Prostate cancer is an androgen-dependent cancer that initially responds but later develops resistance to established endocrine therapies which work by reducing circulating testosterone levels or inhibiting androgen binding to the androgen receptor (AR). Castration-resistant prostate cancer (CRPC) is defined by disease progression despite androgen deprivation therapy (ADT) and may present as either a continuous rise in serum PSA levels, the progression of pre-existent disease, and/or the appearance of new metastases.¹

Introduction

Up until recently the options for metastatic CRPC (mCRPC) were limited. The TAX 327 study was the first to demonstrate a survival benefit in this group of patients using docetaxel plus prednisolone.² Recent years have seen major advances in the treatment of mCRPC with improvements in overall survival (OS) in phase III studies with several agents, and other agents under investigation. 

In this article, the authors will review these novel therapies including sipuleucel-T, cabazitaxel, abiraterone acetate (AA), enzalutamide (MDV3100), alpharadin (radium-223 chloride), cabozantinib and the bone-modifying agents denosumab and zoledronic acid.

Novel therapies

Sipuleucel-T

Sipuleucel-T (Provenge, Dendreon Corporation) is an autologous dendritic cell therapeutic vaccine designed to stimulate an immune response against prostate cancer.³ It was approved by the US Food and Drug Administration (FDA) in April 2010 for patients with mCRPC who are asymptomatic or minimally symptomatic. The effect of sipuleucel-T was studied in three similar, randomised double blind placebo-control phase III studies: D9901, D9902A and IMPACT. 

In the first two, the primary endpoint was progression-free survival (PFS) with overall survival (OS) a secondary endpoint,³ while in the larger IMPACT study OS was the primary endpoint.⁴ In all three trials, patients were randomly assigned in a 2:1 ratio to sipuleucel-T or a placebo vaccine. Sipuleucel-T or the placebo was infused on weeks 0, two and four. Patients with visceral metastases or requiring opioid analgesics were excluded. Patients being treated with a gonadotropin-releasing hormone (GnRH) agonist at enrolment continued this therapy during therapeutic vaccine treatment. Crossover from placebo to sipuleucel-T at progression was allowed at physician discretion. Combined analysis of 225 men enrolled in the D9901 and D9902 studies revealed a non-significant trend toward increased time to progression with sipuleucel-T compared with the control (11.1 versus 9.7 months, p = 0.11).³ Although the increase in PFS was not statistically significant, OS was significantly longer in the sipuleucel-T group compared with placebo (median OS 23.2 versus 18.9 months, hazard ratio [HR] 0.67, 95% CI 0.49-0.91, p = 0.011).

The larger IMPACT study, with 512 men enrolled, showed a significant improvement in the primary endpoint of OS with sipuleucel-T versus placebo (median 25.8 months versus 21.7 months, HR 0.78, 95% CI 0.61-0.98, p = 0.03).⁴ As in D9901 and D9902, PFS was not significantly prolonged (14.6 versus 14.4 weeks, HR 0.95; 95% CI, 0.77 to 1.17; p = 0.63) and there were no significant differences in serum PSA level changes. Although sipuleucel-T significantly prolonged OS, it rarely induced disease regression and did not have a perceptible effect on radiographic progression-free survival (rPFS). Sipuleucel-T is not currently approved for use outside the US, but is enrolling patients in Europe as part of open label study to support its marketing authorisation with the European Medicines Agency (EMA).

