New Hope for Patients with Metastatic Hormone-Refractory Prostate Cancer

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1 european urology supplements 5 (2006) available at journal homepage: New Hope for Patients with Metastatic Hormone-Refractory Prostate Cancer Ronald de Wit * Erasmus University Medical Centre and the Rotterdam Cancer Institute, The Netherlands Article info Keywords: Chemotherapy Docetaxel Hormone-refractory prostate cancer HRPC Multidisciplinary TAX Please visit to read and answer the EU-ACME questions on-line. The EU-ACME credits will then be attributed automatically. Abstract Traditionally, chemotherapeutic agents were viewed as having little or no impact on the natural history of hormone-refractory prostate cancer (HRPC). For many years, patients with HRPC could be offered only palliative treatments and accordingly their prognosis was poor. Recently, two proof-of-concept studies revealed that prostate-specific antigen (PSA) responses can be detected in 38 46% of patients treated with docetaxel every 3 weeks (q3w) and, more importantly, measurable objective responses are also reported in 24 29% of patients. These findings prompted the initiation of two phase 3 trials, TAX 327 and SWOG-99-16, which compared docetaxel-based chemotherapy with the standard combination treatment of mitoxantrone and prednisone and were designed to test for an improvement in survival. The findings of the TAX 327 and SWOG studies challenge the belief that HRPC is a chemotherapy-resistant disease, and reveal that q3w docetaxel plus prednisone is well tolerated and offers superior survival and improved patient quality of life compared with the former standard treatment of mitoxantrone and prednisone. This opens up a number of new directions for our clinical investigations. Not only is docetaxel now being evaluated in patients with earlier stage prostate cancer, for whom chemotherapy may offer better long-term outcomes by decreasing the risk of systemic relapse, but combinations of novel chemotherapeutic agents with docetaxel are also being investigated and may well offer further benefits to patients with HRPC. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Erasmus Medical Center, Locatie Daniel den Hoed, Cancer Institute, P.O. Box 5201, 3008 AE Rotterdam, The Netherlands. Tel ; Fax: address: r.dewit@erasmusmc.nl. 1. History of treatment for metastatic hormone-refractory prostate cancer Traditionally, chemotherapeutic agents were viewed as having little or no impact on the natural history of hormone-refractory prostate cancer (HRPC) [1]. In 1993, Yagoda and Petrylak reviewed 26 trials (n = 1001), published between 1987 and 1991, investigating various cytotoxic agents for the treatment of HRPC. The overall response rate was only 8.7% (95%CI, %) and patients had a median survival of 6 10 mo. Yagoda and Petrylak concluded /$ see front matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eursup

2 818 european urology supplements 5 (2006) that, as previously believed, HRPC was not responsive to chemotherapeutics [2]. Based on this apparent lack of activity, as well as the common perception that patients with prostate cancer are elderly and thus, in general, unsuitable for chemotherapy, patients with androgen-independent prostate cancer have not been routinely treated with chemotherapy in clinical practice [3]. These negative findings can be partially explained by the fact that these early clinical trials specified an eligibility criterion of bidimensionally measurable disease, which, in the setting of metastatic prostate cancer, usually reflects far advanced disease, impaired performance status, and a reduced likelihood of obtaining benefit from any type of treatment. This practice changed in the 1990s when investigators at the Memorial Sloan Kettering Memorial Cancer Center (New York, NY) introduced prostate-specific antigen (PSA) as a surrogate end point and, a few years later, the Canadians introduced palliative end points, such as pain, analgesic requirements, and quality of life (QoL) measures. This allowed study investigators to include patients with less advanced disease in prostate cancer clinical trials [3]. In a Canadian study, mitoxantrone (12 mg/m 2 every 3 wk [q3w]) was used in combination with prednisone (10 mg/d) in 161 patients with symptomatic metastatic prostate cancer. When compared with prednisone alone, combination treatment demonstrated improved pain palliation [4]. Patients treated with mitoxantrone also report a prolonged improvement in QoL; however, no survival advantage was detected [5]. A further American study, the CALGB 9182 study, looked at the effect of combining mitoxantrone (14 mg/m 2 q3w) with a hydrocortisone (40 mg/d) regimen compared with