SEARCH

SEARCH BY CITATION

Abbreviations
CRPC

castration-resistant prostate cancer

TTP

time to progression

ETA

endothelin-A

ETB

endothelin-B

PAP

prostatic acid phosphatise

GM-CSF

granulocyte-macrophage colony-stimulating factor

The recent famous, or rather infamous, case of Abdulbaset ali Al-Megrahy, the convicted Lockerbie bomber, who was released from a Scottish prison after a panel of doctors declared that he was only likely to survive 3 months, serves to emphasize the improving prospects for patients with castration-resistant prostate cancer (CRPC). More than sixteen months after his release, Al-Megrahy is still alive, reputedly as a result of docetaxel (Taxotere)-based chemotherapy back in Libya, a treatment that he had apparently refused in prison in Scotland.

In fact, a prognosis of only 3 months survival at the time of relapse after hormonal therapy was always likely to be a serious underestimate. For men with CRPC, the median survival in recent phase III studies has ranged from 12.2 to 21.7 months, with improvements in survival seen mostly with docetaxel-based regimens [1–4]. Two publications, both appearing in 2004, firmly established the benefits of this therapy. In the landmark TAX-327 trial, 1006 chemotherapy-naïve CRPC patients were randomized to three different treatment arms: 30 mg/m2 docetaxel every week; 75 mg/m2 docetaxel every 3 weeks; and 12 mg/m2 mitoxantrone every 3 weeks. All patients received 5 mg prednisone orally twice a day. Patients receiving docetaxel every 3 weeks had a significant improvement in survival vs. weekly docetaxel and mitoxantrone (18.9 vs. 16.5 months; P < 0.009). PSA response, pain control and health-related quality of life were also significantly better with docetaxel every 3 weeks compared with mitoxantrone [2]. An update of the results of the TAX-327 trial, published in 2007, showed a survival benefit of docetaxel every 3 weeks compared with mitoxantrone, and no survival benefit with the weekly docetaxel. At 3 years, survival was 17.2% for docetaxel every 3 weeks compared with 12.8% with mitoxantrone (P= 0.005) [3].

The Southwest Oncology Group study, SWOG 99-16, also shows a survival benefit with docetaxel. A total of 674 patients with metastatic CRPC were randomized to docetaxel/estramustine and mitoxantrone/prednisone arms. The treatment regimen was 280 mg estramustine 3 times daily on days 1 to 5, 60 mg/m2 docetaxel on day 2 in the docetaxel arm and 12 mg/m2 mitoxantrone on day 1 plus 5 mg prednisone twice daily in the mitoxantrone arm. Docetaxel was reported to be superior to mitoxantrone with a median survival of 17.5 vs. 15.6 months (P= 0.02), median time to progression [TTP (6.3 vs. 3.2 months; P < 0.001] and PSA declines of 50% (50 vs. 27%; P < 0.001) [4]. These two trials showed a 20–24% reduction in mortality in patients with CRPC treated with docetaxel-based chemotherapy.

There is now new hope for patients who relapse after docetaxel-based therapy. Until recently, treatment was only palliative, as no therapy had been shown to produce a survival benefit in this setting. However, a new generation taxane, cabazitaxel, has been developed to overcome docetaxel resistance, and is now available in USA and, one hopes, soon in Europe. Cabazitaxel, similar to docetaxel, is a semi-synthetic microtubule stabilizer extracted from the needles of the European Yew tree. In preclinical studies, cabazitaxel offered the advantage of being active in vitro and in vivo in cell lines and tumour models resistant to docetaxel, and showed a better blood-brain barrier penetration than other taxanes [5,6]. In tumour models sensitive to docetaxel, its antitumour activity is comparable with docetaxel [5,6]. In a large phase III trial, 755 patients with metastatic CRPC progressing during or after docetaxel treatment were randomized to receive cabazitaxel (25 mg/m2 every 3 weeks) plus prednisone/prednisolone (10 mg daily) or mitoxantrone (12 mg/m2 every 3 weeks) plus prednisone/prednisolone, an active treatment commonly used for palliation at this stage of the disease. The primary endpoint was overall survival. Cabazitaxel significantly reduced the risk of death by 30%[hazard ratio (HR) 0.70 (95% CI 0.59–0.83), P < 0.001] with a median overall survival of 15.1 vs. 12.7 months with mitoxantrone. Progression-free survival, tumour response and PSA response were also significantly improved with cabazitaxel compared with mitoxantrone [7]. In this population, with very advanced disease and heavily pretreated with chemotherapy, the most frequent grade 3/4 adverse events observed with cabazitaxel vs. mitoxantrone were neutropenia (81.7 vs. 58%), febrile neutropenia (7.5 vs. 1.3%) and diarrhoea (6.2 vs. 0.3%). Patients should be carefully monitored for these adverse events, especially at treatment initiation, but if they occur they are manageable.

