Curr Urol Rep (2012) 13:170–178 DOI 10.1007/s11934-012-0239-z

PROSTATE CANCER (R REITER, SECTION EDITOR)

Therapeutic Options for Advanced Prostate Cancer: 2011 Update Aurelius Omlin & Johann S. de Bono

Published online: 29 February 2012 # Springer Science+Business Media, LLC 2012

Abstract Up to 40% of male patients diagnosed with prostate cancer develop metastatic disease that generally responds to initial chemical or surgical castration, but this eventually progresses despite castrate levels of testosterone, termed castration-resistant prostate cancer (CRPC). A large phase 3 trial of abiraterone acetate in patients who have progressed following docetaxel based chemotherapy were published in 2011 and dramatically proved that CRPC is still androgen-dependant and responds to CYP17 inhibition. Overall survival benefits were also reported for a novel tubulin-binding drug, cabazitaxel, tested as second-line chemotherapy after docetaxel failure; for sipuleucel-T, an autologous dendritic cell therapy, in chemotherapy-naive patients; for MDV3100, a novel antiandrogen, and for radium-223, which is a bone-seeking α-irradiation–emitting radioisotope. Denosumab, a monoclonal antibody against receptor activator of nuclear factor-kB ligand, was shown to be superior to zoledronic acid for prevention of skeletal-related events in prostate cancer patients with metastatic bone disease. This review will focus on the recent developments in the field of CRPC. Keywords Prostate cancer . Castrate-resistant prostate cancer . CRPC . Docetaxel . Cabazitaxel . Abiraterone . Radium-223 . Sipuleucel-T . Denosumab . Circulating tumor cells . CTC . Biomarker . Update

A. Omlin : J. S. de Bono (*) Drug Development Unit, The Institute of Cancer Research, ICR and Royal Marsden NHS Foundation Trust, Sycamore House, Downs Road, Sutton, Surrey SM25PT, UK e-mail: [email protected]

Introduction The past 2 years have seen an impressive change in the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). Prostate cancer is the most common male cancer and accounted for 37,051 cases, with 10,168 patients dying in 2008 in the United Kingdom (www.cancerresearch.uk.org). Four large trials reported overall survival benefits in 2010/2011 for patients with CRPC with four treatments (abiraterone, cabazitaxel, sipuleucel-T, and radium-223 [Alpharadin; Algeta ASA, Oslo, Norway]), and three of these treatments have been approved by the U.S. Food and Drug Administration (FDA), with the fourth likely to be approved in 2012. However, this changing therapeutic landscape poses many challenges, such as the optimal sequencing of the novel therapies, optimal selection of patients for individual treatments, the increasing need for predictive and prognostic robust biomarkers, and, not least, the management of the rocketing costs for the health care system. Progress in the treatment of advanced prostate cancer has been achieved using different therapeutic strategies, such as targeting androgen-receptor signalling (abiraterone acetate), cytotoxic chemotherapy (cabazitaxel), immunotherapy (sipuleucel-T), and bone-targeting radiation (radium-223 [223Ra]). This review will focus on highlighting the recent advances in the treatment of prostate cancer.

Abiraterone Acetate: Hormonal Treatment Offers Substantial Survival Benefit in Chemotherapy Pretreated Patients Strong evidence supports the hypothesis that, despite castrate levels of testosterone, prostate cancer cells remain