Cabazitaxel

Cabazitaxel (Jevtana, Sanofi Aventis) is a novel taxane chemotherapy drug. It binds to tubulin, promoting assembly into microtubules and inhibiting disassembly. This prevents microtubule depolymerisation and cell division, arresting the cell cycle and inhibiting tumour proliferation. Unlike other taxanes, cabazitaxel has a poor affinity for multidrug resistance (MDR) proteins, therefore conferring activity in resistant tumours. It was approved by the FDA in June 2010 and by the EMA in April 2011 for mCRPC following treatment failure with docetaxel chemotherapy, after it became the first chemotherapy drug to demonstrate a survival benefit in this setting. Initial phase I and II clinical studies indicated promising efficacy in various solid tumours, and established neutropaenia as the primary dose limiting toxicity.^5,6 The randomised multicentre phase III TROPIC study randomised 755 men with mCRPC to cabazitaxel or the previous chemotherapy standard in the post-docetaxel setting, mitoxantrone.⁷ The primary endpoint was OS, while secondary endpoints included PFS and safety. Participants were treated with 10mg of oral prednisolone daily, and were randomly assigned to receive 12mg/m² mitoxantrone intravenously (IV) or 25mg/m² cabazitaxel IV every three weeks. The median OS was 15.1 months in the cabazitaxel group and 12.7 months in the mitoxantrone group (HR 0.70, 95% CI 0.59-0.83, p < 0.0001). Median PFS was also significantly longer with cabazitaxel (2.8 versus 1.4 months, HR 0.74, 95% CI 0.64-0.86, p < 0.0001). 

The most common clinically significant adverse effects were neutropaenia (cabazitaxel 82% versus mitoxantrone 58%), and diarrhoea (6% versus <1%). Eight per cent of patients in the cabazitaxel group and 1% in the mitoxantrone group had febrile neutropenia. This represents an important chemotherapeutic option in the post-docetaxel setting.

Abiraterone acetate

Abiraterone acetate (AA [(Zytiga, Janssen]) selectively and irreversibly inhibits CYP17 (17 alpha-hydroxylase/C17,20-lyase), an enzyme required for androgen biosynthesis which is expressed in testicular, adrenal and prostatic tumour tissues. It inhibits the formation of the testosterone precursors dehydroepiandrosterone (DHEA) and androstenedione. It gained FDA approval in April 2011 and EMA approval in September 2011 for treatment of men with mCRPC following docetaxel chemotherapy. An initial phase I study established safety and preliminary efficacy.⁸ Based on these results, a phase II study enrolled 58 patients with progressive mCRPC who had failed docetaxel therapy to evaluate the efficacy and safety of AA in combination with prednisolone.⁹ The results were encouraging, with 36% of patients experiencing greater than 50% reduction in PSA. The incidence of mineralocorticoid-related toxicities (hypokalaemia/hypertension) were reduced by adding low-dose prednisolone. 

A subsequent phase III study (COU-AA-301) enrolled 1,195 patients with mCRPC previously treated with docetaxel.¹⁰ They were randomised to AA (1,000mg orally daily) or placebo in a 2:1 ratio. Both groups received prednisolone 5mg bd orally. A significant improvement in OS was seen in the AA arm (15.8 months versus 11.2 months, HR 0.74, 95% CI 0.64-0.86; p < 0.0001). Median time to PSA progression (8.5 months versus 6.6 months), median radiographic progression-free survival (5.6 months versus 3.6 months), and PSA response rate (29.5% versus 5.5%) all favoured the AA treatment group (p < 0.0001). AA has also been investigated in the pre-docetaxel setting in the phase III COU-AA-302 study.¹¹ There were 1,088 patients randomised to AA plus prednisolone versus placebo plus prednisolone, with the co-primary endpoints of OS and rPFS. At interim analysis there was a significant improvement in rPFS (16.5 versus 8.3 months, HR 0.53; 95% CI 0.45 to 0.62; p < 0.001) and a trend towards improved survival which as yet has not met the pre-specified boundary for significance, although mature results are eagerly awaited.

Enzalutamide

Enzalutamide (Xtandi, Astellas), formerly called MDV 3100, is a pure androgen receptor signaling inhibitor that inhibits androgen receptor nuclear translocation, DNA binding, and co-activator mobilisation, leading to cellular apoptosis and decreased prostate tumour volume. It has no agonist activity. It was approved by the FDA in August 2012 for the treatment of patients with mCRPC who have previously received docetaxel, and is awaiting EMA approval. 

A phase I/II study enrolled 140 patients with progressive mCRPC who received enzalutamide at doses of 30mg to 600mg orally daily.¹² Reductions in PSA of 50% or more were seen in 56% of patients. In the double-blind phase III AFFIRM study 1,199 men with mCRPC were randomly assigned in a 2:1 ratio to receive oral enzalutamide at a dose of 160mg per day or placebo.¹³ Enzalutamide was superior to placebo with respect to all secondary endpoints: the proportion of patients with a reduction in the PSA level by 50% or more (54% versus 2%), soft-tissue response rate (29% versus 4%), quality-of-life response rate (43% versus 18%), time to PSA progression (8.3 versus 3.0 months), rPFS (8.3 versus 2.9 months), and time to the first skeletal-related event (16.7 versus 13.3 months). 