The prospects for further improvements in survival for men with CRPC are even more promising, considering that several molecules targeting angiogenesis (aflibercept), endothelin receptor (atrasentan, zibotentan), steroid receptor coactivator (dasatinib), RANK Ligand (denosumab) and immune response (sipuleucel-T, prost-vac VF) are either in a late stage of development (phase III) or actually launched (sipuleucel-T). These have been the subject of a recent review [8], but shortage of space precludes the possibility of discussing all of them here.

Among a number of novel targets being evaluated are several endothelin receptor antagonists. Endothelins (endothelin-1, endothelin-2 and endothelin-3) are regulators of cell proliferation, vasomotor tone and angiogenesis. The endothelins bind to two receptors, endothelin-A (ETA) and endothelin-B (ETB), and play a major role in tumour growth, proliferation, apoptosis, angiogenesis and bone metastasis [9]. Patients with metastatic prostate cancer have elevated levels of plasma endothelin-1 compared with patients with organ-confined cancer. ETA is thought to promote osteoblastic activity characteristic of bone metastases in prostate cancer [10].

Atrasentan, predominantly an ETA receptor antagonist, was studied in two phase III trials. In the first study, 809 patients with CRPC were randomized to 10 mg atrasentan daily vs. placebo [11]. The primary endpoints were TTP which was determined according to radiographic and clinical measures. Atrasentan did not reduce the risk of disease progression relative to the placebo (HR 0.89, P= 0.136). In exploratory analyses, however, bone alkaline phosphatase and PSA levels were significantly lower in the atrasentan arm. Atrasentan generally was tolerated well, and the most common adverse events associated with treatment were headache, rhinitis and peripheral oedema, reflecting the vasodilatory and fluid-retention properties of ETA receptor blockade. In a second phase III trial, 941 men with PSA-only CRPC were randomized to receive 10 mg atrasentan daily vs. placebo.

Although not statistically significant, fewer patients treated with atrasentan experienced disease progression compared with placebo (P= 0.288) and the median survival was longer for the atrasentan group (P= 0.176). Although it did not meet the primary endpoint expectations, atrasentan did have an impact on molecular markers that indicate disease progression. There was improvement in bone alkaline phosphatase [−1.51 IU/L (atrasentan) vs. +2.2 IU/l (placebo); P= 0.001] and PSA doubling time was delayed (P= 0.031). An ongoing phase III study, the Southwest Oncology Group trial, SWOG S0421, is evaluating atrasentan in combination with docetaxel/prednisone as a first-line treatment in metastatic CRPC.

Zibotentan (ZD4054) is a specific ETA receptor antagonist that, unlike atrasentan, has no detectable activity at the ETB receptor. The results of early clinical trials supported a large phase II trial in men with CRPC. A randomized, double-blind, placebo-controlled, parallel-group, phase II trial was undertaken in 65 centres in 14 countries across Europe, North America, Australasia and South East Asia. A total of 312 patients with hormone-refractory prostate cancer and bone metastases, who were pain free or mildly symptomatic for pain, were recruited and randomized to receive 10 mg (n= 107) or 15 mg (n= 98) zibotentan once daily, or matching placebo (n= 107). The primary endpoint was TTP, defined as clinical progression, requirement for opiate analgesia, objective progression of soft-tissue metastases, or death in the absence of progression. PSA progression and change in the number or appearance of bone metastases on scintigraphic imaging did not count as progression events. Secondary endpoints included overall survival, PSA progression and safety.

