Secondary Hormone Therapy for
Castration-Resistant Prostate Cancer
1Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston,Massachusetts
The majority of patients with systemic prostate cancer treated with androgen deprivation therapy (ADT) willdevelop castration-resistant prostate cancer (CRPC). CRPC is defined by prostate-specific antigen (PSA) orradiographic progression in the context of castrate levels of testosterone. CRPC patients may or may nothave obvious metastases. Like all stages of prostate cancer, the natural history of nonmetastatic or metastaticCRPC is heterogeneous, and clinical decisions must be made in the context of an individual’s disease pace,symptoms, age, medical condition, and goals.
When a patient initially transitions to CRPC, it’s advisable to confirm that serum testosterone is castrate (<50 ng/dL by convention). Rarely, the serum testosterone level with medical castration (LHRHagonists/antagonists) may be higher than 50 ng/dL and can be lowered with an adjustment in the dose of thetherapeutic agent, proper administration of the agent, or orchiectomy. CRPC can be categorized asnonmetastatic or metastatic. In nonmetastatic CRPC, I generally categorize patients as slow progressors orrapid progressors based on their initial response to ADT and the PSA doubling time (PSAdt). A trial ofdenosumab (Xgeva) in nonmetastatic CRPC (PSAdt 10 months) gives us the best estimate of time todevelopment of metastases and overall survival (OS) in these patients. Patients who had nonmetastaticCRPC with short (< 10 months) PSAdt developed metastases in 29 to 33 months and had an OS of about 44months. Patients with established metastatic CRPC (no prior chemotherapy) have life expectancy in therange of 27 to 32 months and may need more frequent cancer staging and interventions. Patients withnonmetastatic CRPC should be re-imaged at regular intervals (3 to 6 months) in order to be able to takeadvantage, as early as possible, of the option for therapies that require metastases.
An important aspect of the biology of CRPC is that most CRPCs select mechanisms that upregulateintracellular androgens and/or androgen receptor (AR), leading to ongoing AR-directed cancer growthdespite a castrate level of serum androgens. Thus, when patients develop CRPC they are usually sensitiveto sequential “secondary” hormonal therapies directed at AR inhibition. In fact, in a retrospective analysis of436 patients treated with secondary hormonal therapies at our center, we found that the median duration oftime on secondary hormone therapies (antiandrogens, ketoconazole(Drug information on ketoconazole), estrogens(Drug information on estrogens)) was 30 months compared with a median duration of 24 months onprimary ADT. Response to initial ADT predicted subsequent response to secondary ADT; patients whoresponded to primary ADT for > 24 months received secondary ADT for a median of 40 months, whereas themedian was 18 months for men who responded to primary ADT for < 24 months. The recent US Food &Drug Administration (FDA) approval based on survival advantages of a more potent antiandrogen(enzalutamide [Xtandi]) and a potent androgen synthesis inhibitor (abiraterone [Zytiga]) has put to bed thepreviously held notion that prostate cancer doesn’t respond to sequential hormone therapy.[6,7]
Upon development of CRPC, I generally consider anti-androgen therapy as the first “secondary” hormonetherapy, and in fact antiandrogens and ketoconazole are the only options for nonmetastatic CRPC based onFDA label and cost. The possible exception to consideration of sequential antiandrogen therapy would be apatient profile such as a very short response to primary ADT and/or a non–PSA-producing tumor that wouldpredict nonresponsiveness to additional ADT. I commonly use bicalutamide(Drug information onbicalutamide) and nilutamide and rarely use flutamide(Drug information on flutamide) due to theinconvenience of thrice-daily dosing and frequent gastrointestinal toxicity. The rate of PSA response toantiandrogen therapy for CRPC is 20% to 30%, and the duration of response generally ranges from 6 to 24months. Although high-dose bicalutamide (150-200 mg) has been evaluated in this population,bicalutamide is not approved at doses above 50 mg daily, and I generally don’t use bicalutamide at highdoses. Patients who have been on an antiandrogen for a period of time long enough to select out a tumor ARmutation may have a response to stopping antiandrogen therapy, referred to as antiandrogen withdrawalresponse (AAWR). The time needed to select an activating tumor AR mutation is not known, but Igenerally will evaluate for AAWR if a patient has been on an antiandrogen for longer than a year. Patientsmay have sequential responses to antiandrogens, particularly if they have longer than average duration ofresponse to previous primary and secondary ADT.