hydrocortisone alone in 242 patients with metastatic prostate cancer. This study demonstrated that mitoxantrone significantly improved progression-free survival and elicited a decline in PSA, but failed to improve the primary study end point of overall survival; the median survival of patients was 12 mo [6]. Based on the results of these two studies, mitoxantrone in combination with a corticosteroid became the new treatment of choice for HRPC [7]. AtthesametimeastheCanadianandAmerican mitoxantrone studies, proof-of-concept trials were ongoing with single-agent taxoids, paclitaxel and docetaxel, both as the standard q3w regimen [8] and a weekly regimen [9,10]. The rationale for the weekly regimen was the observation that, in patients with breast cancer, the weekly regimen was better tolerated, with fewer acute toxicities, such as myelotoxicity and fatigue [11]. It therefore represents a possible alternative for the predominantly elderly patient population with prostate cancer. Studies were also initiated investigating the combination of taxoids and estramustine [12 17]. Estramustine (oestradiol plus nitrogen mustard), like the taxoids, inhibits microtubule function and mitosis [18] and there is strong preclinical evidence of a synergistic effect between the taxoids and estramustine [19]. Estramustine was, in 1981, the very first chemotherapy drug to be approved by the US Food and Drug Administration (FDA) for patients with HRPC. Given as a single agent, however, it is not very effective [20]. In a total of 262 patients from five studies, only five objective partial responses were observed. Using PSA as a surrogate end point, the response rate was only 14% [21]. In addition, estramustine is a toxic compound, producing nausea and vomiting, anorexia, fluid retention, and, most importantly, cardiac morbidity, including thromboembolic complications and ischaemic heart disease, owing to the effects of oestrogen [20,22]. In view of the preclinical data, however, there is a rationale for combining estramustine with the taxoids. These proof-of-concept studies have revealed that PSA responses can be detected in 38 46% of patients treated with q3w docetaxel and, more importantly, for the very first time, measurable objective responses are also observed in 24 29% of patients. The weekly docetaxel regimen elicits PSA responses in 41 48% of patients and objective responses in 28 40% of patients. Docetaxel/estramustine and paclitaxel/estramustine combinations have similar PSA and objective response rates. The addition of estramustine to docetaxel yields PSA responses in 45 68% of patients and objective responses in 17 55% of patients [23]. Similarly, a PSA response was seen in 61% of patients, and an objective response in 22% of patients, treated with the combination of paclitaxel and estramustine [24]. In one phase 2 study, the median survival with the docetaxel/estramustine combination was 20 mo [25], and in another phase 2 study investigating the paclitaxel/estramustine combination, the median survival was 17 mo [24]. Unfortunately, as was already clear in the early phase 2 trials, the addition of estramustine is associated with increased toxicity, including an increased incidence of thromboembolic complications [21]. However, the promising median survival figures from the above phase 2 trials prompted the initiation of two phase 3 trials, TAX 327 and SWOG-99-16, that compared docetaxel-based chemotherapy with the standard combination treatment of mitoxantrone

3 european urology supplements 5 (2006) and prednisone and were designed to test for an improvement in survival [26]. 2. TAX 327 study The TAX 327 study [4] was the pivotal registration trial a 3-yr, phase 3 investigation of docetaxel versus mitoxantrone, both in combination with prednisone. Two schedules of docetaxel were compared with the standard q3w mitoxantrone (12 mg/m 2 ) regimen: one group was randomised to receive 30 mg/m 2 docetaxel, given every week for 5 consecutive weeks of a 6-wk cycle; the other group was randomised to receive 75 mg/m 2 docetaxel, given q3w. All patients received 5 mg prednisone twice a day continuously. Those patients receiving docetaxel were premedicated with dexamethasone (8 mg given 12 h, 3 h, and 1 h before the docetaxel infusion in the q3w docetaxel group and 8 mg given 1 h before docetaxel in the group treated weekly). Treatment duration in all treatment arms was 30 wk. Patients were stratified by baseline pain level and Karnofsky Performance Status (KPS). A total of 1006 patients were enrolled and baseline characteristics of these patients were well balanced among the treatment groups. The median age of patients enrolled in the study was 68 yr, and nearly 50% of patients experienced baseline