At the primary analysis, no statistically significant difference in TTP was observed for zibotentan vs. placebo [10 mg: HR 0.88, (80% CI 0.71, 1.09); 15 mg: HR 0.83 (80% CI 0.66, 1.03)]. However, a promising signal for prolonged overall survival was observed in the zibotentan treatment groups vs. placebo, based on 40 deaths [10 mg zibotentan: HR 0.38 (80% CI 0.22, 0.64), P= 0.019; 15 mg zibotentan: HR 0.61 (80% CI 0.38, 0.99), P= 0.190]. At the second analysis, after 118 deaths, the survival benefit was sustained [HR vs. placebo: 10 mg zibotentan: HR 0.55 (80% CI 0.41, 0.73), P= 0.008; 15 mg zibotentan: HR 0.65 (80% CI 0.49, 0.86), P= 0.052], while there continued to be no significant difference in TTP. Median overall survival was 24.5 and 23.5 months in the 10 mg and 15 mg zibotentan treatment groups, respectively, vs. 17.3 months in the placebo group. At the final analysis, a total of 211 (68%) deaths had occurred. There was a promising signal for overall survival [HR vs. placebo: 10 mg zibotentan: HR 0.83 (80% CI 0.67, 1.02), P= 0.254; 15 mg zibotentan: HR 0.76 (80% CI 0.61, 0.94), P= 0.103], while there continued to be no significant difference in TTP. Median overall survival was 24.5 and 23.5 months in the 10 mg and 15 mg zibotentan treatment groups, respectively, vs. 17.3 months in the placebo group. Consistent with the previous analyses, no statistically significant differences were observed in TTP for either 15 mg zibotentan vs. placebo [HR 0.86 (80% CI 0.72–1.04), P= 0.309] or 10 mg zibotentan vs. placebo [HR 1.06 (80% CI 0.89–1.27), P= 0.673] at the final analysis. No significant differences were observed in time to PSA progression. Adverse events were in line with the expected pharmacodynamic effects of an ETA receptor antagonist, most commonly headache, peripheral oedema and nasal congestion [12–15].

The promising improvement in overall survival with zibotentan seen in the phase II study supports further investigation in phase III clinical trials, with overall survival as the primary endpoint. The zibotentan ETA inhibitor use (ENTHUSE) phase III clinical trial programme consists of three randomized, double-blind trials, which together will include more than 3000 patients with HRPC across more than 400 centres worldwide.

There is also considerable anticipation, and a good deal of media coverage, concerning the prospects for abiraterone. Several preclinical and clinical studies have shown that despite being ’hormone refractory‘, prostate cancer cells continue to have high androgen receptor expression and thus mediate androgen signalling. Abiraterone acetate is a potent and highly selective irreversible inhibitor of cytochrome P-17 (17 a hydroxylase and C17,20-lyase), a dual enzyme that blocks adrenal androgen production [16].

In a study of 58 patients who had progressive metastatic CRPC and had failed hormonal therapy and up to two cytotoxic regimens, including docetaxel, were treated with abiraterone (1000 mg once daily) and prednisone (5 mg twice daily). Of 56 patients 25 (45%) had a PSA decline ≥50%. The median time to PSA progression was 169 days. The majority of abiraterone-related adverse events were grades 1–2 and no grade 4 adverse events were reported. A significantly better PSA response in the ketoconazole-naïve post-docetaxel CRPC population was also noted. A randomized phase III pivotal study to confirm these results is ongoing [17].

Recent evidence has also indicated an important role for vaccine-based immunotherapy in CRPC. Sipuleucel-T (Provenge) consists of autologous peripheral blood mononuclear cells, including antigen-presenting cells, that have been activated during a defined culture period with a recombinant fusion protein consisting of prostatic acid phosphatase (PAP), an antigen expressed in prostate cancer tissue, linked to granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune cell activator. The patient’s peripheral blood mononuclear cells are obtained via a standard leukapheresis procedure approximately 3 days before the infusion date. The active components are autologous antigen presenting cells and human PAP-GM-CSF fusion protein. During culture, the recombinant antigen can bind to and be processed by antigen-presenting cells into smaller protein fragments. The recombinant antigen is designed to target antigen-presenting cells, and may help direct the immune response to PAP. Minimal residual levels of the intact human PAP-GM-CSF fusion protein are detectable in the final sipuleucel-T product. The cellular composition of sipuleucel-T is dependent on the composition of cells obtained from the patient’s leukapheresis. The activated, antigen-loaded APCs are then infused into the patient, where it can potentially stimulate a T-cell response against prostate cancer cells. The process is performed three times over the course of a 4-week period. The vaccine has been studied in three phase III clinical trials. In the first phase III study, D9901, consisting of 127 men with asymptomatic, metastatic CRPC, sipuleucel-T every 2 weeks for three cycles was compared 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 [14]. In another similar phase III trial, D9902A, 98 men with asymptomatic, metastatic CRPC demonstrated a 21.4% improvement in overall survival for patients randomized to sipuleucel-T. In both studies, the vaccine was well tolerated, and the most common adverse events were chills and fatigue. The third phase III trial, D9902B, also known as the IMPACT trial (immunotherapy for prostate adenocarcinoma treatment) was a randomized, double-blind, placebo-controlled study comparing Provenge with placebo in 512 men with CRPC randomized in 2:1 ratio. The median overall survival favoured the vaccine arm with a 4.1-month increase in overall survival for patients treated with sipuleucel-T (25.8 vs. 21.7 months; P= 0.032). Also, the 36-month survival probability was 31.7% in the sipuleucel-T group vs. 23.0% in the placebo group. Therapy with sipuleucel-T was also associated with a positive overall survival effect in an analysis that included 18 additional deaths observed between the data-cutoff and study-completion dates, with a median of 36.5 months of follow-up [HR 0.76 (95% CI 0.61–0.95), P= 0.02][18]. Sipuleucel-T is the first active immunotherapy to demonstrate an improvement in overall survival for advanced prostate cancer. Given the short duration of the therapy (1 month) and its favourable benefit-to-risk ratio, sipuleucel-T provides an attractive new option for the management of advanced prostate cancer. It remains to be shown that this treatment, and indeed most of the other treatment options discussed above, result in improved health-related quality of life as well as improved survival, particularly as health-related quality of life can often be severely affected by CRPC [19].

