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Current Opinion in Oncology:
doi: 10.1097/CCO.0b013e3283380939
Genitourinary system: Edited by Arif Hussain

Update on castrate-resistant prostate cancer: 2010

Lassi, Kiran; Dawson, Nancy A

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Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, District of Columbia, USA

Correspondence to Kiran Lassi, MD, 3800 Reservoir Road NW, Washington, DC 20007, USA Tel: +1 202 444 7358; fax: +1 202 444 9429; e-mail: kiranlassi@yahoo.com

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Abstract

Purpose of review: Prostate cancer remains a medical dilemma and a major cause of morbidity and mortality in many western countries. It represents the most common cancer in US men, with an estimated 192 280 new cases diagnosed in 2009. The median survival for men with metastatic castrate-resistant prostate cancer is 1–2 years, with improvements in survival seen primarily with docetaxel-based therapies. The purpose of this article is to discuss developments of novel agents in the field of metastatic castration-resistant prostate cancer (CRPC), including new cytotoxic agents, immune-based therapies, circulating tumor markers and targeting agents.

Recent findings: During this past year, several promising approaches yielded disappointing results in the phase III setting (GVAX); nonetheless, expectations for other agents (Abiraterone, MDV3100, Zibotentan, immunotherapy agents) still remain high.

Summary: Systemic therapy options are limited in CRPC and survival benefit remains to be seen with the new therapies. Circulating tumor cells continue to provide important prognostic information and will likely become an important aspect of future clinical decision-making.

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Introduction

Prostate cancer is the most common cancer in men in the United States, with an estimated incidence of 192 280 cases in 2009 [1,2]. It is estimated that 27 360 men will die of prostate cancer. Most patients with localized disease have excellent cure rates; however, patients with metastatic disease continue to pose a challenge. In cases of widespread disease, prostate cancer initially responds to androgen deprivation therapy; however, after 12–18 months on average, the malignant cells become resistant. Second-line hormonal agents such as ketoconazole and cytotoxic agents provide only temporary disease control. Many novel approaches are currently in development and include new cytotoxic agents, antiproliferative drugs, immune-based and targeted therapies.

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New cytotoxic agents

Cytotoxic agents offering some promise are currently under investigation in castration-resistant prostate cancer (CRPC), and include cabazitaxel and the epitholones.

Cabazitaxel (XRP-6258), a novel taxane, has similar mechanism of action to other taxanes as a microtubule destabilizer inhibiting cell division. However, unlike other taxanes, this agent is a poor substrate for the multidrug resistance P-glycoprotein (pgp) efflux pump which is over expressed in taxane-resistant tumor cells. A phase III multicenter trial is currently evaluating cabazitaxel in patients with CRPC after progression on docetaxel-based therapy [3].

Epothilones are a new class of nontaxane microtubule-stabilizing agents. Two epothilones, ixabepilone and patupilone, have been studied in CRPC.

Ixabepilone, an epitholone B analog, has been tested in a multicenter phase II trial. Ixabepilone at 35 mg/m2 every 3 weeks was compared to mitoxantrone (14 mg/m2 every 3 weeks) and prednisone [4]. A prostate-specific antigen (PSA) decline of more than 50% was observed in 17% of the ixabepilone versus 20% of the mitoxantrone/prednisone-treated patients. Also, prior taxane response was associated with increased likelihood of second-line therapy response with ixabepilone. Overall survival (OS) was similar in both groups: 10.4 months for ixabepilone and 9.8 months for mitoxantrone/prednisone. In another phase II trial, ixabepilone was given to chemotherapy-naive CRPC patients; PSA response was seen in 33% of the patients [5]. Currently, phase III trials in CRPC are in development.