pain. This, therefore, clearly reflects findings in daily clinical practice [4]. The primary study end point was overall survival. A 2.4-mo improvement in median survival was observed in patients treated with q3w docetaxel compared with those treated with mitoxantrone (Fig. 1). This equates to a 24% reduction in the odds of death (hazard ratio [HR] = 0.76; p = 0.009). The Fig. 2 Response to treatment, as measured by decreases in pain, PSA level, and tumour burden. y Apainresponse was defined as a two-point reduction in the Present Pain Intensity (PPI) score without an increase in the analgesic score or a reduction of at least 50% in the analgesic score without an increase in the PPI score, which was maintained for at least 3 weeks. z Data on 54% and 63% of patients were censored in the Kaplan Meier analysis of the median duration of pain and PSA response, respectively. The chief reason for data censoring was further antitumour therapy after progression of disease as defined by other criteria. # 2004 Massachusetts Medical Society. Fig. 1 TAX 327: overall survival. Reproduced with permission from Tannock et al. [4]. # 2004 Massachusetts Medical Society. median survival was 16.5 mo in patients treated with mitoxantrone, 18.9 mo in patients treated with q3w docetaxel, and 17.4 mo in patients treated with weekly docetaxel. When the two docetaxel groups were combined and compared with the mitoxantrone group, the reduction in the odds of death was still significant at p = 0.03 (HR = 0.83). Significant improvements were also reported for several of the secondary study end points (Fig. 2). The PSA response was higher with each docetaxel regimen compared with mitoxantrone. A PSA decline of 50% was achieved in 45% and 48% of patients in the weekly and q3w docetaxel groups, respectively, compared with only 32% of patients in

4 820 european urology supplements 5 (2006) the mitoxantrone group ( p < 0.001). A pain response (defined as a 2-point reduction in the Present Pain Intensity [PPI] score without an increase in analgesic score, or as a 50% reduction in the analgesic score without an increase in PPI score, maintained for at least 3 wk) was also significantly more frequent in the docetaxel arm (q3w regimen) than in the mitoxantrone arm. Significant pain reduction was achieved in 22% of the patients in the mitoxantrone group compared with 35% ( p = 0.01) and 31% ( p = 0.08) in the q3w and weekly docetaxel groups, respectively. The tumour response rate was 12% and 8% in the q3w and weekly docetaxel groups, respectively, and 7% in the mitoxantrone group. This difference did not reach statistical significance. Treatment-related adverse events were both predictable and manageable. There was a higher incidence of cardiac events among patients who received mitoxantrone; however, adverse events were generally more common in the docetaxel arms, as were serious adverse events (29%, 26%, and 20% for the weekly docetaxel, q3w docetaxel, and mitoxantrone groups, respectively). The incidence of grade 3/4 neutropenia was higher in patients treated with docetaxel (32%, 2%, and 22% for q3w docetaxel, weekly docetaxel, and mitoxantrone, respectively); however, febrile neutropenia (2.7%, 0.0%, and 1.8% for q3w docetaxel, weekly docetaxel, and mitoxantrone, respectively) and documented infection during neutropenia (3.0%, 0.0%, and 0.9% for q3w docetaxel, weekly docetaxel, and mitoxantrone, respectively) were both rare in all treatment groups [4] (Fig. 3). The toxicity of the q3w docetaxel regimen should be examined in the light of the demonstrated improvement in QoL in 25% of patients; it appears that the superior efficacy of the regimen offsets the observed toxicity [3]. The greater haematologic toxicity did not result in clinical sequelae and, with regard to nonhaematologic toxicity, the only grade 3/4 adverse event experienced by >5% of patients was fatigue: 4.5% in the docetaxel q3w group, 5.5% in the docetaxel weekly group, and 5.1% in the mitoxantrone group [4]. This further demonstrates that the docetaxel 75 mg/m 2 q3w regimen is very well tolerated in this elderly patient population. Furthermore, significant improvements in QoL (defined as at least a 16-point improvement from baseline in the Functional Assessment of Cancer Therapy-Prostate [FACT-P] score on two measurements obtained at least 3 wk apart) were also reported in the docetaxel arms; nearly 25% of patients in each docetaxel arm had a significant improvement in QoL, whereas only 13% of the patients in the mitoxantrone arm achieved this ( p = and p = for the two docetaxel groups, respectively). The greatest benefit in the docetaxel treatment groups was in the QoL subscale representing prostate-specific concerns (e.g., weight loss, appetite, pain, physical comfort, and bowel and genitourinary functions) [4]. Therefore, not only did the patients on the docetaxel q3w treatment arm survive longer, they also already felt better during the process of chemotherapy. The conclusions of the TAX 327 study, as published in the New England Journal of Medicine, is that docetaxel q3w plus prednisone improves median overall survival by 2.4 mo (HR = 0.24; 95%CI, ; p = 0.009), reduces the odds of death by 24%, improves pain (35% vs. 22%; p < 0.01), reduces PSA (48% vs. 32%; p < 0.001), improves QoL during the course of treatment, and is associated with a manageable safety profile. 