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      The changing landscape of hormonal therapy in castration-resistant prostate cancer

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          Abstract

          Androgen deprivation therapy (ADT) is generally the initial treatment for men with advanced prostate cancer. Standard approaches include orchiectomy, a gonadotropin-releasing hormone (GnRH) agonist, or a combination of a GnRH agonist plus an antiandrogen (combined androgen blockade). Despite initial response rates of 80-90%,[1] nearly all men eventually develop castration-resistant prostate cancer (CRPC), which is defined as progressive prostate cancer despite castrate levels of serum testosterone (>50 ng/dl). Androgenic steroids act as growth factors for prostate cancer. When disease progresses to CRPC, discontinuation of hormonal therapy can result in a rebound increase in serum testosterone and thus contribute to progressive disease. There are no trials that directly address the utility of continued ADT in men with CRPC. However, a multivariate analysis of 341 patients with CRPC who were treated in four clinical trials found observational evidence that continued testicular androgen suppression was associated with a median survival benefit of 2-6 months.[2] In a patient with CRPC, prior to initiating chemotherapy, several alternative hormonal manipulation strategies exist. These include newer antiandrogens, higher doses of the same antiandrogens, antiandrogen withdrawal, ketoconazole, glucocorticoids, megestrol acetate, and estrogens.[3 4 5] These have not been demonstrated to improve survival. However, these approaches may induce clinical responses and provide palliation in terms of decrease in pain, improvement of anemia, reduction in prostate specific antigen (PSA), and better quality of life. Secondary endocrine therapies are often used sequentially and may be useful in postponing interventions such as chemotherapy or when no other effective options are available. The activity of flutamide was illustrated by a series of 209 men treated after failing initial endocrine therapy with orchiectomy, diethylstilbestrol, or a GnRH agonist. The overall response rate was 35%, and the mean duration of response was 24 months.[6] The potential utility of using an alternative nonsteroidal antiandrogen was illustrated by a retrospective series of 232 patients who progressed after initial treatment with combined androgen blockade. There was no significant difference in those who switched from bicalutamide to flutamide compared to those who changed from flutamide to bicalutamide. Multivariate analysis found that any response to second-line antiandrogen therapy was significantly associated with an improved cause-specific survival.[7] The potential role of DES as a second-line agent was evaluated in a trial in which 58 men who had progressed on GnRH agonist therapy were randomly assigned to either DES or bicalutamide. Both the PSA response rate and median response durations were similar in the two groups (23% vs. 31% and 9 vs. 12 months, respectively).[8] The role of antiandrogen withdrawal was studied in men with CRPC in a Phase III trial conducted by the Cancer and Leukemia Group B (CALGB 9583) In this trial, 260 patients who had progressed on ADT were randomly assigned to antiandrogen withdrawal plus simultaneous ketoconazole or antiandrogen withdrawal alone, with ketoconazole reserved for subsequent use upon progression. More patients had a PSA response or an objective tumor response when ketoconazole was initiated immediately rather than waiting to see if an antiandrogen withdrawal response occurred (27% vs. 11% and 20% vs. 2%, respectively). However, there was no statistically significant difference in overall survival with the two treatment strategies (15.3 vs. 16.7 months, P = 0.94).[9] Two other observational series that each included over 200 patients observed antiandrogen withdrawal leads to PSA response rates of 15% and 21%, respectively.[7 10] The major drawback of secondary hormonal manipulation is that there is no proven survival benefit. However, until recently, the only other therapeutic option was chemotherapy, which although proven to enhance survival, comes at the cost of significant toxicity. Contemporary research has demonstrated that even after failure of hormonal therapy, androgen-based pathways continue to play a clinically significant role in the progression of CRPC. In addition to androgen production by the adrenal gland and testis, several of the enzymes involved in the synthesis of testosterone and dihydrotestosterone, including cytochrome P450 17-alpha-hydroxysteroid dehydrogenase (CYP17), are highly expressed in tumor tissue. This understanding has led to the development of drugs that act by inhibition of the enzymes responsible for androgen production, as well as agents that inhibit the androgen receptor. Abiraterone, a new androgen synthesis inhibitor was developed through screening chemical derivatives of a parent structure of pregnenolone. The structural changes in abiraterone account for potent and irreversible inhibition of CYP17. In preclinical studies, abiraterone was ten times more potent than ketoconazole as an inhibitor of CYP17 although ketoconazole is a more potent inhibitor of the side chain cleavage enzyme, which plays a critical role in adrenal steroidogenesis; patients treated with either of these agents are at risk for adrenal insufficiency and require steroid replacement therapy. The use of ketoconazole is further limited by the potential for drug-drug interactions, particularly with statins and anti-depressants. Abiraterone is an orally administered small molecule that irreversibly inhibits the products of the CYP17 gene (including both 17,20-lyase and 17-alpha-hydroxylase). In doing so, abiraterone blocks the synthesis of androgens in the tumor as well as in the testes and adrenal glands. The activity of abiraterone was established in two Phase III trials in men with metastatic, castration-resistant prostate cancer, the first in patients who had received prior docetaxel, and the other in patients with chemotherapy-naive disease. In the first Phase III trial, 1195 men who had previously been treated with a docetaxel-containing chemotherapy regimen were randomly assigned in a 2:1 ratio to abiraterone (1000 mg/day) plus prednisone (5 mg twice a day) or placebo plus prednisone. Treatment was continued until disease progression. Statistically significant improvements were seen in time to PSA progression, progression-free survival, and PSA response rate (10.2 vs. 6.6 months, 5.6 vs. 3.6 months, and 29% vs. 6%, respectively).[11] Abiraterone also delays disease progression and probably prolongs overall survival in men with castrate-resistant prostate cancer who have not received chemotherapy.[12] Side effects that were more common with abiraterone included fluid retention (33%), hypokalemia (18%), non-specific cardiac abnormalities (16%), and transaminase elevation (11%).[11] Enzalutamide binds to the androgen-binding site in the androgen receptor, thereby leading to inhibition of nuclear translocation of the androgen receptor, and inhibition of the association of the androgen receptor with nuclear DNA. Phase I/II studies showed that enzalutamide had significant activity in men with CRPC.[13] This has led to the assessment of enzalutamide in Phase III trial (AFFIRM trial) which showed an overall survival benefit of 4.8 months. Enzalutamide was also significantly better than placebo in all secondary efficacy endpoints, including PSA response, soft-tissue response, quality-of-life response, time to PSA progression, radiographic progression-free survival, and time to first skeletal-related event. There was a higher incidence of fatigue, diarrhea, hot flashes, musculoskeletal pain, and headache. The concern was the development of seizures, which occurred in seven patients (0.9%) treated with enzalutamide and no patients assigned to placebo.[14] Thus, after decades, we now have two new medications in the hormonal therapy armamentarium. Abiraterone and enzalutamide will play a significant role in the management of men with advanced prostate cancer. They have proven to be efficacious with a very tolerable toxicity profile. Currently, unanswered questions exist regarding sequencing of these agents with respect to each other and with relation to chemotherapy. With the introduction of a new chemotherapeutic agent, Cabazitaxel, and these two new hormonal therapies, being a medical oncologist taking care of patients with prostate cancer has just become infinitely exciting.