Patupilone, another epitholone, is currently being studied in CRPC patients who have progressed within 6 months of docetaxel therapy [6,7]. In a phase II study of 83 patients, patupilone given at 8 mg/m2 every 3 weeks was fairly well tolerated with PSA declines of greater than 30 and 50% in 44/78 (56%) and 35/78 (45%) patients, respectively. Grade 3–4 adverse events included fatigue, diarrhea and anorexia [6]. The initial data seem encouraging; however, whether this drug will impact OS remains to be seen.

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Androgen receptor antagonist

Several preclinical and clinical studies have shown that despite being ‘hormone refractory’, the prostate cancer cells continue to express high androgen receptor levels and thus mediate ongoing androgen signaling. One potential therapeutic strategy might be to target these receptors via selective androgen receptor manipulation. Two such agents showing promise are abiraterone and MDV3100.

Abiraterone is a new oral agent under investigation showing promising results. It is a highly selective irreversible inhibitor of cytochrome P-17 (17 alpha hydroxylase and C17,20-lyase). Cytochrome P-17 is a dual enzyme that blocks the androgen production from adrenal glands. A phase I trial found abiraterone acetate 1000 mg once daily dose to be well tolerated and efficacious [8].

Early phase II data with abiraterone have been quite promising, including in docetaxel-refractory patients. In a phase II trial, 47 patients were treated with abiraterone 1000 mg a day (n = 10) or abiraterone and prednisone (n = 37). PSA declines of at least 50% were achieved in 45% of patients, and no grade 4 toxicities were seen [9]. A similar phase II trial with abiraterone reported decline in PSA of at least 50% in 28/42 (67%) patients and declines of at least 90% in 8/42 (19%) patients [10•]. In addition, decline in circulating tumor cell (CTC) counts were observed and median time to progression (TTP) was 225 days [10•]. A randomized phase III trial of abiraterone acetate and prednisone versus placebo and prednisone is ongoing.

MDV3100 is another potent androgen-receptor antagonist. It has five-fold higher binding affinity for androgen receptor than bicalutamide. As opposed to bicalutamide, MDV3100 prevents cellular DNA translocation, DNA binding and has no agonist activity. A phase I/II trial demonstrated greater than 50% decline in baseline PSA in 12 weeks in 57% of chemotherapy-naive and 45% of postchemotherapy patients [11]. This trial found 240 mg once daily of MDV3100 to be the optimal dose in terms of safety and efficacy for further testing in a currently ongoing phase III trial.

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Immunotherapy

Cancer immunotherapy attempts to stimulate one's own immune system to create antitumor effect.

Development of an effective immunotherapy requires targeting a unique tumor antigen such as prostate acid phosphatase (PAP). PAP is highly expressed in more than 90% of prostate tumors. Utilizing this concept, Dendreon created Provenge (sipuleucel-T) activating T-cell mediated immunity.

A phase III study, D9901, consisting of 127 men with asymptomatic, metastatic CRPC compared sipuleucel-T every 2 weeks for three cycles with placebo in a 2: 1 ratio [12]. The final 3-year follow-up of the D9901 phase III study showed a median survival benefit of 4.5 months and a three-fold improvement in survival at 36 months for patients who were randomized to receive Provenge. D9902, a similar trial of 98 men with asymptomatic, metastatic CRPC demonstrated a benefit of 3.3 months. In both studies, Provenge was well tolerated.

A final phase III trial, Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT), D9902B, was conducted in 500 patients with OS being the primary endpoint. The results for this trial were recently presented at the 2009 American Urological Association Annual Meeting, confirming a median survival advantage of 4.1 months for patients treated with sipuleucel-T compared to placebo (25.8 versus 21.7 months, respectively; P = 0.032) and increasing the 3-year OS by 38% compared to placebo [13•]. Dendreon Corporation submitted the amended Biologics License Application (BLA) for PROVENGE to the U.S. Food and Drug Administration (FDA) in November 2009.

Unlike Provenge, GVAX is a cell-based gene-transduced multiantigen vaccine. It was developed using two human prostate cancer cell lines, LNCaP and PC-3.

On the basis of encouraging phase II results [14], two phase III clinical trials in metastatic CRPC have been completed.

The first phase III trial (VITAL-1) compared GVAX with Taxotere and prednisone for 6 months [15]. The second phase III trial (VITAL-2) compared GVAX/Taxotere (D+G) with Taxotere/prednisone (D+P). VITAL-2 was terminated in August 2008 because of excessive deaths in the GVAX arm. VITAL-1, which completed accrual, was terminated because of futility analysis indicating that there was less than 30% chance of achieving a survival benefit [15,16•]. Updated results from VITAL-2 reveal OS was shorter in the D + G arm with median survival of 12.2 versus 14.1 months in the D + P arm (P = 0.0076) [16•]. The authors conclude that the differences may be due to immunotherapy impacting efficacy of chemotherapy. Further studies are underway to explore whether there was a subgroup that derived some benefit from the D + G combination therapy.

Recently, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) has emerged as a potential target for immunomodulatory therapy. CTLA-4 is an inhibitory molecule on T cells that induces T-cell down-regulation. Ipilimumab (Mederex Inc., MDX-010), a fully human antibody that binds to CTLA-4, blocks its activity, thereby allowing sustained immune response. In a phase II experience of ipilimumab (IPI) alone and in combination with radiotherapy (XRT) in patients with metastatic CRPC, 10 of 45 patients had confirmed PSA declines at least 50% and the median duration of response was 23 weeks (3–84+ weeks) [17•]. Adverse immune-related events were seen in 26 patients, including diarrhea, rash, and hepatitis, with almost all resolving upon immunosuppression. A trial comparing ipilimumab with and without docetaxel therapy has completed accrual [18]. Several other trials are currently ongoing, testing CTLA-4 blockade with ipilimumab.

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Circulating tumor cells

CTCs are epithelial cells that shed from tumors. In 120 patients with metastatic prostate cancer, Danila et al. [19] found a higher CTC count in patients with bone metastases alone (median 10.5 cells) and in patients with bone and soft tissue tumor involvement (median 13.5 cells) versus soft tissue tumors alone (median 2.5 cells). Higher CTC and PSA were correlated with worsening survival. CTC of less than 5 was correlated with improved survival versus at least 5 CTC (22.7 versus 9 months; P = 0.01).

Similar results were seen in a prospective trial evaluating pretreatment and post-treatment CTC counts and correlation with OS [20,21•]. Patients were categorized as favorable (<5 CTC) or nonfavorable (≥5 CTC). Median OS was 21.7 months in the favorable group versus 9.5 months in the unfavorable group. Recently presented data on patients treated with abiraterone actetate after progression on docetaxel therapy showed that among patients with baseline CTC greater than 5, a CTC decline to less than 5 was associated with a decline in PSA by above 50% (P < 0.001) [22].

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Targeting tumor vasculature

Tumor angiogenesis represents a critical step in tumor development and growth. Angiogenesis is driven by the up-regulation of vascular endothelial growth factor (VEGF) in the tumor cells, and targeting the VEGF receptor has led to antitumor effects in preclinical models of prostate cancer [23].

Bevacizumab, a well known antiangiogenic agent, is a humanized monoclonal antibody against VEGF. In a phase II trial, bevacizumab in combination with docetaxel in docetaxel pretreated patients showed 11 patients (55%) had major PSA responses, and 3 (37.5%) had objective responses [24]. The treatment was well tolerated. On the basis of these and other similar results, a phase III trial comparing docetaxel with or without bevacizumab (CALGB 90401) has completed accrual, and the results are expected to be reported in 2010.

Sunitinib and sorafenib are orally administered tyrosine kinase inhibitors that have demonstrated antiangiogenic and antitumor activity as well, and are approved for the treatment of advanced renal cell carcinoma. In a phase II trial of 36 patients with prior docetaxel therapy, the median PFS was 19.4 weeks on sunitinib. Four patients (12.1%) had an at least 50% PSA decline and seven (21.2%) had an at least 30% PSA decline. Two of 18 patients (11.1%) with measurable disease demonstrated 30% declines in tumor size by RECIST and 8 (44.4%) displayed some shrinkage. A decline in pain score of at least 2 points occurred in 13.6% of 22 assessable patients. Drug discontinuation due to toxic effects occurred in 52.8% of patients [25].