With regards to toxicity, the enzalutamide group experienced higher rates of fatigue, diarrhoea and hot flashes. An important, although rare, toxicity is seizures, reported in five patients (0.6%) receiving enzalutamide.

Radium-223 

Alpharadin (Alpharadin, Bayer [radium-223 chloride]) is an alpha particle-emitting radiopharmaceutical that has been evaluated in patients with CRPC and multiple symptomatic bone metastases. The decay of radium-223 allows the deposition of high-energy radiation over a much shorter distance if compared with beta-particle-emitting radioisotopes, thus potentially treating tumour while minimising toxicity. Alpharadin has not yet been approved by the FDA and EMA. It is currently available in Ireland through an expanded access protocol for patients who have symptomatic bone metastases and who are not candidates for, or refuse, docetaxel chemotherapy (NCT 01516762).

The phase III randomised ALpharadin in SYMptomatic Prostate CAncer (ALSYMPCA) study demonstrated increased OS and a reduction in the incidence of serious skeletal-related events.^14,15 The study enrolled men with mCRPC with multiple bone metastases who had either progressed on docetaxel chemotherapy or were not candidates for docetaxel. Patients were required to have two or more bone metastases, and those with known visceral metastases were excluded. Generally radium-223 was well tolerated with only minimal increases in bone marrow suppression (grade 3 or 4 neutropenia 1.8 versus 0.8%, and grade 3 or 4 thrombocytopenia 6 versus 2%). Alpharadin is an attractive option for patients with slowly progressive bone metastases, particularly those unsuitable for docetaxel chemotherapy.

Cabozantinib

Cabozantinib (Cometriq, Exelixis [previously XL184]) is a potent oral tyrosine kinase inhibitor of MET and vascular endothelial growth factor receptor-2 (VEGFR2).¹⁶ It is not yet approved by the FDA or EMA. It has shown preliminary evidence of activity against bone metastases in patients with castration-resistant prostate cancer in a phase II randomized discontinuation trial, with primary endpoints of objective response rate at 12 weeks and progression free survival (PFS).¹⁶ 

One hundred and seventy-one patients with mCRPC received 12 weeks of treatment with cabozantinib. After the initial treatment, patients with a partial or complete response were allowed to continue treatment in an open-label extension. Seventy-five per cent of evaluable patients had stable disease per Response Evaluation Criteria In Solid Tumors (RECIST) at week 12 and were randomly assigned to cabozantinib or placebo. Thirty-one patients with stable disease at week 12 were randomised before random assignment was halted early based on the observed activity of cabozantinib. Among these patients, PFS following randomisation was significantly longer with cabozantinib when compared with placebo (23.9 weeks versus 5.9 weeks, hazard ratio 0.12; p < 0.001). 

Among all cabozantinib-treated patients, 72% had regression of soft tissue lesions and 68% of evaluable patients had improvement on bone scan, including 12% with complete resolution. Subjective improvement in bone pain was seen in 67% of cases, and 56% decreased or stopped narcotic usage. Key grade ≥ 3 toxicities included fatigue in 16%, hypertension in 12% and hand-foot syndrome in 8%. Cabozantinib is currently being evaluated in the double-blind placebo-controlled phase III COMET-1 study, with results expected in the first half of 2014.

Denosumab

Denosumab (Xgeva, Amgen) is a human monoclonal antibody against RANK-ligand, the main driver of osteoclast formation, function and survival – as a result, it inhibits osteoclast-mediated bone destruction. Denosumab is approved for the treatment of bone loss in men receiving ADT (as Prolia) and for the prevention of skeletal-related events in men with mCRPC and bony metastases (as Xgeva). In the mCRPC setting, it was compared to the standard therapy of zoledronic acid in preventing skeletal-related events in men with bony metastases.¹⁷ 

There were 1,904 men with mCRPC, no previous exposure to intravenous bisphosphonate, and at least one bone metastasis randomised to receive denosumab 120mg subcutaneously plus intravenous placebo, or 4mg intravenous zoledronic acid plus subcutaneous placebo every four weeks. Calcium and vitamin D supplementations were strongly recommended on both treatment arms. 

