicalutamide in patients with high-risk mHSPC. However, further study with longer follow-up is needed.

Topics: Abiraterone Acetate; Androgen Antagonists; Anilides; Antineoplastic Combined Chemotherapy Protocols; Comparative Effectiveness Research; Humans; Japan; Liver Function Tests; Liver Neoplasms; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Nitriles; Nonsteroidal Anti-Androgens; Prednisolone; Prognosis; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Risk Assessment; Tosyl Compounds

Combining abiraterone (Abi) with androgen deprivation therapy (ADT) improves overall survival, compared to ADT only, in patients with metastatic castration-sensitive prostate cancer (mCSPC). In Japan, bicalutamide (Bica) and ADT (combined androgen blockade: CAB) is frequently provided for mCSPC. Because these two treatments have not been compared, mCSPC patients who received either treatment were retrospectively analyzed.. Of 178 patients with LATITUDE high-risk mCSPC, 103 had received ADT plus upfront Abi (Abi group) and 75 had received ADT plus Bica (Bica group) in multiple institutions of the Tokai Urologic Oncology Research Seminar. Kaplan-Meir curves were used to retrospectively analyze survival and cancer recurrence. Univariate and multivariate Cox regression analyses identified potential prognostic factors for progression-free survival (PFS).. Significant differences in major clinicopathological characteristics between the two groups were not observed. The rate of castration-resistant development was higher in the Bica compared to Abi group (50.6 vs. 25.2%, p < 0.001). The median PFS in the Bica group was 13.6 months {95% confidence interval [CI] 9.2-22.2}; however, in the Abi group, PFS did not reach the median {95% CI 18.5-not assessed [NA]; p < 0.001}. Time to second progression for the Abi group was superior (p = 0.07). Univariate and multivariate analyses revealed Gleason pattern 5, high alkaline phosphatase levels, and conventional CAB using Bica as significant prognostic factors for short PFS.. In patients with LATITUDE high-risk mCSPC, upfront use of Abi combined with ADT resulted in favorable prognostic outcomes compared with conventional ADT with Bica.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Androstenes; Anilides; Antineoplastic Combined Chemotherapy Protocols; Humans; Japan; Male; Neoplasm Recurrence, Local; Nitriles; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Tosyl Compounds

The treatment landscape for men with metastatic hormone-naïve prostate cancer (mHNPC) has dramatically changed with the approval of next-generation anti-androgen drugs. We compared the treatment efficacy of abiraterone with that of combined androgen blockade (CAB) therapy and androgen deprivation therapy (ADT) alone in men with high-risk mHNPC.. In total, 146 Japanese men with high-risk mHNPC were retrospectively analyzed. As initial hormonal therapy, 30, 83, and 33 men were treated with ADT plus abiraterone (ABI group), ADT plus bicalutamide (CAB group), and ADT alone (ADT group), respectively. Treatment efficacy was compared using time to castration resistance (TTCR) and prostate-specific antigen (PSA) response among the groups. Propensity score matching analysis was also performed to adjust for baseline differences.. The median (95% confidence interval [CI]) TTCR in the ABI, CAB, and ADT groups were not reached, 10.7 (7.6-13.8) months and 11.0 (7.9-12.4) months, respectively, and it was significantly longer in the ABI group than in the other groups (p = 0.0012, p = 0.0008). In propensity score matching analysis, the median TTCR was also significantly longer in the ABI group than in the other groups (hazard ratio [HR], 0.47; 95% CI, 0.22-0.98; p = 0.010; HR, 0.32; 95% CI, 0.12-0.85; p = 0.004). The number of men who achieved PSA levels ≤0.2 ng/mL after propensity score matching were significantly higher in the ABI group than in the other groups.. Our results provide important evidence regarding the superiority of abiraterone over CAB therapy and ADT alone for initial treatment for men with newly diagnosed mHNPC.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Treatment Outcome

