New Horizons in the Treatment of Hormone Refractory Prostate Cancer

Martin Gleave MD, FRCSC, FACS
Professor of Surgery, University of British Columbia
Director, Clinical Research
The Prostate Centre at Vancouver General Hospital

Androgen withdrawal is the only effective form of systemic therapy for men with advanced disease, producing symptomatic and/or objective response in 80% of patients. Unfortunately, androgen-independent (AI) progression and death occurs within a few years in most men (1). Hormone refractory prostate cancer (HRPC) is highly chemoresistant with objective response rates of 10% and no demonstrated survival benefit(2). In 1985, Eisenberger et al. reviewed 17 randomized clinical trials of 1,464 evaluable patients and found an objective response rate of 4.5% (3). In 1992, Yagoda and Petrylak reviewed 26 trials of chemotherapy conducted between 1987 and 1991, the reported overall response rate was 8.7% (4). Lack of effective treatment of HRPC remains the main obstacle to improving the survival and quality of life for patients with advanced disease. Novel therapeutic strategies that target the molecular basis of androgen and chemo-resistance are therefore required.

Definition of Hormone Refractory Prostate Cancer

HRPC is commonly defined as demonstration of two to three serial rises in serum prostate specific antigen (PSA) obtained at least 2 weeks apart with castrate serum testosterone levels. Using these criteria alone, a very heterogeneous population of patients is included. It is helpful to subcategorize patients in terms of extent of disease and presence or absence of symptoms, usually bone pain.

Patients with localized prostate cancer and rising PSA levels after definitive surgery or radiotherapy and no demonstrable metastatic disease are often treated with hormonal therapy. When serum PSA rises again while on hormonal therapy, restaging studies are often negative for metastases. This situation, sometimes referred to as biochemical HRPC, represents a growing population of otherwise asymptomatic patients. There is no standard approach to these patients, although many clinical trials are now targeting this population.

Most often, HRPC is thought of in the context of widely metastatic bone disease. In this setting, it is helpful to distinguish between those who are asymptomatic and those who have bone pain or other symptoms of metastatic disease. The median time to symptomatic progression after a rise in PSA over 4 ng/mL is approximately 6-8 months, while the median time to death from PSA progression is 12-18 months (1). Once patients become symptomatic, however, the median survival ranges from 8 to 12 months. Symptomatic patients need immediate attention; palliation of pain and treatment options are varied and are reviewed below.

And finally, in terms of contemplating treatment options, it is important to know that the term androgen independence or hormone refractory is somewhat of a misnomer. In some cases, the prostate cancer may still exhibit some dependence on the hormonal milieu while in other cases the disease may function independently. Unfortunately, at present, there is no way to predict which patients may benefit from a second or subsequent hormonal manipulation, and androgen dependence or independence can only be determined retrospectively based on response to further hormonal manipulation.

Second Line Hormonal Manipulations

Antiandrogen Withdrawal. Patients with rising serum PSA while on an antiandrogen in combination with either orchiectomy or LHRH analog should initially have the antiandrogen discontinued for observation of the antiandrogen withdrawal (AAW) response. This phenomenon was first observed after flutamide was discontinued and the PSA subsequently declined without other intervention s (5). It has now been described with other hormones such as megesterol acetate and diethylstilbestrol, as well as the other nonsteroidal antiandrogens, bicalutamide and nilutamide (6-9). The antiandrogen withdrawal response occurs in practice 15% to 30% of the time (5,10,11). Although the median duration of PSA response is only 3.5 months, the range of duration of response is from 1 to 12 or more months. Along with a decline in PSA, both subjective and objective responses have been reported (5,9,12) Although the precise mechanism of the AAW remains undefined, it likely results from altered structure of the steroid binding domain of the androgen receptor (ie mutation or cleavage) or presence of coactivators that permit the antiandrogen to act as an agonist rather than an antagonist with subsequent transcriptional activation of cell survival and mitogenesis signaling pathways (13,14). Discontinuation of the antiandrogen thus disrupts this stimulus.