Sorafenib as a single agent has also been assessed in CRPC. A phase II trial in chemotherapy-naive CRPC patients revealed a partial response in 20% of patients with a PFS of 5.9 months [26]. Other phase II trials have demonstrated similar results [27,28]. Due to their modest efficacy in CRPC, further studies are needed to evaluate if there is a subset of patients who would benefit most from these agents.

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Endothelin-receptor antagonist

The endothelin pathway has been implicated in the progression of prostate cancer. Endothelins (endothelin-1, endothelin-2, endothelin-3), modulators of vasomotor tone, nociception, cell proliferation and angiogenesis, bind two receptors, endothelin-A and endothelin-B. Levels of endothelin-1 are high in metastatic prostate cancer [29]. Endothelin-A is thought to promote osteoblastic activity characteristic of bone metastases in prostate cancer [30,31].

Atrasentan, a selective endothelin-A antagonist, has shown a positive impact as single agent on PSA progression, bone markers and median TTP in phase III studies. In the first multicenter trial, 809 men with CRPC were randomized in a 1: 1 fashion to atrasentan 10 mg daily versus placebo [31]. The primary endpoints were TTP, assessed radiographically and clinically. Atrasentan did not reduce TTP relative to the placebo arm (P = 0.136). In an exploratory analysis, however, bone alkaline phosphatase and PSA levels were significantly lower in the atrasentan arm (P < 0.05). A second phase III trial yielded similar results [32]. Although atrasentan did not meet the primary endpoint expectations, it did have an impact on molecular markers that indicate disease progression. Hence, Southwest Oncology Group is currently conducting a phase III trial investigating docetaxel with or without atrasentan in men with metastatic CRPC.

Zibotentan (ZD4054) is another selective endothelin-A receptor antagonist. In a phase II trial on men with CRPC, 308 symptomatic patients were randomized to doses of either 15 or 10 mg, once daily, or placebo. No improvement in TTP was seen; however, an interim analysis revealed improvement in OS (23.5, 24.5 versus 17.3 months for placebo) [33•]. Based on these results, ZD4054 is currently being tested in a phase III trial in CRPC in the metastatic and nonmetastatic settings.

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Chaperone proteins

Antisense therapy utilizing oligonucleotides inhibiting the translation of malignancy specific proteins is also emerging as a potential therapeutic strategy.

Clusterin is a cytoprotective chaperone protein that promotes cell survival and has been identified as a potential target in CRPC. OGX-011(OncoGenex Pharmaceuticals, Inc.) is designed to inhibit the production of clusterin. A recent phase II study with OGX-011 randomized 82 patients with chemotherapy-naive metastatic CRPC to receive first-line docetaxel with or without OGX-011 [34]. The OGX-011 and docetaxel arm had at least 58% of the patients with PSA declines of 50% or greater. A recent press release has reported a median OS of 16.9 months for the docetaxel group and 27.5 months for those treated with the docetaxel–OGX-011 combination. Other phase II studies have yielded similar results [35]. A phase III trial is being planned comparing docetaxel–OGX-011 versus docetaxel in patients with metastatic CRPC, with primary endpoint of OS.

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Conclusion

Over the past decade, our understanding of the molecular pathogenesis of prostate cancer has continued to expand. These developments have led to novel agents that specifically target molecular pathways in the treatment of CRPC. Although several of these agents show initial promise, they have yet to demonstrate a survival benefit. CTCs have consistently shown to provide important prognostic information and will likely be incorporated in future clinical decision-making.

