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Korean J Uro-Oncol 2004;2(3):147-153

Recent Advances in the Management of Hormone Refractory

Mari Nakabayashi, William K. Oh Lank Center for Genitourinary Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

A typical treatment strategy after AAWD is to use secondary INTRODUCTION hormonal manipulations, although studies have not yet demonstrated a survival benefit with this class of treatment. Prostate cancer is the most common cancer in men in the Options in this category include (1) the secondary use of anti- United States and accounted for 29,900 deaths in 2003.1 (e.g., high-dose , ), (2) thera- Although most men with advanced prostate cancer respond pies targeted against adrenal synthesis (e.g., ketocona- initially to deprivation therapies (ADT) by either zole, ), and (3) estrogenic therapies (e.g. diethy- bilateral orchiectomy or leuteinizing hormone releasing hor- lstilbestrol). Symptomatic improvement and PSA responses mone (LHRH) analogues, patients eventually progress to an (defined as PSA decline ＞50% after treatment) have been androgen-independent state in which the initial ADT no longer reported in approximately 20% to 80% of patients with is adequate to control disease.2 Progression of the disease hormone-refractory prostate cancer (HRPC) with a typical manifests as an increase in serum prostate-specific antigen duration of response of 2 to 6 months. is generally (PSA) or may be accompanied by radiographic evidence of mild for these oral therapies, although serious side effects, tumor growth. Here we report a brief summary of recent including adrenal insufficiency, toxicity, and , advances in the management of hormone refractory prostate may occur (Table 1). cancer (HRPC). 1. Non-steroidal

SECONDARY HORMONAL THERAPIES Bicalutamide is a , which has a dose-response effect in normalizing PSA levels. Thus, For patients with a rising PSA and/or radiographic evidence high-dose bicalutamide (150 to 200mg) may be associated with of progressive disease despite castration, physicians should first PSA declines ＞50% in up to 20% of patients with HRPC.4,5 consider anti-androgen withdrawal (AAWD). It has been Nilutamide is another nonsteroidal antiandrogen, with PSA reported that 15% to 30% of patients respond to AAWD with responses reported in approximately 40% of HRPC patients. 3 a median duration of response of 3.5 to 5.0 months. The These treatments are orally administrative drugs and well mechanism of AAWD has been attributed to alteration in the tolerated with the most common side effects such as hot flashes (AR) signaling, resulting in the antiandrogen and nausea. However, treatment is expensive ($1,000 US or behaving as an activator of the AR, rather than an inhibitor. more per month). On should wait 4-6 weeks after stopping an antiandrogen and 2. Inhibitors of Adrenal Steroid Synthesis repeat the PSA test. Approximately 5-10% of circulating androgens are produced Corresponding to：William K. Oh, Dana-Farber Cancer Institute, 44 Binney Street, D1230, Boston, MA 02115. Tel: 617-632-4524, by the adrenal glands. In HRPC, some prostate tumor cells may Fax: 617-632-2165, E-mail: [email protected] remain sensitive to lower levels of circulating androgens.

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Table 1. Secondary hormonal therapies for HRPC ꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚ PSA response rates Therapy Number of trials References (≥50% decline) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ High dose bicalutamide 2 20-22.5% 4, 5 Nilutamide 2 29-50% 18, 19 Corticosteroids 4 16-22% 8-11 +Corticosteroids 4 27-62.5% 3, 6, 7, 20 Estrogenic therapies 5 24-81% 12-15, 17 ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