3. SWOG study Fig. 3 Haematologic toxicity. The SWOG study [27] was a phase 3 investigation of docetaxel plus estramustine versus mitoxantrone plus prednisone in patients with HRPC. Patients were randomised to one of two treatment arms receiving either docetaxel (60 mg/m 2 ), estramustine (280 mg given orally 3 times a day for 5 d), and premedication with dexamethasone (20 mg orally 3 times a day, beginning the day prior to docetaxel treatment), with cycles repeated q3w, or mitoxantrone (12 mg/m 2 ) q3w with continuous prednisone at a dose of 5 mg twice a day. A total of 674 patients were enrolled; baseline characteristics of these patients were well balanced between the two treatment groups [27] and quite similar to

5 european urology supplements 5 (2006) possibility inferior, although the study was not designed to allow comparison of the two docetaxel treatment arms, and it has a similar toxicity profile and is not better tolerated than the q3w docetaxel regimen. There is therefore little incentive to continue with the weekly regimen in clinical trials. Finally, the addition of estramustine to docetaxel chemotherapy does not appear to be advantageous. Not only does it fail to offer superior survival, it is also associated with enhanced gastrointestinal and cardiovascular toxicity. Thus, the gold standard for patients with metastatic (mhrpc) is now docetaxel plus prednisone [3]. Fig. 4 SWOG 99-16: overall survival. Reproduced with permission from Petrylak et al. [27]. # 2004 Massachusetts Medical Society. those of the patients enrolled in the TAX 327 study. The median age was 70 yr and about one third of patients had pain [3]. Again, the docetaxel/estramustine combination was associated with superior survival when compared with the mitoxantrone/prednisone combination (Fig. 4). The median overall survival in the docetaxel/estramustine treatment group was 17.5 mo compared with only 15.6 mo for the mitoxantrone/prednisone group ( p = 0.02). This is a difference of 1.9 mo, which equates to a 20% reduction in the odds of death in patients treated with docetaxel/ estramustine (HR = 0.80; p = 0.02). These findings are therefore comparable with those reported by Tannock et al. [4,27]. Unfortunately, as expected, the addition of estramustine to the docetaxel regimen increased toxicity; 56% of patients in the docetaxel/estramustine group had grade 3/4 toxicity compared with 34% of patients in the mitoxantrone/prednisone group. Gastrointestinal toxicity was higher in the docetaxel/estramustine group (20% compared with 5% in the mitoxantrone/prednisone group), as was cardiovascular toxicity (15% compared with 7% in the mitoxantrone/prednisone group; p = 0.001). The prophylactic use of Coumadin # halfway through the study, through a protocol amendment, did not appear to reduce the incidence of cardiovascular side effects [27]. Taken together, the results of the TAX 327 and SWOG-9916 studies indicate that we have finally obtained an effective chemotherapy option in patients with HRPC. The regimen of 75 mg/m 2 q3w docetaxel plus prednisone improves survival and reduces the odds of death by 24%, which is clinically meaningful. The weekly docetaxel regimen is 4. Patient subgroups A subgroup analysis (Fig. 5) of the TAX 327 study population was also performed. The survival benefit of q3w docetaxel as compared with mitoxantrone was seen in all patient subgroups: patients aged <65 yr, >65 yr, and >75 yr; patients with or without pain at baseline, and patients with a baseline KPS of >80% or >70%. Furthermore, the TAX 327 study enrolled both symptomatic and asymptomatic patients; a Forest plot demonstrated that the asymptomatic patients benefit from docetaxel as well as the symptomatic patients [3,28]. The results of subgroup analyses should always be interpreted with caution because over-interpretation can lead to misguided research and, in the worse case, to suboptimal patient care [29]. However, the results from these analyses suggest that all specific Fig. 5 Subgroup analysis of TAX 327 study population. Reproduced with permission from Petrylak et al. [27]. # 2004 Massachusetts Medical Society.