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References and recommended reading

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Papers of particular interest, published within the annual period of review, have been highlighted as:

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• of special interest

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•• of outstanding interest

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Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 293–294).

1 American Cancer Society. What are the key statistics about prostate cancer. http://www.cancer.org

2 Beardsley EK, Chi KN. Systemic therapy after first line docetaxel in metastatic castration-resistant prostate cancer. Curr Opin Support Palliat Care 2008; 2:161–166.


4 Rosenberg JE, Weinberg VK, Kelly WK, et al. Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients: randomized phase 2 study of ixabepilone or mitoxantrone and prednisone. Cancer 2007; 110:556–563.

5 Hussain M, Tangen CM, Lara PN Jr, et al. Ixabepilone (epothilone B analogue BMS-247550) is active in chemotherapy-naive patients with hormone-refractory prostate cancer: a Southwest Oncology Group trial S0111. J Clin Oncol 2005; 23:8724–8729.

6 Beardsley E, Saad F, Venner F, Winquist Y. A phase II study of patupilone in patients (Pts) in metastatic castrate resistant prostate cancer (CRPC) who have progressed after docetaxel. J Clin Oncol 2009 [abstract 5139].

7 Chi KN, Beardsley EK, Venner PM, et al. A phase II study of patupilone in patients with metastatic hormone refractory prostate cancer (HRPC) who have progressed after docetaxel. J Clin Oncol 2008 [Abstract 5166].

8 De Bono JS, Attard G, Reid AH, et al. Antitumor activity of abiraterone acetate (AA), a CYP17 inhibitor of androgen synthesis, in chemotherapy naive and docetaxel pretreated castration resistant prostate cancer (CRPC). J Clin Oncol 2008 [Abstract 5005].

9 Danila DC, Rathkopf DE, Morris MJ, et al. Abiraterone acetate and prednisone in patients (Pts) with progressive metastatic castration resistant prostate cancer (CRPC) after failure of docetaxel-based chemotherapy. J Clin Oncol 2008 [abstract 5019].

10• Attard G, Reid AH, A’Hern R, et al. Selective inhibition of CYP 17 with abiraterone acetate is highly active in the treatment of castrate-resistant prostate cancer. J Clin Oncol 2009; 27:3742–3748. More data on abiraterone acetate showing significant decline in PSA and CTC counts confirming that prostate cancer continues to remain hormone driven.

11 Scher HI, Beer TM, Higano CS, et al. Antitumor activity of MDV3100 in a phase I/II study of castration-resistant prostate cancer. J Clin Oncol 2009 [abstract 5011].

12 Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 2006; 24:3089–3094.

13• http://www.dendreon.com/pipeline/sipuleucel_t/ The IMPACT study seems promising showing immunotherapy prolonging survival in patients with advanced prostate cancer.

14 Corman J, Small E, Smith D, et al. Immunotherapy with GVAX® vaccine for prostate cancer improves predicted survival in metastatic hormone refractory prostate cancer: results from two phase 2 studies. Proceedings from the American Urological Association Annual Meeting. Atlanta, Georgia. 2006 [abstract 976].


16• Small E, Demkow T, Gerritsen WR, et al. A phase III study of GVAX immunotherapy for prostate cancer in combination with docetaxel versus docetaxel plus prednisone in symptomatic, castration-resistant prostate cancer (CRPC). Genitourinary Cancers Symposium. ASCO 2009 [Abstract 7]. Results of the combination of docetaxel with GVAX immunotherapy were disappointing in comparison to docetaxel + prednisone therapy.

17• Slovin SF, Beer TM, Higano CS, et al. Initial phase II experience of ipilimumab (IPI) alone and in combination with radiotherapy (XRT) in patients with metastatic castration-resistant prostate cancer (mCRPC) abstr 5138. J Clin Oncol 2009; 27:15s. Encouraging small phase II study on ipilimumab. More phase II data needed.