There is a discrepancy in the efficacy of abiraterone acetate for overall survival (OS) in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). This study aimed to identify predictive factors for the efficacy of abiraterone acetate for OS in high-risk mHSPC patients by analyzing them over a longer observation period.. Five hundred high-risk mHSPC patients were retrospectively identified at our hospital and affiliated hospitals in the Kindai Oncology Study Group and Kyoto Prefectural University of Medicine Oncology Study Group between December 2013 and March 2022. Two hundred patients were treated with abiraterone acetate (1000 mg/day) plus prednisolone (5 mg/day) combined with androgen deprivation therapy (ADT). A total of 300 patients were treated with bicalutamide (80 mg/day) in combination with ADT.. OS was not significantly different between the two treatments in the overall cohort (p = 0.1643). In the subgroup without Gleason pattern 5 at the primary lesion, OS was significantly better in patients treated with abiraterone acetate than in those treated with bicalutamide (p = 0.0192). In the subgroup with Gleason pattern 5 at the primary lesion, no significant difference was found between the two treatments (p = 0.1799). Univariate and multivariate analyses in the subgroup without Gleason pattern 5 at the primary lesion suggested that abiraterone therapy may be an important and independent predictor of OS in high-risk mHSPC patients.. The presence of Gleason pattern 5 at the primary lesion may be a predictor for high-risk mHSPC patients who could benefit from abiraterone acetate treatment.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Hormones; Humans; Male; Prostatic Neoplasms; Retrospective Studies; Treatment Outcome

The objective of this study was to compare the efficacy of abiraterone acetate with that of bicalutamide in combination with gonadotropin-releasing hormone (GnRH) antagonist treatment for patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). A total of 149 patients with mHSPC who underwent treatment at our hospital and affiliated hospitals between December 2013 and July 2020 were retrospectively identified. Fifty patients were administered abiraterone acetate (1000 mg/day) plus prednisolone (5 mg/day) with a GnRH antagonist (degarelix) (group A), and 99 patients were administered bicalutamide (80 mg/day) with a GnRH antagonist (group B). The prostate-specific antigen (PSA) progression-free survival (PSA-PFS) was significantly longer in group A than in group B. Abiraterone acetate therapy and Gleason score were significant independent factors of PSA-PFS. Using propensity score matching, 56 matched patients were obtained. The PSA-PFS (p < 0.001) and overall survival (OS) (p = 0.0071) of patients with high-risk mHSPC were significantly longer in group A of matched patients. Abiraterone acetate therapy and Gleason score were significant independent factors for PSA-PFS in matched patients. The PSA-PFS and OS of patients treated with abiraterone acetate in combination with a GnRH antagonist were significantly better than those treated with bicalutamide.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Combined Chemotherapy Protocols; Drug Therapy, Combination; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Neoplasm Grading; Nitriles; Oligopeptides; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Tosyl Compounds; Treatment Outcome

There has been no established clinical evidence for using sequential treatment in castration-resistant prostate cancer (CRPC). Despite evident cross-resistance, androgen receptor axis-targeted agents (ARTAs), namely abiraterone (ABI) and enzalutamide (ENZ), are often used sequentially owing to less toxicity compared with chemotherapy.. A multicenter retrospective review of chemotherapy-naive patients with CRPC who had received ABI followed by ENZ (ABI-to-ENZ) or ENZ followed by ABI (ENZ-to-ABI) was conducted. Combined progression-free survival (PFS), overall survival (OS), and prostate-specific antigen (PSA) response (≥ 50% PSA decline) to each drug were compared between the 2 groups at the median follow-up of 36.0 months.. There were no significant differences in combined PFS (12.4 vs. 10.9 months; hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.72-1.23; P = .6594) or OS (28.3 vs 29.3 months; HR, 0.96; 95% CI, 0.66-1.38; P = .8314) between the ABI-to-ENZ and ENZ-to-ABI groups. PSA response rate was not significantly different in first-line ARTAs (48.9% vs. 58.4%; P = .153) but significantly higher in ENZ as a second-line ARTA (40.4% vs. 13.7%; P < .0001). Although multivariate analysis revealed that the ABI-to-ENZ sequence was associated with favorable PFS on second-line ARTA (HR, 0.65; 95% CI, 0.49-0.85; P = .0019), it was not associated with an increased combined PFS or OS.. With relatively longer follow-up, ARTA sequence did not affect clinical outcomes of CRPC treatment except for PSA response and PFS on a second-line ARTA. These findings will be useful information in clinical decision-making, particularly in chemotherapy-unfit patients with CRPC.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Receptor Antagonists; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Flutamide; Follow-Up Studies; Humans; Kallikreins; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Tosyl Compounds