Much of the political storm surrounding the release of Mr Al-Megrahy stems from the erroneous medical conclusion that he only had 3 months to live. If any of the new agents mentioned above, or others in the pipeline [20], are added to his current purative docetaxel-based chemotherapy regime, it seems possible that he may survive a good deal longer yet. In which case, the controversy surrounding his release on compassionate grounds and return to Libya seems only likely to grow.

CONFLICT OF INTEREST

  1. Top of page
  2. CONFLICT OF INTEREST
  3. REFERENCES

None declared.

REFERENCES

  1. Top of page
  2. CONFLICT OF INTEREST
  3. REFERENCES
  • 1
    Saad F, Gleason DM, Murray R et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002; 94: 145868
  • 2
    Tannock IF, de Wit R, Berry W et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 150212
  • 3
    Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival of Tax 327. J Clin Oncol 2008; 26: 2425
  • 4
    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: 151320
  • 5
    Mita AC, Denis LJ, Rowinski EK et al. Phase I and pharmacokinetic study of XRP6258 (RPR116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res 2009; 15: 72330
  • 6
    Pivot X, Koralewski P, Hidalgo JL et al. A multicenter phase II study of XRP6258 administered as a 1-h i.v. infusion every 3 weeks in taxane-resistant metastatic breast cancer patients. Ann Oncol 2008; 19: 154752
  • 7
    De Bono JS, Oudard S, Ozguroglu M et al. Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: final results of a multinational phase III trial (TROPIC). J Clin Oncol 2010; 28 (Suppl.): 450815
  • 8
    Fizazi K, Sternberg CN, Fitzpatrick JM, Watson RW, Tabesh M. Role of targeted therapy in the treatment of advanced prostate cancer. BJU Int 2010; 105: 74867
  • 9
    Thakkar SG, Choueiri TK, Garcia JA. Endothelin receptor antagonists: rationale, clinical development, and role in prostate cancer therapeutics. Curr Oncol Rep 2006; 8: 10813
  • 10
    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: 9449
  • 11
    Carducci MA, Saad F, Abrahamsson P 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: 195966
  • 12
    Warren R, Liu G. ZD4054: a Specific Endothelin A receptor antagonist with promising activity in metastatic castration-resistant prostate cancer. Expert Opin Investig Drugs 2008; 17: 123745
  • 13
    James ND, 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 II trial. Eur Urol 2009; 55: 111223
  • 14
    James ND, Caty A, Payne H et al. Final safety and efficacy analysis of the specific endothelin A receptor antagonist zibotentan (ZD4054) in patients with metastatic castration-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic for pain: a double-blind, placebo-controlled, randomized Phase II trial. BJU Int 2010; 106: 96673
  • 15
    Dawson N, Payne H, Battersby C, Taboada M, James N. Health-related quality of life in pain-free or mildly symptomatic patients with metastatic hormone-resistant prostate cancer following treatment with the specific endothelin A receptor antagonist zibotentan (ZD4054). J Cancer Res Clin Oncol 2011; 137: 99113 [Epub ahead of print] doi: 10.1007/s00432-010-0864-1
  • 16
    Attard G, Belldegrun AS, de Bono JS. Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer. BJU Int 2005; 96: 12416
  • 17
    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: 308994
  • 18
    Kantoff P, Higano C, Shore D et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 41121
  • 19
    Berthold DR, Pond GR, Roessner M et al. Treatment of hormone-refractory prostate cancer with docetaxel or mitoxantrone: relationships between prostate-specific antigen, pain, and quality of life response and survival in the TAX-327 study. Clin Cancer Res 2008; 14: 27637
  • 20
    Vishnu P, Tan WW. Update on options for treatment of metastatic castration-resistant prostate cancer. Oncol Targets Ther 2010; 3: 3951