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strongly androgen-dependent, and the androgen receptor has been identified as one of the most important proteins in prostate cancer cells [1]. Enzymes involved in intratumoral conversion of cholesterol to testosterone and synthesis of testosterone from adrenal androgens have been shown to be upregulated in CRPC cells, allowing ongoing androgendependent growth [2•, 3, 4]. Abiraterone acetate (abiraterone) is a pregnenolonederived 3-pyridyl steroidal drug, developed at the Institute of Cancer Research (ICR), that irreversibly inhibits the key CYP17 enzymes in androgen biosynthesis, 17αhydroxylase and 17,20-lyase [5]. In the phase 1/2 studies with daily single-agent administration of abiraterone, prostate-specific antigen (PSA) falls of 50% or higher were seen in 50%–60% of patients. Radiological response rates in patients prechemotherapy were seen in 37% and in 27% in patients post-docetaxel [6–9]. As expected, the inhibition of CYP17 resulted in a sideeffect profile of hypertension, hypokalemia, and fluid retention as a result of secondary mineralocorticoid excess. These side effects were largely abrogated by the coadministration of low-dose glucocorticoids or mineralocorticoid antagonists. The results of a large randomized phase 3 trial with abiraterone plus prednisone versus prednisone alone recently have been published [10••]. In this trial, 1195 patients with CRPC postchemotherapy were randomly assigned in a 2:1 ratio to receive either abiraterone plus prednisone or placebo with prednisone. Overall, 70% of patients had received one prior chemotherapy regimen and 30% of patients had received two lines of prior chemotherapy. The primary end point was overall survival, which was significantly longer in patients receiving abiraterone plus prednisone 14.8 months, compared to 10.9 months in patients on placebo (HR 0.65; 95% CI, 0.54–0.77; P< 0.001). The trial was unblinded at the time of the interim analysis and patients on placebo were allowed to cross over to abiraterone. The final survival data were updated at the European Cancer Organisation (ECCO) conference in Stockholm in September 2011 and showed an improved overall survival benefit of 4.6 months (15.8 vs 11.2 months; HR 0.74; 95% CI, 0.64–0.86; P<0.0001) [11•]. Adverse events related to abiraterone were mostly of mild to moderate intensity, namely fluid retention (31% vs 22%, P00.04) and hypokalemia (17% vs 8%, P<0.001). The incidence of hypertension was not statistically different in the two groups (10% vs 8%). Due to an early observation of episodes of grade 4 aspartate transaminase elevation, liver function tests were more frequently monitored on the study. However, in the final analysis, neither any grade in liver function test changes (10% vs 8%) nor grade 3 or 4 elevation of liver function tests (3.5% vs 3%) were statistically

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more frequent in the abiraterone-treated patients. Overall, the safety profile of abiraterone was excellent, with slightly fewer patients who discontinued treatment in the abiraterone group versus the placebo group (19% vs 23%, P00.09) and mean duration of treatment was 10.1 cycles for abiraterone versus 6.7 in the placebo group [10••]. Looking at the preplanned subgroup analysis, it is important to highlight that the overall survival benefit was maintained in all subgroups, including older patients aged 75 years and older (15.6 m vs 9.3 m; HR 0.64; 95% CI, 0.48–0.85) and in patients with pain as measured by the brief pain inventory (worst pain ≥4: 13.3 m vs 9.3 m; HR 0.78; 95% CI, 0.63–0.96) [11•]. Patient-reported functional status as measured by the functional assessment of cancer therapy-prostate (FACT-P) questionnaire showed significant improvement of the FACT-P total score in 48% versus 32% of patients (P< 0.0001) and also significantly delayed time to decline 363 days versus 253 days (P<0.0001). Interestingly, the prostate cancer subscale showed an improvement in almost 20% of patients (58% vs 40%, P<0.0001) and the only subscale with no observed difference (54% vs 49%, P=0.284) was the social/family well-being subscale, which includes support from partners and family or satisfaction with sexual life [12]. The optimal sequencing of abiraterone in the treatment of patients with CRPC is of great importance and may be answered by the trial that completed recruitment in May 2010 of approximately 1,000 patients with asymptomatic or mildly symptomatic CRPC who had not received prior chemotherapy (NCT00887198). Other smaller trials are looking at various combinations with antiandrogens and abiraterone as a neoadjuvant treatment, before and after chemotherapy, or in combination with docetaxel (www. clinicaltrials.gov).

Cabazitaxel Prolongs Survival after Docetaxel Cabazitaxel, a tubulin-binding drug with anticancer activity in cell-lines resistant to docetaxel or paclitaxel, received FDA approval in 2010 based on the positive results of the TROPIC (Treatment of Hormone-Refractory Metastatic Prostate Cancer Previously Treated With a TaxotereContaining Regimen) study, a randomized phase 3 trial comparing cabazitaxel (25 mg/m2 every 3 weeks) plus prednisone versus mitoxantrone (12 mg/m2 every 3 weeks) plus prednisone in 755 men who had progressed during or after docetaxel-based chemotherapy [13••]. Median overall survival on cabazitaxel was significantly longer compared to mitoxantrone (15.1 vs 12.7 months; HR 0.70; 95% CI, 0.59–0.83; P<0.0001). Based on the safety profile of cabazitaxel with considerable rates of grade 3/4 toxicities (neutropenia 81.7%,