18 Gerritsen W, Van Den Eertwegh AJ, De Gruijl TD, et al. A dose-escalation trial of GM-CSF-gene transduced allogeneic prostate cancer cellular immunotherapy in combination with a fully human anti-CTLA antibody (MDX-010, ipilimumab) in patients with metastatic hormone-refractory prostate cancer (mHRPC) Data presented at the 3rd annual ASCO Prostate Cancer Symposium, Orlando, Florida, February 22–24, 2007.

19 Danila DC, Heller G, Gignac GA, et al. Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res 2007; 13:7053–7058.

20 Shaffer DR, Leversha MA, Danila DC, et al. Circulating tumor cell analysis in patients with progressive castration resistant prostate cancer. Clin Cancer Res 2007; 13:2023–2029.

21• De Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 2008; 14:6302–6309. Prospective study on circulating tumor markers and prognostic information.

22 Fleisher D, Danila C, Leversha M, et al. Circulating tumor cells (CTC) in patients with metastatic castration-resistant prostate cancer (CRPC) receiving abiraterone acetate (AA) after failure of docetaxel-based chemotherapy. J Clin Oncol 2009; 27:15s [Abstract 5049].

23 Melynk O, Zimmerman M, Kim KJ, Shuman M. Neutralizing antivascular endothelial growth inhibits further growth of established prostate cancer and metastases in a preclinical model. J Urol 1999; 161:960–963.

24 Di Lorenzo G, Figg W, Fossa S, et al. Giuliano combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: a phase 2 study. Eur Urol 54:1089–1096.

25 Sonpavde G, Periman PO, Bernold, D, et al. Sutinib malate for metastatic castration-resistant prostate cancer after docetaxel based chemotherapy. Ann Oncol 2009 [Epub ahead of print].

26 Dahut WL, Scripture C, Posadas E, et al. A phase II clinical trial of sorafenib in androgen-independent prostate cancer. Clin Cancer Res 2008; 14:209–214.

27 Safarenijad MR. Safety and efficacy of sorafenib with castrate resistant prostate cancer. Urologic Oncol 2008; 28:21–27.

28 Aragon-Ching JB, Jain L, Gulley JL, et al. Final analysis of a phase II trial using sorafenib in castrate resistant prostate cancer. BJU Int 2009; 103:1636–1640.

29 Akhavan A, McHugh KH, Guruli G, et al. Endothelin receptor A blockade enhances taxane effects in prostate cancer. Neoplasia 2006; 8:725–732.

30 Nelson JB, Hedican SP, George DJ, et al. Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat Med 1995; 1:944–949.

31 Carducci MA, Saad F, Abrahamsson PA, et al. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer 2007; 110:1959–1966.

32 Nelson JB, Love W, Chin JL, et al. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. J Clin Oncol 2007; 25(18S):5018.

33• James N, Caty A, Borre M, et al. Safety and efficacy of the specific endothelin A receptor antagonist ZD4054 in patients with hormone-resistant prostate cancer and bone metastases who were pain-free or mildly symptomatic: a double-blind, placebo-controlled, randomized, phase 2 trial. Eur Urology 2008; 55:1112–1123. A well tolerated drug with data showing a survival benefit in the ZD4054 arm in a phase II study leading to a phase III trial.

34 Chi KN, Hotte SJ, Yu E, et al. A randomized phase II study of OGX-011 in combination with docetaxel and prednisone or docetaxel and prednisone alone in patients with metastatic hormone refractory prostate cancer (HRPC). J Clin Oncol 2007; 25 [abstract 5069].

35 Saad F, Hotte SJ, North SA, et al. A phase II randomized study of custirsen (OGX-011) combination therapy in patients with poor-risk hormone refractory prostate cancer (HRPC) who relapsed on or within six months of 1st-line docetaxel therapy. J Clin Oncol 2008; 26 [abstract 5002].

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Keywords:

castrate-resistant prostate cancer; circulating tumor markers; immunotherapy

© 2010 Lippincott Williams & Wilkins, Inc.

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