Antiandrogen Addition. If a patient has not been on antiandrogens previously, a trial of an antiandrogen may result in a PSA response (>50% decline) in 15% to 80% of cases; however, the median duration of response is only 4 months (15-17). Subjective responses have been reported as well. The effects of second line antiandrogen therapy in HRPC on survival remain unknown.

Ketoconazole. The combination of ketoconazole (KC) and hydrocortisone (HC) is generally well tolerated and often effective, but the cost (ranging from $300 to $500 per month) can be prohibitive. Prostate specific antigen responses (>50% decline) have been reported in 62% of patient and subjective responses have been observed in 20% to 50% (18-20). At a dose of 400 mg TID, KC blocks production of adrenal hormones including hydrocortisone, and hence replacement doses of 20 mg to 25 mg in the morning and 10 mg to 15 mg at 4:00 pm are usually prescribed. Ketoconazole must be taken on an empty stomach and requires an acid stomach environment for adequate absorption. If patients are on acid-lowering drugs such as H2 blockers or ion pump inhibitors, vitamin C 1,000 mg can be added to each KC dose to provide acidity. Some drugs should not be given concurrently because of adverse drug-drug interactions (terfenadine, astemizole, cisapride, fluconazole, erythromycin), which can cause arrhythmias. Because KC interacts with the cytochrome p-450 enzyme system, patients on drugs, such as warfarin, metabolized by this pathway need to be monitored more closely. Side effects of KC include nausea, gastrointestinal bloating, hepatotoxicity, sticky skin syndrome and asthenia.

Corticosteroids. Corticosteroids alone have definite activity against prostate cancer and provide significant palliation in terms of anorexia, pain and depression. The optimal drug and dose have not been determined, but even prednisone at a dose of 5 mg BID resulted in subjective and PSA responses in the Canadian randomized trial discussed below (21). Higher doses of corticosteroids are often reserved for patients with very endstage disease or those with spinal cord compression, since long-term administration results in manifestations of Cushingoid syndrome including fluid retention, easy bruisability, glucose intolerance, camels hump, facial erythema and bloating.

Radiation Therapy
External beam radiation therapy (EBRT) has traditionally provided successful palliation of bone pain for patients with symptomatic HRPC or pending spinal cord compression (22). Radiopharmaceuticals may be indicated in a patient with multiple painful bone metastases who is otherwise not eligible to receive chemotherapy. Radiopharmaceuticals, like Strontium-89 and samarium 153, are preferentially taken up and deliver beta irradiation in sites where there is new bone formation (23,24). The exact mechanism of action of pain relief is not known, although PSA declines reported after treatment in some studies suggest there is some direct cell kill. A randomized trial of EBRT vs EBRT with samarium 153 showed a delay in the appearance of painful new bone metastases, decreased analgesic intake, greater freedom from metastases at 3 months, and improved quality of life compared with EBRT alone (24).

Chemotherapy Options
Historically, prostate cancer has not been considered a chemosensitive disease due to the poor survival outcomes reported in older clinical trials. Many of these trials were performed in the pre-PSA era when patients were treated at later and more symptomatic stages and survival or objective response rates were primary (and often underpowered) endpoints. Single agent chemotherapy has been associated with relevant palliative effects but no single agent has been associated with an objective response rate greater than 30% (3,4). The use of palliation as an endpoint, along with the availability of PSA as an indicator of disease response, have renewed interest in the use of chemotherapy in HRPC and led to multiple phase II and several phase III trials that demonstrate effective palliation, PSA response, and/or objective response. PSA as a measure of disease outcome in metastatic HRPC has emerged as an acceptable surrogate endpoint to evaluate new agents in this clinical setting (25). There is also some evidence of correlation between PSA response and survival based upon retrospective data but a cause and effect relationship remains to be confirmed through prospective investigations.

Mitoxantrone
Palliative effects have been observed in HRPC patients following the administration of corticosteroids (26), or mitoxantrone with either prednisone or hydrocortisone (27-30). A phase III Canadian trial randomized 161 symptomatic patients with HRPC to receive either best palliative care with prednisone 5 mg BID or prednisone plus mitoxantrone 12 mg/M2 (21). The primary endpoints were palliation and duration of palliation with secondary endpoints of improved time to progression and survival. A reduction of two or more points in a six-point pain scale lasting for at least two evaluations 3 weeks apart without any increase in analgesic use was achieved in 29% of patients in the mitoxantrone arm vs 12% of those receiving prednisone alone. Importantly, the median duration of palliation was significantly longer in the mitoxantrone arm, 43 weeks vs 18 weeks in the prednisone alone arm (p<.0001). Although PSA was not an endpoint of the trial, PSA responses (>50% decline) were higher in the mitoxantrone arm (44%) compared to the prednisone alone arm (21%). 22% of 50 patients crossed over to the mitoxantrone arm at progression achieved a palliative response which lasted a median of 18 weeks. Median time to progression was also better in the mitoxantrone arm, 24 weeks vs 10 weeks (P=.0001). There was, however, no difference in survival between the treatment arms.

The Cancer and Leukemia Group B (CALGB) recently published results of a similar trial conducted in the United States (30). Unlike in the Canadian trial, survival was the primary endpoint of this study with palliation secondary and no crossover to the mitoxantrone containing arm was allowed. Furthermore, patients did not need to be symptomatic. Over on third of the 242 patients in the CALGB trial were asymptomatic at randomization. As in the Canadian trial, there was a significant difference between arms in time to disease progression (median 16.1 vs 9.9 weeks, P=.0218). Forty-two of 112 patients (38%) receiving mitoxantrone had >=50% reduction in PSA as opposed to 25 of 116 patients (22%) receiving hydrocortisone alone (P=.008). Evaluation of survival by PSA reduction in both groups (N=228) demonstrated a survival advantage for those patients with a PSA response. Despite the improvement in time to disease progression and PSA response in the mitoxantrone containing arm, overall survival was not better than the hydrocortisone-alone arm (median 12.3 months vs 12.6 months, respectively). Based on results from thesetwo phase III randomized trials, the combination of mitoxantrone with corticosteroids is recognized now as the reference treatment in metastatic HRPC (21,29).

Estramustine Combinations
When used alone, estramustine is a relatively ineffective drug with significant nausea and vomiting, edema, thromboembolic events and gynecomastia. At a dose of 280 mg TID, the cost is approximately $40/day, making prolonged dosing prohibitive.

In combination with other antimicrotuble drugs including vinblastine, etoposide, paclitaxel and docetaxel, however, estramustine appears to be synergistic. Multiple phase II trials have evaluated estramustine-based combinations and have demonstrated objective, PSA and palliative responses in the 40% to 50% range (Table 1) (30-33). A phase III trial of vinblastine alone vs vinblastine plus estramustine showed statistically significant improvement in progression-free survival (3.7 vs 2.1 months), but whether this difference is significant clinically is debatable (34).

Although the 3-weekly conventional schedule is the currently approved schedule with an extensive clinical experience in solid tumors such as breast cancer, lung cancer, ovarian cancer, there is a growing clinical experience with the docetaxel weekly schedule including HRPC. Several studies in HRPC suggest that weekly docetaxel is a suitable alternative which can result in a higher dose intensity without increased toxicity (33,37-41). The safety profile was assessed as acceptable throughout these studies with a good risk/benefit ratio in this clinical setting. Objective response of 13% and PSA responses (>50% decline) of 41% has been reported (Berry et al). The weekly schedule appears to have similar activity as the conventional three-weekly schedule but a better safety profile, which is a significant advantage in the elderly . In addition, theoretically, more frequent exposure of tumor cells with weekly docetaxel may result in enhanced anti-angiogenesis and apoptotis (bcl-2 phosphorylation) (42).

Based on a report of greater than additive cytotoxicity in vitro when docetaxel is combined with estramustine, several clinical trials have tested this combination in HRPC (33). However, the respective contribution of the 2 drugs in the clinically observed response rate remains unclear. Evidence of the activity of the docetaxel-estramustine combination includes PSA decline (>50% decline in the range of 31%-92% of patients), objective response in bidimensionally measurable lesions (17%-75%), improved Karnofsky performance score or pain/symptom control in 53%-88% (Table 2). Median survival was 22.8 months in reported by Petrylak et al (33), but not yet reported in the others. The safety of the combination has been assessed as acceptable (33). Two episodes of grade 4 granulocytopenia were observed in patients who received more than 3 cycles of therapy. No myocardial infarctions or pulmonary emboli were reported on the study. Gastrointestinal toxicity was observed, primarily nausea in 29% and vomiting in 12% of patients. Fluid retention, generally of minimal severity, was reported in 65% of patients.

Docetaxel is currently being evaluated in a number of Phase III trials. SWOG is comparing mitoxantrone and prednisone with docetaxel and estramustine in HRPC. Both the CALGB and the North Central Cancer Treatment Group (NCCTG) will participate in the SWOG phase III trial. A large international trial comparing mitoxantrone and prednisone to docetaxel (weekly vs q3 weekly) and prednisone in HRPC has recently been initiated in Europe, Canada, and the US with primary endpoint of overall survival and secondary endpoints of time to progression, PSA response, and quality of life.

Table 2: Activity of docetaxel in combination with estramustine in HRPC

* NA = Not available ** Calculated among patients with bidimensionally measurable lesions

Bisphosphonates
Bisphosphonates are stable analogs of calcium pyrophosphate that inhibit osteoclast activity in bone. They have been FDA-approved for palliation of pain due to osteolytic bone metastases of breast cancer and myeloma and have been reported to be palliative in small phase II studies in prostate cancer (43,44). A phase III trial evaluating pamidronate in symptomatic HRPC has recently been completed and is currently undergoing evaluation. In addition to the potential for palliation, bisphosphonates may also have an effect on disease progression. In breast cancer, clodronate, a relatively low potency bisphosphonate available in Europe, resulted in a reduction in the incidence and number of new bone and visceral metastases (45). A phase III trial randomizing men with HRPC to mitoxanthrone and prednisone plus or minus clonidronate is active in Canada. A phase III trial is now in progress with zoledronate, one of the most potent bisphosphonates, in early asymptomatic patients with HRPC.

Chemohormonal Approaches
Progression to androgen independence is a complex process involving variable combinations of clonal selection (46), adaptive upregulation of anti-apoptotic survival genes (47-49), androgen receptor transactivation in the absence of androgen from mutations or increased levels of co-activators (50) and alternative growth factor pathways (51,52). Androgen withdrawal results in a programmatic drift in gene expression and upregulation of numerous genes, many of which are cell survival genes that help confer resistance to subsequent chemotherapy. Poor responses of chemotherapy result from multiple complex and inter-related processes, including low proliferation index, high levels of cell survival genes like Bcl-2 (53), Bcl-xL (54), and clusterin (55), as well as presence of co-morbities limiting effective chemotherapy dosing in an elderly population. The rationale behind chemo-hormonal regimens for hormone naïve advanced disease is based on exposing prostate cancer cells to cytotoxic chemotherapy earlier, before clonal expansion of androgen-independent cells or constitutive over-expression of cell survival genes become established, and before patients develop lower performance status associated with aging and HRPC. Preclinical experiments with the Dunning model indicated improved outcome with chemo-hormonal therapy compared to either treatment alone (56). Pummer and associates (57) randomized 145 men with advanced hormone naïve prostate cancer to total androgen blockade (TAB, orchiectomy + flutamide) alone or with weekly epirubicin for 18 weeks. They reported that time to progression (18 vs 12 months, p<0.02) and overall survival (30 vs 22 months, p=0.12) were longer in D2 patients in the TAB+epirubicin group; differences in overall survival did not reach statistical significance. The EORTC compared orchiectomy with or without mitomycin C every 6 weeks in 189 men with metastatic prostate cancer, and reported no difference in progression-free survival, and better quality of life and overall survival in the orchiectomy only group (58). These conflicting results illustrate the importance of identifying an active and well tolerated cytotoxic agent that will balance potential gains in survival with effects on quality of life.