Ketoconazole has been noted for many years to effectively Table 2. 1st and 2nd generation for HRPC suppress testicular and adrenal androgen production. Recently, ꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚ PSA a phase III (CALGB 9583) of high dose Measurable Therapy N decline References ketoconazole (400mg PO TID) and hydrocortisone (30mg PO response ≥50% each morning and 10mg every night) with AAWD demon- ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ strated this treatment has modest activity in 128 HRPC + 199 33% NR 8, 11 + 83 41-61% 14-43% 26-28 patients.6 27% of patients responded to this treatment by PSA Estramustine+ 131 63-82% 17-57% 29-32 criteria with mild . A recent phase II study also ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ suggested the similar response rate with half the traditional dose (200mg PO TID) with fewer side effects.7 Ketoconazole should be administered on an empty stomach, as it is better absorbed because of concerns about contamination.15,17 in an acid environment. Low-dose corticosteroids suppress androgens through CYTOTOXIC CHEMOTHERAPY negative feedback on the secretion of adrenocorticotrophic hormone (ACTH). Although inexpensive and well-tolerated, As recently as the early 1990s, cytotoxic chemotherapy for corticosteroids are associated with a modest overall response HRPC was considered to be inactive.21,22 In 1985, Eisenberger rate and a short duration of response compared to other et al. reported a total response of 4.5% of 17 chemotherapy secondary hormonal manipulations.8-11 This therapy is typically studies21, and in 1993 the review of 26 chemotherapy trials combined with ketoconazole, though it could be used alone. performed between 1987 and 1991 reported an overall response (10mg PO QD) is an alternative to the hydro- rate of 8.7% (Table 2).23 dosing noted above. 1. 1st Generation Chemotherapy 3. Estrogenic Therapies Over the past decade, pessimism accompanying chemo- (DES) is a synthetic that reduces therapy for HRPC has been replaced by increasing evidence of testicular androgen production by inhibiting the pituitary- clinical efficacy.2 Improvements in measuring response (e.g. by gonadal axis. However, several studies suggest that DES and using PSA endpoints), and in supportive care treatments other estrogenic therapies may also induce PSA responses in including improved , have contributed to this trend. 24-81% of HRPC patients, with median durations ranging from The first important milestone for chemotherapy in the manage- 3 to 7 months.12-15 The mechanism for the effect has been ment of HRPC was achieved in 1996 with a Canadian multi- postulated to be from either mitotic arrest or direct cytotoxic institutional phase III trial.11 One hundred sixty one men with effects on the cells.16 The dose of DES that has been studied symptomatic HRPC were randomized to either mitoxantrone has ranged from 1 to 3 mg daily. Similarly, the estrogenic (12mg/m2, every 3 weeks) plus prednisone (10mg daily) versus herbal therapy, PC-SPES, appeared to have similar rates of prednisone alone. The primary end point of the trial was response in HRPC, though this product is no longer available palliative response, and secondary end points included 50% Mari Nakabayashi․William K. Oh：Recent Advances in the Management of Hormone Refractory Prostate Cancer 149 reduction in the total amount of pain without an chemotherapy was active in HRPC, though these regimens had increase in pain, duration of responses and survival. Although only modest efficacy. no survival benefit was found, there was a significant decrease 2. 2nd Generation Chemotherapy in pain (29% vs 12%) as well as a significant prolongation in the duration of pain relief(43 wks vs 18 wks) in the are among the most active class of drugs tested so mitoxantrone+prednisone arm. Palliation was also significantly far in phase II and III trials.2 Combination chemotherapy more likely in men with a PSA response than those without regimens of estramustine plus demonstrated PSA such a response (50% vs 29%). response rates of 38-53%, and were generally well-tolerated.33,34 In 1999, the Cancer and Leukemia Group B (CALGB) Docetaxel is a semisynthetic with significant activity as reported a comparable phase III trial of 242 HRPC patients a single agent and in combination with estramustine.35-38 randomized to mitoxantrone (14mg/m2, every 3 wks) plus hy- Two landmark phase III studies comparing docetaxel- drocortisone (40mg daily) versus hydrocortisone alone.8 The containing regimens to mitoxantrone were recently reported primary endpoint of this study was overall survival, and (Table 3).39 In SWOG 9916, 674 patients were randomized to secondary end points were time to disease progression, ob- receive docetaxel (60-70mg/m2 every 3 wks) plus estramustine jective and PSA response rates and quality of life (QOL). (280 mg TID for 5 days every 21 days) (n=338) or mito- Though no difference in survival was noted, improvements in xantrone (12-14mg/m2) plus prednisone (5 mg BID daily) pain control and QOL were noted in the mitoxantrone arm. (n=336). Overall survival was longer in the docetaxel plus Based on these 2 randomized trials, mitoxantrone was approved estramustine arm (17.5 months vs 15.6 months), and median in the United States for the palliative treatment of HRPC. time to progression was also longer in docetaxel plus estra- is a conjugate of mustine arm (6.3 months vs 3.2 months). Although there were and and has synergistic effects when combined with more adverse effects observed in docetaxel plus estramustine other drugs that target action.24 Three phase II arm, pain palliation was similar in both arms. This is the first trials of estramustine plus vinblastine, a vinca alkaloid, were large randomized trial demonstrated the survival advantage of conducted in 83 patients with HRPC. PSA responses were combination chemotherapy of docetaxel and estramustine in observed in 41-61% of patients. In a subsequent phase III trial, HRPC. 201 patients were randomized to receive either vinblastine The other landmark phase III study is the TAX327 study.40 (4mg/m2 weekly) alone or together with estramustine phos- One thousand six patients were randomized to receive docetaxel phate (600mg/m2/day) for 6 weeks. Although overall survival (75mg/m2 every 3 weeks), docetaxel (30mg/m2 weekly for 5 was not significantly different, the combination therapy arm of of every 6 weeks) or mitoxantrone (12mg/m2 every 3 weeks). estramustine and vinblastine showed a significantly longer time All patients also received prednisone 10mg daily. Median to progression (3.7 months vs 2.2 months) and higher PSA survival was significantly longer in the docetaxel every 3 weeks response rate (25.2% vs 3.2%).25 These studies suggested that arm compared to the mitoxantrone arm (18.9 months vs 16.5