6 822 european urology supplements 5 (2006) subgroups derive less benefit from docetaxel q3w treatment compared with mitoxantrone treatment. Docetaxel q3w should therefore also be considered in patients who remain asymptomatic but who already have clinical evidence of disease progression, such as new lesions on bone scan or computed tomography (CT) scan progression. Of note, if there are new lesions on the bone scan, the median interval between an asymptomatic state and a symptomatic state is only 2 3 mo. Therefore, if a patient is eager to receive active treatment, there is no reason to withhold treatment until the patient develops symptoms. The same applies to elderly patients. Age alone should therefore not be used as a criterion to withhold docetaxel-based chemotherapy. 5. Defining the standard of care for patients with mhrpc Until recently, the use of systemic chemotherapy for mhrpc has offered little to patients. Further hormonal manipulations were rarely associated with clinical benefit and any response was usually short-lived. However, results of the TAX 327 and SWOG studies revealed superior survival with docetaxel versus mitoxantrone [3] and thus provide the proof of principle that chemotherapy can prolong survival. Docetaxel-based chemotherapy is well tolerated and associated with QoL benefits. Docetaxel q3w plus low-dose prednisone has become the new standard treatment and a reference guide for future drug development in patients with mhrpc [3,26]. 6. Conclusions For many years, patients with HRPC could only be offered palliative treatments and accordingly their prognosis was poor. The findings of the TAX 327 and SWOG studies challenge the belief that HRPC is a chemotherapy-resistant disease and reveal that q3w docetaxel plus prednisone is well tolerated and offers superior survival in addition to improved patient QoL compared with the former standard treatment of mitoxantrone and prednisone. This opens up a number of new directions for our clinical investigations. Not only is docetaxel now being evaluated in patients with earlier stage prostate cancer, for whom chemotherapy may offer better long-term outcomes by decreasing the risk of systemic relapse, but combinations of novel chemotherapeutic agents with docetaxel are also being investigated and may well offer further benefits to patients with HRPC. Conflict of interest This article was developed from a presentation given at a scientific symposium sponsored by sanofi-aventis at the European Association of Urology (EAU) Annual Congress, Paris, France, 5 8 April References [1] Kish JA, Bukkapatnam R, Palazzo F. The treatment challenge of hormone-refractory prostate cancer. Cancer Control 2001;8: [2] Yagoda A, Petrylak D. Cytotoxic chemotherapy for advanced hormone-resistant prostate cancer. Cancer 1993;71: [3] de Wit R. Shifting paradigms in prostate cancer; docetaxel plus low-dose prednisone finally an effective chemotherapy. Eur J Cancer 2005;41: [4] Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351: [5] Osoba D, Tannock IF, Ernst DS, Neville AJ. Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. J Clin Oncol 1999;17: [6] Kantoff PW, Halabi S, Conaway M, et al. Hydrocortisone with or without mitoxantrone in men with hormonerefractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol 1999;17: [7] Bhandari MS, Petrylak DP, Hussain M. Clinical trials in metastatic prostate cancer has there been real progress in the past decade? Eur J Cancer 2005;41: [8] Picus J, Schultz M. Docetaxel (Taxotere) as monotherapy in the treatment of hormone-refractory prostate cancer: preliminary results. Semin Oncol 1999;26:14 8. [9] Berry W, Dakhil S, Gregurich MA, Asmar L. Phase II trial of single-agent weekly docetaxel in hormone-refractory, symptomatic, metastatic carcinoma of the prostate. Semin Oncol 2001;28:8 15. [10] Beer TP, Pierce W, Lowe B, Henner WD. Phase II study of weekly docetaxel (Taxotere) in hormone refractory prostate cancer (HRPC). Proc Am Soc Clin Oncol 2000;19:348a, (Abstract 1368). [11] Burstein HJ, Manola J, Younger J, et al. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol 2000;18: [12] Savarese D, Taplin ME, Halabi S, Hars V, Kreis W, Vogelzang N. A phase II study of docetaxel (Taxotere), estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: preliminary results of cancer and leukemia group B Trial Semin Oncol 1999;26:39 44.