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          Most cited references 11

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          Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study.

          Abiraterone acetate improved overall survival in metastatic castration-resistant prostate cancer at a preplanned interim analysis of the COU-AA-301 double-blind, placebo-controlled phase 3 study. Here, we present the final analysis of the study before crossover from placebo to abiraterone acetate (after 775 of the prespecified 797 death events). Between May 8, 2008, and July 28, 2009, this study enrolled 1195 patients at 147 sites in 13 countries. Patients were eligible if they had metastatic castration-resistant prostate cancer progressing after docetaxel. Patients were stratified according to baseline Eastern Cooperative Oncology Group (ECOG) performance status, worst pain over the past 24 h on the Brief Pain Inventory-Short Form, number of previous chemotherapy regimens, and type of progression. Patients were randomly assigned (ratio 2:1) to receive either abiraterone acetate (1000 mg, once daily and orally) plus prednisone (5 mg, orally twice daily) or placebo plus prednisone with a permuted block method via an interactive web response system. The primary endpoint was overall survival, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00091442. Of the 1195 eligible patients, 797 were randomly assigned to receive abiraterone acetate plus prednisone (abiraterone group) and 398 to receive placebo plus prednisone (placebo group). At median follow-up of 20·2 months (IQR 18·4-22·1), median overall survival for the abiraterone group was longer than in the placebo group (15·8 months [95% CI 14·8-17·0] vs 11·2 months [10·4-13·1]; hazard ratio [HR] 0·74, 95% CI 0·64-0·86; p<0·0001). Median time to PSA progression (8·5 months, 95% CI 8·3-11·1, in the abiraterone group vs 6·6 months, 5·6-8·3, in the placebo group; HR 0·63, 0·52-0·78; p<0·0001), median radiologic progression-free survival (5·6 months, 5·6-6·5, vs 3·6 months, 2·9-5·5; HR 0·66, 0·58-0·76; p<0·0001), and proportion of patients who had a PSA response (235 [29·5%] of 797 patients vs 22 [5·5%] of 398; p<0·0001) were all improved in the abiraterone group compared with the placebo group. The most common grade 3-4 adverse events were fatigue (72 [9%] of 791 patients in the abiraterone group vs 41 [10%] of 394 in the placebo group), anaemia (62 [8%] vs 32 [8%]), back pain (56 [7%] vs 40 [10%]), and bone pain (51 [6%] vs 31 [8%]). This final analysis confirms that abiraterone acetate significantly prolongs overall survival in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel treatment. No new safety signals were identified with increased follow-up. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study.

            MDV3100 is an androgen-receptor antagonist that blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. It also induces tumour cell apoptosis, and has no agonist activity. Because growth of castration-resistant prostate cancer is dependent on continued androgen-receptor signalling, we assessed the antitumour activity and safety of MDV3100 in men with this disease. This phase 1-2 study was undertaken in five US centres in 140 patients. Patients with progressive, metastatic, castration-resistant prostate cancer were enrolled in dose-escalation cohorts of three to six patients and given an oral daily starting dose of MDV3100 30 mg. The final daily doses studied were 30 mg (n=3), 60 mg (27), 150 mg (28), 240 mg (29), 360 mg (28), 480 mg (22), and 600 mg (3). The primary objective was to identify the safety and tolerability profile of MDV3100 and to establish the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT00510718. We noted antitumour effects at all doses, including decreases in serum prostate-specific antigen of 50% or more in 78 (56%) patients, responses in soft tissue in 13 (22%) of 59 patients, stabilised bone disease in 61 (56%) of 109 patients, and conversion from unfavourable to favourable circulating tumour cell counts in 25 (49%) of the 51 patients. PET imaging of 22 patients to assess androgen-receptor blockade showed decreased (18)F-fluoro-5alpha-dihydrotestosterone binding at doses from 60 mg to 480 mg per day (range 20-100%). The median time to progression was 47 weeks (95% CI 34-not reached) for radiological progression. The maximum tolerated dose for sustained treatment (>28 days) was 240 mg. The most common grade 3-4 adverse event was dose-dependent fatigue (16 [11%] patients), which generally resolved after dose reduction. We recorded encouraging antitumour activity with MDV3100 in patients with castration-resistant prostate cancer. The results of this phase 1-2 trial validate in man preclinical studies implicating sustained androgen-receptor signalling as a driver in this disease. Medivation, the Prostate Cancer Foundation, National Cancer Institute, the Howard Hughes Medical Institute, Doris Duke Charitable Foundation, and Department of Defense Prostate Cancer Clinical Trials Consortium. Copyright 2010 Elsevier Ltd. All rights reserved.
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              Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583).

              Antiandrogen withdrawal (AAWD) results in a prostate-specific antigen (PSA) response (decline in PSA level of > or =50%) in 15% to 30% of androgen-independent prostate cancer (AiPCa) patients. Thereafter, adrenal androgen ablation with agents such as ketoconazole (K) is commonly utilized. The therapeutic effect of AAWD alone was compared with simultaneous AAWD and K therapy. AiPCa patients were randomized to undergo AAWD alone (n=132), or together with K (400 mg orally [p.o.] tid) and hydrocortisone (30 mg p.o. each morning, 10 mg p.o. each evening; n=128). Patients who developed progressive disease after AAWD alone were eligible for deferred treatment with K. Eleven percent of patients undergoing AAWD alone had a PSA response, compared to 27% of patients who underwent AAWD and simultaneous K (P=.0002). Objective responses were observed in 2% of patients treated with AAWD alone compared to 20% in patients treated with AAWD/K (P=.02). There was no difference in survival. PSA and objective responses were observed in 32% and 7%, respectively, of patients receiving deferred K, and were more common in patients with prior AAWD response. Treatment with K was well tolerated, and resulted in a decline in adrenal androgen levels, which rose at the time of disease progression. K has modest activity in AiPCa patients, while AAWD alone has minimal activity. Adrenal androgen levels fall with treatment with K and then climb at the time of progression, suggesting that progressive disease while on K may be due to tachyphylaxis to the adrenolytic properties of K.
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                Author and article information

                Journal
                South Asian J Cancer
                South Asian J Cancer
                SAJC
                South Asian Journal of Cancer
                Medknow Publications & Media Pvt Ltd (India )
                2278-330X
                2278-4306
                Oct-Dec 2012
                : 1
                : 2
                : 53-55
                Affiliations
                Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India
                Author notes
                Author for correspondence: Dr. Vanita Noronha, Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India E-mail: vanita.noronha@ 123456gmail.com
                Article
                SAJC-1-53
                10.4103/2278-330X.103707
                3876609
                Copyright: © South Asian Journal of Cancer

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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