Enzalutamide is considered a second-generation antiandrogen; it is more potent than first-generationantiandrogens because of its ability to block nuclear translocation of AR. Enzalutamide is approved foruse in metastatic CRPC post-chemotherapy based on a 5-month survival advantage vs placebo. It isexpected that the pre-chemotherapy enzalutamide phase III trial will mature in 2013. It is anticipated that thiswill be a positive trial, as it clearly makes biologic sense that a potent antiandrogen will be effective in earlyCRPC. A critical question is that of the utility of prescribing enzalutamide in earlier stages of prostate cancer,such as nonmetastatic CRPC, or even at initiation of first ADT. Clinical trials are underway to evaluate thedrug in early-stage prostate cancer. Despite enzalutamide’s potency and favorable toxicity profile, it may notcompletely replace first-generation antiandrogens, since mechanisms of resistance to one antiandrogen mayselect for a response to a second or third antiandrogen in a sequential fashion. Additional approaches toAR antagonism, such as agents that inhibit the AR N-terminus, are in development. Future strategies mayinclude combining divergent AR antagonists or dual AR and ligand inhibitors, such as galeterone.
Abiraterone acetate selectively inhibits CYP17 -hydroxylase and C17,20-lyase, which are enzymes criticalfor androgen synthesis. Abiraterone acetate was initially approved in 2010 after demonstrating a 4-monthsurvival benefit in docetaxel(Drug information on docetaxel)-refractory metastatic prostate cancer. In 2012 itreceived an expanded indication for use in the pre-chemotherapy setting after eliciting significant delays indisease progression and a strong trend to increased OS. Abiraterone is relatively easy to use and has fewerside effects than chemotherapy. To prevent possible mineralocorticoid excess from resultantadrenocorticotropic hormone (ACTH) production, the label recommends concomitant use of prednisone(Drug information on prednisone) at 5 mg twice daily. In the phase III studies, hypokalemia, hypertension,and edema were seen in 17%, 10% to 22%, and 28% to 31% of patients, respectively.[3,6] Ongoinginvestigations are evaluating abiraterone’s efficacy in earlier disease states (ie, nonmetastatic CRPC) and incombination with other therapeutic agents, as well as assessing the necessity of concurrent administration ofcorticosteroids or gonadal suppression. Further optimization of its use will require identification of predictivebiomarkers for response and resistance.
The pivotal issues in regard to the evolving treatment options for secondary hormone therapies in CRPCinclude drug costs, the question of what is the most effective sequencing or combination of agents, andelucidation of mechanisms of resistance. Abiraterone and enzalutamide cost approximately $5,500 to $7,500monthly, which can be prohibitive for patients without prescription drug coverage or with large monthlycopays. Some patient assistance programs exist, but the coverage is not enough to address patient needs. Forpatients who can’t afford abiraterone, ketoconazole can often affect a similar response at a lower cost.When the patient can tolerate the maximal dose, I prescribe ketoconazole at 400 mg three times daily (on anempty stomach) with hydrocortisone(Drug information on hydrocortisone) at 30 mg AM/10 mg PM, and I oftenconcomitantly use dutasteride(Drug information on dutasteride) to lower intracellular
dihydrotestosterone. Additionally, regarding older secondary hormonal options, I rarely use estrogensany longer due to the expanded options discussed above. In certain situations (long sequential hormonalresponses, aversion to chemotherapy, low risk for thrombosis), however, estrogens can still be considered,and in these cases I use either Premarin (conjugated estrogen tablets) or estradiol(Drug information onestradiol) patches.
The key to optimizing secondary hormonal therapy sequencing and combinations is to understand tumorresistance. There are programmatic (Stand Up To Cancer; http://www.standup2cancer.org) efforts underwayto obtain metastasis biopsies in patients who become resistant to abiraterone or enzalutamide and thenanalyze the tumor genome in order to determine drivers of tumor growth and make recommendations forsubsequent therapy. Currently these are high-cost efforts requiring coordinated programs in medicaloncology, radiology, pathology, and molecular laboratories. The hope is that these types of programs willbecome translatable to the community and will lead to more prolonged responses to therapy targeted atspecific drivers of prostate cancer growth.
Financial Disclosure: Dr. Taplin has served on the advisory boards of and received research funding from
Johnson & Johnson, Medivation, Inc, and Tokai Pharmaceuticals
Key Points in Dr. Taplin’s Approach to Secondary Hormone Therapy for CRPC
• The timing of therapeutic interventions should be tailored to patient metrics of disease aggressiveness, suchas duration of response to primary ADT, PSA doubling time, and metastases.
• Most patients will respond to sequential secondary hormone therapy, and the duration of response to priorhormone interventions can predict response to subsequent ADT.
• Important questions remain unanswered, such as what constitutes the most effective sequenceorcombination of secondary hormone therapies in CRPC, and what are the mechanisms of resistance to thesetherapies.
ADT = androgen deprivation therapy; CRPC = castration-resistant prostate cancer; PSA = prostate-specificantigen.
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Institute of Quantum Medicine ZAO MILTA-PKP GIT Department of Urology and Nephrologic Surgery Russian University of Friendship of People QUANTUM THERAPY USING RIKTA DEVICE IN MANAGEMENT OF PATIENTS WITH ERECTILE DYSFUNCTION Printed by the decision of the Scietific Council of the Institute (Rector: A.Y.Grabovshchiner, Academician of the Academy Russian University of Frien
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