7 european urology supplements 5 (2006) [13] Petrylak D, Shelton G, England-Owen C, et al. Response and preliminary survival of a phase II study of docetaxel and estramustine in patients with androgen-independent prostate cancer. Proc Am Soc Clin Oncol 2000;19:334a, (Abstract 334). [14] Sinibaldi V, Carducci M, Moore-Cooper S, Laufer M, Eisenberger M. A phase II study evaluating docetaxel (D) and one day of estramustine phosphate (EMP) in patients (Pts) with hormone refractory prostate cancer (HRPC): updated preliminary analysis. Proc Am Soc Clin Oncol 2000;19:346a, (Abstract 1361). [15] Kreis W, Budman D. Daily oral estramustine and intermittent intravenous docetaxel (Taxotere) as chemotherapeutic treatment for metastatic, hormone-refractory prostate cancer. Semin Oncol 1999;26:34 8. [16] Savarese DM, Halabi S, Hars V, et al. Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB Cancer and Leukemia Group B. J Clin Oncol 2001;19: [17] Petrylak DP, Macarthur RB, O Connor J, et al. Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol 1999;17: [18] Panda D, Miller HP, Islam K, Wilson L. Stabilization of microtubule dynamics by estramustine by binding to a novel site in tubulin: a possible mechanistic basis for its antitumor action. Proc Natl Acad Sci USA 1997;94: [19] Sitka Copur M, Ledakis P, Lynch J, et al. Weekly docetaxel and estramustine in patients with hormone-refractory prostate cancer. Semin Oncol 2001;28: [20] Benson R, Hartley-Asp B. Mechanisms of action and clinical uses of estramustine. Cancer Invest 1990;8: [21] Petrylak DP. Chemotherapy for advanced hormone refractory prostate cancer. Urology 1999;54:30 5. [22] Petrylak DP, Macarthur R, O Connor J, et al. Phase I/II studies of docetaxel (Taxotere) combined with estramustine in men with hormone-refractory prostate cancer. Semin Oncol 1999;26: [23] Pienta KJ, Smith DC. Advances in prostate cancer chemotherapy: a new era begins. CA Cancer J Clin 2005;55: [24] Athanasiadis A, Tsavdaridis D, Rigatos SK, Athanasiadis I, Pergantas N, Stathopoulos GP. Hormone refractory advanced prostate cancer treated with estramustine and paclitaxel combination. Anticancer Res 2003;23: [25] Petrylak DP. Future directions in the treatment of androgen-independent prostate cancer. Urology 2005; 65:8 12. [26] Aus G, Abbou CC, Bolla M, et al. EAU guidelines on prostate cancer. Eur Urol 2005;48: [27] Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351: [28] de Wit R. A multicenter phase III comparison of docetaxel + prednisone (P) and mitoxantrone (MTZ) + P in patients with androgen-independent prostate cancer (AIPC): secondary analysis of survival in patient subgroups. The TAX 327 Investigators. Ann Oncol 2004; 15(Suppl 3):iii12, (Abstract 44IN). [29] Lagakos SW, Eisenberger MA, Tannock IF. The challenge of subgroup analyses reporting without distorting. N Engl J Med 2006;354: