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.
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 .
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 . 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 . 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 . The initial data seem encouraging; however, whether this drug will impact OS remains to be seen.
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 .
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 . 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 . 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.
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 . 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 , 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 . 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 . Several other trials are currently ongoing, testing CTLA-4 blockade with ipilimumab.
Circulating tumor cells
CTCs are epithelial cells that shed from tumors. In 120 patients with metastatic prostate cancer, Danila et al.  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) .
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 .
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 . 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 .
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 . 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.
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 . 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 . 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 . 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.
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 . 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 . A phase III trial is being planned comparing docetaxel–OGX-011 versus docetaxel in patients with metastatic CRPC, with primary endpoint of OS.
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.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 293–294).
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