Table 3. Landmark phase III chemotherapy trials ꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚ PSA decline Measurable Overall Progression free Therapy N References ≥50% response survival (mos) survival (mos) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Docetaxel+Estramustine q 3 weeks 386 50%* 17% 17.5* 6.3 39 Mitoxantrone+Prednisone 384 27% 11% 15.6 3.2

Docetaxel+Prednisone q 3 weeks 335 45%* 12% 18.9* 40 Docetaxel weekly+Prednisone 334 48%* 8% 17.3 NR Mitoxantrone+Prednisone 337 32% 7% 16.4 ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ *Statistically significant vs Mitoxantrone+Prednisone. 150 대한비뇨기종양학회지：제 2 권 제 3 호 2004 months). In addition, higher PSA response (PSA decline ≥ 1. Bisphosphonates 50%) (47% vs 32%) and better pain control (33% vs 22%) was observed in the docetaxel every 3 weeks arm compared to the Smith et al investigated bone mineral density (BMD) in 41 mitoxantrone arm. Based on these 2 trials, docetaxel every 3 hormone-naive men with prostate cancer and found that there weeks with prednisone was approved by the FDA for the is an increased risk of osteoporosis and bone fractures. It has management of HRPC and has become the new standard been shown that osteopenia and vitamin D deficiency are chemotherapy for HRPC in 2004. common in men starting hormonal therapy for prostate cancer. Bisphosphonates currently are the most potent class of drugs 3. New Chemotherapy Combinations in the management of skeletal complications of prostate cancer New investigational chemotherapy trials are underway, often and androgen ablation-associated osteoporosis. Bisphosphonates combining a taxane with a newer drug. A randomized phase are synthetic analogs of pyrophosphonate, an endogenous regu- II trial of docetaxel (30mg/m2 weekly) +/- thalidomide lator of bone mineralization.44 They target areas of bone (200mg/day daily) in HRPC was conducted in 75 patients.41 turnover and especially sites of osteoclastic bone resorption.45-47 PSA responses were seen more often in the docetaxel+ Studies have shown that osteoclasts become apoptotic after thalidomide arm than the single agent docetaxel arm (53% vs treatment with bisphosphonates in vitro and in vivo.48,49 37%). Also, 18-month survival was 68.2% in the docetaxel+ Furthermore, bisphosphonates have been reported to inhibit thalidomide arm while it was 42.9% in the docetaxel alone arm, tumor cell invasion and adhesion to bone.50-53 although this difference was not statistically significant. In an important clinical trial, 643 HRPC patients with bone A phase II trial of estramustine (280mg po TID), docetaxel metastases were randomized to receive zoledronic acid (either (70mg/m2) + (15mg/kg) was conducted in 79 4 or 8mg) or placebo intravenously every 3 weeks for 15 patients (CALGB90006).42 65% of first 20 evaluable patients months. Endpoints included the rate of skeletal-related events had PSA response, and 9 out of 17 (53%) with measurable (SRE) (including fracture and need for irradiation to bone), disease had partial measurable response. Two patients died of time to first SRE, skeletal morbidity rate, pain, analgesic scores, and of a perforated sigmoid colon thought to be disease progression, and adverse events were investigated.54 unrelated to treatment. To date, the combination therapy The time to the 1st SRE in the 4mg zoledronic acid arm was appears to be active with acceptable toxicities and is now significantly longer than the placebo arm (13.8 months vs 10.6 proceeding to phase III trial. Other investigational agents being months, p=0.01). The incidence of SREs was reduced by 25% studied in HRPC include , imatinib mesylate, in the zoledronic acid arm compared to placebo.54,55 No calcitriol, bcl-2 antisense and others. significant differences in time to progression of disease, time In summary, a series of phase II and III chemotherapy trials to progression of bone metastases, global QOL, ECOG demonstrate improvement in time to disease progression, pain performance status, analgesic usage, and survival was observed control, QOL, and, importantly, survival in men with metastatic between the zoledronic acid and placebo arms. At 4 mg IV over HRPC. The favored first-line cytotoxic 15-minute, zoledronic acid was well tolerated. At 8mg, for the management of HRPC now should be docetaxel every treament was associated with deterioration of renal function and 3 weeks and daily prednisone. this arm was abandoned. Based on the results from this large phase III trial, zoledronic acid was approved in 2002 by the MANAGEMENT OF SKELETAL COMPLICATIONS FDA to treat HRPC patients with bone metastases. Additional clinical trials have been conducted to determine the optimal Management of skeletal complications is critical since more schedule and duration of bisphosphonates treatment and to than 80% of the patients with advanced prostate cancer will evaluate effects on survival in men with metastatic prostate have radiographic evidence of bone metastases.43 Skeletal cancer.56-58 Renal function should be carefully monitored by complications are a prominent cause of morbidity and mortality clinicians since some studies report renal deterioration in up to among men with HRPC. 9-15% of patients.59,60 Mari Nakabayashi․William K. Oh：Recent Advances in the Management of Hormone Refractory Prostate Cancer 151

such treatments need to be determined by further studies. For 2. Radiopharmaceuticals most patients who fail secondary hormonal manipulations, Various radiopharmaceutical drugs have demonstrated effica- chemotherapy is usually the next treatment option. A series of cy in the palliative management of pain secondary to bone phase II and III chemotherapy trials demonstrated impro- metastases.61 There are three FDA-approved radiopharmaceuti- vements in pain control, QOL, time to progression, and most cals: -89 chloride (89Sr), samarium-153 lexidronam importantly, overall survival. Based on these results, docetaxel (153Sm), and sodium phosphorus-32 (32P). 32P is rarely used for every 3 weeks has become the gold standard chemotherapy bone pain palliation because of excessive myelosuppression. regimen in the management of symptomatic HRPC. In addition, Randomized trials of single agent radiopharmaceuticals demon- with an increased understanding of the molecular mechanisms strated the pain palliation response rates of 60-80% for several for prostate cancer, trials of various non-traditional, investiga- months.61 The use of radiopharmaceuticals has become less tional agents targeting specific molecules/pathways are cur- frequent than previous decades because of the improvements of rently underway. Some of them are being tested in combination second line hormonal therapy and regimens. with standard chemotherapy such as docetaxel. Other ongoing Recently, bone-targeted radiopharmaceuticals have been clinical trials are actively investigating the timing of chemo- evaluated in combination with chemotherapy to test possible therapy, including their use in the neoadjuvant and adjuvant synergistic and additive effects of radiopharmaceuticals and settings, sequencing of therapies to improve QOL and survival, chemotherapy on alleviating bone pain and improving bone and testing new agents in the second-line setting after docetaxel disease progression compared with either radiopharmaceutical failure. or chemotherapy alone. A randomized phase II trial was conducted to evaluate the efficacy of bone targeted REFERENCES consolidation therapy consisting of 89Sr and given to patients with stable or responding disease after systemic 1. Jemal A, et al. Cancer statistics, 2004. CA Cancer J Clin induction chemotherapy in 103 patients.62 Interestingly, in 72 2004:5;8-29 evaluable patients, the median survival was significantly longer 2. Oh WK, Kantoff PW. Management of hormone refractory prostate cancer: current standards and future prospects. J Urol in the combination therapy arm than the chemotherapy alone 1998;160:1220-9 arm (27.7 months vs 16.8 months, p=0.0014). A randomized 3. Small EJ, et al. Ketoconazole retains activity in advanced phase III trial of 70 patients treated with low-dose plus prostate cancer patients with progression despite 89Sr versus 89Sr alone demonstrated that the addition of cisplatin withdrawal. J Urol 1997;157:1204-7 to 89Sr treatment induced a significant improvement in pain 4. Kucuk O, et al. Phase II trial of bicalutamide in patients with advanced prostate cancer in whom conventional hormonal palliation (91% vs 63%) although difference in overall survival 63 therapy failed: a Southwest Oncology Group study (SWOG was not significant between two arms. The key for using 9235). Urology 2001;58:53-8 radiopharmaceuticals is to select appropriate candidates with 5. Joyce R, et al. High dose bicalutamide for androgen inde- painful bone metastases and poor analgesic control despite the pendent prostate cancer: effect of prior hormonal therapy. J use of opioids. Urol 1998;159:149-53 6. Small EJ, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent pros- SUMMARY tate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol 2004;22:1025-33 Over the past decade, treatment options for the management 7. Harris KA, et al. Low dose ketoconazole with replacement of HRPC have undergone significant evolution. Although no doses of hydrocortisone in patients with progressive androgen study has yet demonstrated a survival benefit, the use of independent prostate cancer. J Urol 2002;168:542-5 8. Kantoff PW, et al. Hydrocortisone with or without mito- secondary hormonal therapy plays an important role as the first xantrone in men with hormone-refractory prostate cancer: choice of drugs in the management of HRPC because they are results of the cancer and leukemia group B 9182 study. J Clin orally administered drugs with relatively little toxicity. The Oncol 1999;17:2506-13 optimal use including appropriate timing and sequencing of 9. Small EJ, et al. therapy for patients with symptomatic 152 대한비뇨기종양학회지：제 2 권 제 3 호 2004

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