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anemia 11%, thrombocytopenia 4%, febrile neutropenia 8%, diarrhea 6%) it was concluded that administration of cabazitaxel requires careful monitoring of symptoms, dose modification for toxicity, and prophylactic treatment with colony-stimulating factor in high-risk patients (eg, age >65 years, extensive prior radiation, poor nutrition, previous febrile neutropenia, poor nutritional status, and serious medical comorbidities) [14]. Overall, 18 (5%) patients on cabazitaxel died within 30 days of receiving the last study medication versus 9 patients on the mitoxantrone arm (2.5%). Of these 18 patients in the cabazitaxel arm, 7 died of neutropenic sepsis, 5 died of cardiac disease, and 3 died because of renal failure [13••]. Compared to the first-line TAX 327 trial of docetaxel plus prednisone versus mitoxantrone plus prednisone trial, where the treatment-related death rate was equal and very low in both arms (one patient in each arm [0.3%]), the treatment-related mortality for cabazitaxel is higher, highlighting the need for careful selection of patients and physician awareness of the higher rates of neutropenic fever (8% with cabazitaxel vs 3% with docetaxel) [13••, 15]. The recommended phase 2 doses based on two phase 1 trials were 20 mg/m2 and 25 mg/m2, and in the TROPIC trial, the higher of the two doses (25 mg/m2) has been tested [16, 17]. The PROSELICA study (NCT01308580) is a randomized phase 3 trial with planned 1,200 patients that will test the noninferiority of cabazitaxel at 20 mg/m² compared to 25 mg/m² with prednisone, aiming for an improved toxicity profile. Given that the activity of cabazitaxel in docetaxel-pretreated patients was similar to the survival benefit of 2.4 months observed with first-line docetaxel, the question of whether cabazitaxel would be better placed in the first-line setting will be addressed by the FIRSTANA trial, which is recruiting patients to a randomized phase 3 trial comparing docetaxel with cabazitaxel as first-line chemotherapy in 1170 patients with CRPC (NCT01308567).

Docetaxel Retreatment: An Option for Selected Patients? From studies combining docetaxel with other agents, such as bevacizumab or carboplatin, and from retrospective studies, evidence was gathered that re-treatment with docetaxel could be beneficial in a selected patient population [18–20]. Although Level I evidence is not available, a recently published phase 2 study enrolled patients with CRPC who progressed at least 5 months after first-line treatment with docetaxel and have had at least a 50% PSA response to this first-line treatment. Of the 45 patients enrolled, docetaxel retreatment resulted in 50% or greater PSA decline in 24.5% [11•], and 4 (25%) of the 16 patients with measurable disease had a documented partial response. The median

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overall survival in this trial was 13 months (95% CI, 7– 18). Docetaxel retreatment was well tolerated, with 11 (24.5%) patients having grade 3 or 4 neutropenia, in line with the 32% reported in the TAX 327 trial. Although the overall survival results are comparable to those shown in trials with radium-223 or cabazitaxel, retreatment does not appear very promising, given that this was a highly selected patient population [21].

Overall Survival Benefit with Bone-targeting Radium-223 (Alpharadin) Radium-223 (Alpharadin) is a bone-seeking α-radiation– emitting radioisotope, with a preferential uptake mainly in skeletal metastases compared to normal bone [22]. Strontium-89 (89Sr, Metastron [GE Healthcare Ltd., Little Chalfont, Buckinghamshire, United Kingdom]) and Samarium-153 (153Sm, Quadramet [EUSA Pharma USA, Langhorne, PA]), which are FDA-approved bonetargeted agents, are β-emitters and have been shown to result in superior pain control compared to placebo [23, 24]. Alpharadin emits α-particles, which have a very high linear energy transfer (LET) within a short range of action (of about <100 μm) and cause predominantly DNA double-strand break [25]. In a randomized, placebo-controlled, phase 2 study in patients with CRPC and painful bony metastases, Alpharadin was well tolerated with minimal hematotoxicity (<5% grade 3 and <1% grade 4). Alpharadin was administered as four repeated monthly injections of 50 kBq/kg 223Ra provided as a ready-to-use solution. Although time to skeletal-related events (SRE) and pain control were not statistically different, Alpharadin treatment resulted in improved progression-free survival (PFS; 26 weeks vs 8 weeks, P=0.048) and prolonged survival (65 weeks vs 46 weeks, P=0.066) [26]. The ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) phase 3 trial, with 922 patients randomly assigned in a 2:1 ratio to Alpharadin (615 patients) or placebo (307 patients), was reported at the ECCO conference after a positive interim analysis showed improved overall survival of Alpharadin 14 months versus placebo 11.2 months (P=0.00185; HR 0.695; 95% CI, 0.552–0.875) and the trial was stopped and unblinded at that time point [27••]. In this trial, Alpharadin (50 kBq/kg intravenous [IV]) was administered as 6 monthly IV injections. Eligible patients had progressive and symptomatic CRPC with at least two bone metastases on bone scan and no known visceral metastases. Patients were either pretreated with docetaxel or were considered unfit for docetaxel (42% of patients enrolled) [27••]. The toxicity profile of Alpharadin was very favorable with very low rates of grade 3/4 neutropenia (1.8% Alpharadin vs 0.8% placebo), thrombocytopenia

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(4% vs 2%), diarrhea (1% in both arms), and nausea (2% in both arms). Based on these results, Alpharadin has been granted Fast Track designation by the FDA. Overall, therefore, Alpharadin offers a novel welltolerated treatment option for patients with advanced prostate cancer and bone metastasis who have failed docetaxel-based chemotherapy or are unfit to receive docetaxel. However, the true potential of Alpharadin might be in combination with a systemic therapy, in the adjuvant setting, or in patients with small-volume bone metastasis.

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generating results will be further examined in a phase 3 trial with PROSTVAC with or without granulocytemacrophage colony-stimulating factor in minimally symptomatic patients with CRPC that will start recruiting patients very soon (NCT01322490). Two phase 3 studies with ipilimumab, a monoclonal antibody against a cytotoxic T-lymphocyte antigen, are currently enrolling patients to a chemonaïve and a postdocetaxel trial (NCT01057810, NCT00861614). The place of sipuleucel-T in the treatment algorithms of CRPC will have to be defined and patients selected because benefit was mainly seen in an asymptomatic population. The cost of this treatment will be prohibitive in many countries.

Immunotherapies: An Emerging Therapeutic Approach The first immunotherapy for the treatment of prostate cancer to be FDA approved was sipuleucel-T, an autologous activated dendritic cell therapy, given as 3 consecutive infusions every 2 weeks. The IMPACT (Immunotherapy Prostate Adenocarcinoma Treatment) trial, in which 512 chemotherapynaive patients with CRPC were randomly assigned in a 2:1 ratio to either sipuleucel-T or placebo, reported an overall survival benefit of 4.1 months (25.8 vs 21.7 months; HR 0.78; 95%CI, 0.61–0.98; P00.03) [28••]. To better understand the patient population, it is noteworthy that more than 80% of patients were chemotherapy-naive, 75% had a Gleason score of 7 or lower, 43% had five or fewer (or no) bone metastases, and 52% had no pain at study entry. Also, patients were required to be off steroids for at least 4 weeks and off chemotherapy for at least 3 months before entering the study. These results were in line with two previously reported trials of sipuleucel-T. In a small randomized phase 3 trial of 127 patients, the primary end point of time to tumor progression did not reach statistical significance, but a survival benefit was documented (median survival 25.9 months for sipuleucel-T and 21.4 months for placebo; HR 1.70; 95% CI, 1.13–2.56). In the integrated analysis of the D9901 and D9902A trials, with 225 patients with CRPC, a reduction in the risk of death of 33% was reported for patients on sipuleucel-T (HR 1.50; 95% CI, 1.10–2.05; P00.011) [29, 30]. A phase 2 trial with PROSTVAC-VF (Bavarian Nordic, Kvistgaard, Denmark), a recombinant vaccinia viral expression cassette expressing PSA and co-stimulatory molecules, was published in 2010. In this trial, 125 chemotherapy-naive patients with CRPC without visceral metastases were randomly assigned to receive the viral treatment (82) or placebo (40); three patients did not receive treatment for different reasons. Although PFS in both arms was similar, there was a significant survival benefit of 8.5 months (25.1 on PROSTVAC-VF vs 16.6 on placebo; HR 0.56; 95% CI, 0.37–0.85; P00.0061) [31]. These hypothesis-

Prevention of Skeletal-related Events: Zoledronic Acid Versus Denosumab Up to 90% of patients with advanced CRPC have detectable bone metastases [10••, 15]. The incidence of SRE in patients with CRPC varies depending on the source. In 250 patients treated as part of the ASCENT trial (Androgen-Independent Prostate Cancer Study of Calcitriol Enhancing Taxotere; weekly DN-101, calcitriol plus docetaxel compared to placebo plus docetaxel) the rate of SRE was 33% at 18.3 months of follow-up. 34% of patients on the trial were treated with zoledronic acid. The main SRE were radiotherapy to painful bone metastasis (18.8%), fractures (10%), spinal cord compression (4%), and bone surgery (0.4%) [32, 33]. Zoledronic acid is the only FDA-approved bisphosphonate for the prevention of SREs in patients with advanced prostate cancer and bone metastasis. A phase 3 trial with 643 men who were randomly assigned to either zoledronic acid (4 mg or 8 mg) or placebo, with a primary end point of SRE within 15 months, showed an improved rate of SRE on the zoledronic arm (38% vs 49%, P=0.28; 95% CI, 20.2%– 1.3%). Median time to first SRE was also prolonged (488 days vs 321 days); however, no survival benefit could be demonstrated for patients on zoledronic acid [34]. Results of a randomized phase 3 trial of denosumab, a monoclonal antibody against receptor activator of nuclear factor-kB ligand (RANKL; 120 mg subcutaneously every 4 weeks), versus zoledronic acid (4 mg IV every 4 weeks) in 1,904 patients with CRPC and bony metastasis have been published this year [35•]. Denosumab was superior to zoledronic acid with regards to median time to SRE (20.7 versus 17.1 months; HR 0.82; 95% CI, 0.71–0.95; P00.0002 for noninferiority, P00.008 for superiority). However, it is important to point out that overall survival and PFS were similar in the two groups: 41% of patients on zoledronic acid and 36% of patients on denosumab experienced SREs

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(radiation to bone 21% vs 19%; pathological fracture 15% vs 14%; spinal cord compression 4% vs 3%; and surgery to bone <1%). Adverse events were mostly evenly distributed between the two treatments, but patients on denosumab experienced more hypocalcaemia (13% vs 6% on zoledronic acid; P<0.0001) and also more osteonecrosis of the jaw (2.3% vs 1.3% on zoledronic acid; P=0.09). Of patients on zoledronic acid, 22% needed dose adjustments and 15% needed doses to be withheld because of impaired renal function. The main advantages of denosumab are the subcutaneous administration and the lack of renal dosing or toxicity; however, the increased costs and risk of osteonecrosis of the jaw have to be taken into account. Denosumab has been FDA approved for the prevention of SREs in patients with bone metastasis from solid tumors. The optimal timing and the sequence of administration of bisphosphonates or the RANKL antibody to prevent SREs in patients with bone metastasis or even possible prevention of bone metastasis needs to be investigated. A randomized, placebo-controlled, phase 3 trial of denosumab versus placebo in 1435 men with CRPC and no detectable bone metastasis has been completed and may answer the question of whether the RANKL inhibitor can prevent the time to development of bone metastases (NCT00286091).

cytotoxic chemotherapy on CTCs in patients with CRPC, the fold change of CTC at 4, 8, and 12 weeks following treatment was the most important prognostic factor in multivariate analyses (P<0.0001), indicating that CTC count falls identify patients likely to benefit from cytotoxic chemotherapy [2•]. For the abiraterone phase 3 trial, CTC data were presented for 972 patients at the American Society of Clinical Oncology (ASCO) annual meeting in 2011. Using standard definitions for unfavorable (CTC ≥5) and favorable (CTC <5) counts were predictive of overall survival as early as 4 weeks after starting treatment with abiraterone, and the inclusion of CTC counts into a multivariate prognostic model significantly reduced the treatment effect at all post-treatment time points (HR 0.74–0.97) [38•]. However, to prove surrogacy, CTCs need to be evaluated in several other large phase 3 trials. CTCs not only can be used as prognostic markers but also can serve as markers to molecularly characterize prostate cancer by using fluorescence in situ hybridization (FISH) and immunohistochemistry for genomic rearrangement of ERG, gain of androgen receptor (AR), or loss of phosphatase and tensin homolog (PTEN), which may assist in the future in allowing individualization of treatments [39••].