Investigational Trials of Novel Agents
In addition to the more conventional approaches discussed above, there are many interesting ongoing clinical trials using investigational agents either alone or in combination with chemotherapy. Some of these approaches include gene or vaccine therapy, matrix metalloproteinase inhibitors, antiangiogenesis drugs, telomerase inhibitors and signal transduction inhibitors. A comprehensive discussion of these agents is beyond the scope of this chapter. Some selected strategies enhance chemosensitivity by targeting apoptosis are presented below. Improved understanding of the pathways regulating apoptosis is identifying cell survival genes that may serve as new therapeutic targets.

Antisense Strategies. Targeting cell survival genes upregulated by androgen withdrawal or cytotoxic chemotherapy may enhance apoptosis and improve response to hormone or chemotherapy. Antisense oligodeoxynucleotide (AS-ODN) therapy is one strategy to specifically target functionally relevant genes. AS-ODNs are chemically modified stretches of single-strand DNA complementary to mRNA regions of a target gene that inhibit translation by forming RNA/DNA duplexes, thereby reducing mRNA and protein levels of the target gene (59). The specificity and efficacy of antisense ODN’s rely on precise targeting afforded by strand hybridization, where only a perfect match between the target sequence and the antisense ODN will lead to hybridization and inhibition of translation (Fig 1). Phosphorothioate AS-ODNs are water soluble, stable agents manufactured to resist nuclease digestion through substitution of a nonbridging phosphoryl oxygen of DNA with sulfur which become associated with high capacity, low affinity serum binding proteins after parental administration (59). AS-ODNs targeting several oncogenes have been reported to specifically inhibit expression of these genes and delay progression in several types of tumors (59-63).

Bcl-2 has emerged as a critical regulator of apoptosis in numerous tissues as part of a growing family of apoptosis regulatory gene products. In prostate cancer cells, Bcl-2 is upregulated within months after androgen withdrawal (64) and remains increased in AI tumors (65) serving as an adaptive mechanism that helps mediate hormone and chemoresistance. Bcl-2 also blocks pro apoptotic signals by a variety of chemotherapy agents, conferring a multi-drug resistant phenotype which may be operative in AI prostate cancer. This evidence raises the possiblity that bcl-2 overexpression in AI prostate cancer helps mediated intrinsic chemoresistance, and suggests that modulation of bcl-2 levels may enhance chemosensitivity. Recent reports indicate that Bcl-2 AS-ODNs induce apoptosis and enhance chemosensitivity in various types of malignant cell lines, including small cell lung cancer (62), melanoma (63). Preclinical studies report synergistic activity between Bcl-2 AS-ODN and taxanes in several prostate tumour model systems (53,54). Indeed, the IC50 of taxanes are reduced by a factor of 1 log when combined with Bcl-2 AS-ODNs in both LNCaP and Shionogi tumor models (53,66). Adjuvant in vivo administration of Bcl-2 AS-ODN and taxol following castration resulted in significant delay in the emergence of AI recurrent tumors compared to administration of either agent alone. Furthermore, regression of established AI Shionogi tumors was significantly greater with combined Bcl-2 AS-ODN plus taxol compared to treatment with either agent alone. Synergistic activity between AS-ODN and taxanes results from AS-ODN induced decreases in Bcl-2 mRNA and protein levels and taxol induced Bcl-2 phosphorylation. Clinical studies using Bcl-2 AS-ODN's either alone or in combination with chemotherapy in prostate cancer are now underway at several institutions.

Testosterone-repressed prostate message-2 (TRPM-2), also known as clusterin or sulfated glycoprotein-2, is increased in various normal and malignant tissues undergoing apoptosis(67), TRPM-2/clusterin inhibits apoptosis, in part, by functioning as a chaperone-like molecule to prevent protein unfolding during times of cell stress (68). TRPM-2/clusterin staining increases in prostate cancer cells after neoadjuvant hormone therapy and in androgen-independent tumors. Overexpression of TRPM-2 in LNCaP cells enhances resistance to apoptosis induced by TNF-a (69), androgen withdrawal (48), and paclitaxel chemotherapy (55). The upregulation of TRPM-2 in human prostate cancer tissues after castration serves as an adaptive mechanism that helps mediate hormone and chemoresistance and identifies it as a therapeutic target to enhance castration- and chemotherapy-induced apoptosis. Paclitaxel chemosensitivity is enhanced by a factor of 1 log when combined with TRPM-2 AS-ODNs both in vitro and in vivo (55). Regression of established AI human PC3 tumors was significantly greater with combined TRPM-2 AS-ODN plus taxol compared to treatment with either agent alone. Clinical trials using combined docetaxel and TRPM-2 AS-ODN early next year.

Sulindac sulfone. Sulindac sulfone (Exisulind) and other NSAIDs have been reported to inhibit tumor formation and progression in several experimental tumour systems. Sulindac is a prodrug that is metabolized to either a sulfide or sulfone derivative after oral administration. The sulfide is COX I and II inhibitor and is responsible for its anti-inflammatory properties. The growth inhibitory effects of exisulind have been reported to be independent of COX inhibition or p53 induction, and appears to involve induction of apoptosis via phosphodiesterase inhibition. Exisulind causes regression and prevents recurrence of polyps in patients with familial adenomatous polyposis (69,70), and inhibits mammary carcinogenesis (71). Phase I and II studies of exisulind in FAP showed a chemopreventive effect with minimal toxicity, and phase III trials are underway in patients with FAP. In preclinical prostate cancer studies, Exisulind delayed LNCaP tumor growth in vivo in a nude mouse model, presumably via increased apoptosis (72). Ninety six patients with rising PSA after radical prostatectomy were randomized to receive placebo or Exisulind for 1 year. The drug was well tolerated; after 6 months of treatment, serum PSA increased from 2.78±0.4 to 4.76±0.3 ng/ml (mean 1.98) in the placebo group compared to 2.16±0.28 to 2.9±0.5 ng/ml (mean 0.74) in the Exisulind group (73). Moreover, PSA doubling time was prolonged by 6 months in the men on drug compared to those on placebo. The attraction of this drug is its oral administration and low toxicity; longer additional trials are underway to assess its efficacy in HRPC and whether it possesses additive or synergistic effects with cytotoxic chemotherapy.

Summary
Treating patients with HRPC is challenging and requires consideration of multiple disease and patient- related factors. It is important to individualize the approach to therapy based on the patient’s performance status, other co-morbidities, symptoms, logistical issues and desires and expectations. At the present time, until evidence is obtained that survival can be improved with systemic therapy, maintaining or improving quality of life should be the primary goal of therapy. In the future, there is optimism that in addition to improving or maintaining quality of life, treatment options for HRPC will also extend survival.


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Figure Legends.

1. Schema illustrating sequence-specific interaction between TRPM-2 antisense oligonucleotides (ASO) and mRNA. Following systemic administration, the ASO enters cells through endocytosis and hybridizes with its target message, leading to activation of RNAse H and enzymatic degradation of TRPM-2 mRNA.

2. Combined use of antisense oligonucleotides targeting human TRPM-2 significantly enhanced the apoptotic effects of micellar paclitaxel and mitoxantrone in human androgen-independent PC-3 tumors, reducing mean tumor volume by more than 80% and 60%, respectively, by 8 weeks following initiation of treatment.