Circulating Tumor Cells: A Robust and Rapidly Evolving Biomarker in Advanced Prostate Cancer

Outlook: New Treatment Strategies in Prostate Cancer

Surrogate biomarkers of treatment response in patients with prostate cancer are urgently needed because PSA is an unreliable marker of clinical benefit, most patients lack measurable disease (40% of patients had measurable disease in the TAX 327 and in the Abiraterone phase 3 trial), and imaging modalities currently used for assessment of bone metastasis are inadequate [36]. Baseline circulating tumor cell (CTC) count and changes following treatment are associated with overall survival in prostate cancer, with patients having an unfavorable count of 5 or more CTCs before initiating chemotherapy having a median overall survival of 21.7 months versus 11.5 months in patients with a favorable count of less than 5 CTCs at baseline (P<0.0001; Cox HR 3.3). Even more important is the finding that patients with an unfavorable count of 5 or more CTCs at baseline who had a fall to less than 5 CTCs on treatment had a statistically significant longer median overall survival compared to patients in whom the CTC count remained high (21.3 vs 6.8 months; P<0.0001) [37••]. CTC testing using the CellSearch® (Veridex, LLC, Raritan, NJ) platform is reproducible and highly prognostic in advanced prostate cancer and is FDA approved for routine use. In the IMMC38 trial, which evaluated the impact of

Treatment options for patients with advanced prostate cancer are likely to increase in the next 5 years as a number of novel agents are currently in clinical testing. A complete overview of all new targets and compounds being tested in prostate cancer would be beyond the scope of this article; however, a few compounds deserve mention. MDV3100 is a novel potent antiandrogen inhibiting AR and its nuclear translocation and has been successfully tested in a phase 1/2 study with impressive PSA response rates (≥ 50% PSA drop in 56% of patients) [40•]. It is now being tested in phase 3 studies in patients who are chemonaïve (PREVAIL, planned 1,680 patients, ongoing; NCT01212991) and post-chemotherapy (AFFIRM study, recruitment completed; NCT00974311). Data for the AFFIRM trial have very recently been presented at the ASCO GU meeting 2012 showing a significant OS survival benefit for patients on MDV3100 compared to placebo of 18.4 months compared to 13.6 months respectively (P<0.0001, HR 0.631). MDV3100 offers another exciting treatment options for patients who progressed after docetaxel-based chemotherapy [41]. TAK-700, an oral selective 17,20 lyase inhibitor, has been tested in a phase 1 trial that was reported in 2010. Of 15 patients who received TAK-700, at a dose of

1.9

Mitoxantrone plus prednisone

Docetaxel plus estramustine [45]

4.6

2.4

2.8

Placebo plus prednisone

Mitoxantrone plus prednisone

Placebo

Abiraterone plus prednisone [10••]

Cabazitaxel plus prednisone [13••]

Radium-223 [27••]

14 vs 11.2

15.1 vs 12.7

15.8 vs 11.2

17.5 vs 15.6

18.9 vs 16.5

25.8 vs 21.7

0.695 (0.552–0.875)

0·70 (0.59–0.83)

0.74 (0.64–0.86)

0.8 (0.67–0.97)

0.76 (0.62–0.94)

0.78 (0.61–0.98)

HR (95% CI)

Median PSA: 159 ng/mL Prior chemotherapy: 58% (docetaxel)

Visceral metastasis: excluded

Median PSA: 143 ng/mL Prior chemotherapy: 69% 1 line; 25% 2 lines; 6% >2 lines Median age: 70 years Bone metastasis: 100% LN metastasis: not available

Visceral metastasis: 25%

Soft tissue: 50%

Median age: 68 years Bone metastasis: 80%

Prior chemotherapy: 70% 1 line; 30% 2 lines

LN metastasis: 45% Median PSA: 129 ng/mL

Visceral metastasis: 11%

Median age: 69 years Bone metastasis: 89%

Prior chemotherapy: none

Visceral metastasis: 18% Median PSA: 84 ng/mL

LN metastasis: 24%

Median age: 70 years Bone metastasis: 84%

Median PSA: 114 ng/mL Prior chemotherapy: none

LN metastasis: not reported

Median age: 68 years Bone metastasis: 90% Visceral metastasis: 22%

Median PSA: 52 ng/mL Prior chemotherapy: 20%

Visceral metastasis: excluded

Soft tissue only: 7%; Bone and soft tissue: 42%

Median age: 72 years Bone metastasis: 50.7%

Patient population

OS overall survival, CRPC castration-resistant prostate cancer, HR hazard ratio, PSA prostate-specific antigen, LN lymph node

CRPC post–docetaxelbased chemotherapy

2.4

Mitoxantrone plus prednisone

Docetaxel plus prednisone [15]

4.1

CRPC standard first-line chemotherapy

Placebo

Sipuleucel-T [28••]

OS, mo

CRPC pre-chemotherapy

Comparator

Investigational treatment

Setting

Table 1 Phase 3 trials with OS benefit for patients with CRPC: an overview with focus on patient characteristics

Well-tolerated treatment option for patients with symptomatic bone metastases only. 40% of patients were chemotherapy-naive. Sequencing and combination treatments to be evaluated in clinical trials

Second-line chemotherapy after failure of docetaxel. Careful patient selection and monitoring because of risk of neutropenic sepsis and diarrhea

Well-tolerated therapy option after firstor second-line chemotherapy for patients with bone and/or lymph node metastases. Results of phase 3 trial in chemonaïve patients will likely clarify the place of abiraterone in the treatment of CRPC

Docetaxel and estramustine not widely used because docetaxel and prednisone considered standard

Standard option of chemotherapy for patients with CRPC

Option for patients with small-volume disease, bone metastases only, good performance status

Comment

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300 mg or greater, twice daily for 3 months or more months, 12 (80%) had a PSA response rate of 50% or higher [42]. TAK-700 is currently being evaluated in two phase 3 trials (NCT01193257 and NCT01193244, recruiting patients pre- and post-chemotherapy, respectively). A number of other compounds targeting the AR or androgen biosynthesis are in earlier stages of development, such as ARN-509, AZD3514, ASP9521, and TOK-001 (www.clinicaltrials.gov). Results of a randomized discontinuation trial with cabozantinib, an oral and potent broad spectrum inhibitor of multiple targets (including MET and VEGFR2), were presented at the ASCO annual meeting 2011. Of the 68 evaluable patients with bone metastases from prostate, breast cancer, or melanoma, 59 patients had a partial or complete bone scan resolution [43]. At least six large randomized phase 3 trials are currently ongoing testing combination strategies of docetaxel and prednisone plus a novel agent, including aflibercept (a soluble vascular endothelial growth factor [VEGF] fusion protein binding and neutralizing VEGF), OGX-11 (a clusterin antisense oligonucleotide), dasatinib (an SRC kinase inhibitor), and two endothelin receptor antagonists, zibotentan and atrasentan (www.clinicaltrials.gov). A recent preclinical paper demonstrated reciprocal feedback regulation of the PI3K signaling pathway and AR signalling, supporting strongly the rational to combine AR-targeting drugs with compounds targeting the PI3K/ AKT pathway [44••]. Multiple trials evaluating combined AR and PI3K/AKT targeting are now ongoing.

Conclusions Patients with CRPC previously had one treatment option with a proven survival benefit, but besides standard treatment with docetaxel, four new treatment modalities are now available. However, these advances also impose increasing challenges that will need to be addressed by future research, namely: (1) Sequencing or combination of therapies (immunotherapy, chemotherapy, AR-targeting therapies, targeted therapies, and radiation) and evaluation of crossresistance between different treatment strategies; (2) Robust predictive and prognostic markers for patient selection and discontinuation of ineffective treatments; (3) Health economic evaluations of the different treatment options in an increasingly competitive environment with limited health resources; and, (4) Conduct of scientifically sound, well-powered clinical trials to achieve further progress in the field of CRPC. In summary, significant advances have been achieved for the benefit of patients with CRPC, but the research energy

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has to continue in view of the increasing complexity of selecting the right patients for the different treatments (Table 1). Disclosures Dr. Johann S. de Bono has served as a consultant for Johnson & Johnson, Sanofi-Aventis, Medivation, Astellas, AstraZeneca, Dendreon, Genentech, Pfizer, and GlaxoSmithKline. Dr. de Bono and Dr. Aurelius Omlin are both employees of the Institute for Cancer Research (ICR); the ICR has a commercial interest in abiraterone and PI3K and AKT inhibitors.

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