The primary endpoint was time to first on-study skeletal-related event (defined as pathological fracture, radiation therapy, surgery to bone, or spinal cord compression). Median time to first on-study skeletal-related event was 20.7 months (95% CI 18.8-24.9) with denosumab versus 17.1 months (15.0-19.4) with zoledronic acid ([HR] 0.82, 95% CI 0.71-0.95 p = 0.0002 for non-inferiority, p = 0.008 for superiority). There was no difference in time-to-progession or OS. Osteonecrosis of the jaw (ONJ) occurred in 2% of patients treated with denosumab and 1% treated with zoledronic acid (p = 0.09). A key toxicity with these agents is hypocalcaemia, which occurred at ≥ G3 in 5% of denosumab and 1% of zoledronic acid patients.

Sequencing strategies

With a wealth of new therapies available or on the horizon for mCRPC, the question of how best to sequence these agents becomes more important. Do some therapies work better in the pre- and post-chemotherapy settings, and will use of drug X prior to drug Y cancel its efficacy? 

To a large extent the answers to these questions are unknown. There are limited data for abiraterone response after prior enzalutamide,¹⁸ and none for the reverse sequence. Recent results suggest that response rate to cabazitaxel may be maintained in patients who have received abiraterone in addition to docetaxel.¹⁹ It is essential that the effects of sequencing strategies are explored further, in order to maximise the potential benefits for our patients. In the meantime, current sequencing options are to a large extent dictated by the availability of novel therapies via expanded access programmes and the National Cancer Control Programme (NCCP).  

References

1. Saad F, Hotte SJ. Guidelines for the management of castrate-resistant prostate cancer. Can Urol Assoc J 2010; 4(6): 380-384
2. Tannock IF, De Wit R, Berry WR et al . Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351(15): 1502-1512
3. Higano CS, Schellhammer PF, Small EJ et al. Integrated data from 2 randomized , double blind ,placebo-controlled, Phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 2009; 115(16): 3670-3679
4. Kantoff PW, Higano CS, Shore ND et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411-422
5. Mita AC, Denis LJ, Rowinsky EK et al. Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res 2009; 15: 723-730
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: 1547-1552
7. de Bono JS, Oudard S, Ozguroglu M et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment : a randomized open-label trial. Lancet 2010; 376; 1147-1154
8. Attard G, Reid A, Yap T et al. Phase I clinical trial of selective inhibitor of CYP17, Abiraterone Acetate, confirms that castration- resistant prostate cancer commonly remains hormone driven. J Clin Oncol 2010; 28(9): 1481-1488
9. Danila D, Morris M, Bono JS et al. Phase II multicenter study of Abiraterone Acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol 2010; 28(9): 1496-501
10. Fizazi K, Scher HI, Molina A et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012; 13(10): 983-992
11. Ryan CJ, Smith MR, De Bono JS et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368(2): 138-148
12. Scher HI, Beer TM , Higano CS , et al , Antitumour Activity of MDV3100 in castration resistant prostate cancer : a phase 1-2 study. Lancet 2010; 375: 1437-1446
13. Howard IS ,Fizazi K , Saad F et al.Increased survival with Enzalutamide  in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187-1197
14. Parker C, Nilsson S, Heinrich Det al. Updated analysis of the phase III, double-blind, randomized, multinational study of radium-223 chloride in castration-resistant prostate cancer (CRPC) patients with bone metastases (ALSYMPCA). J Clin Oncol 30, 2012 (suppl; abstr LBA4512)
15. Sartor AO, Heinrich D, O’Sullivan JM et al. Radium-223 chloride (Ra-223) impact on skeletal-related events (SREs) and ECOG performance status (PS) in patients with castration-resistant prostate cancer (CRPC) with bone metastases: Interim results of a phase III trial (ALSYMPCA). J Clin Oncol 2012 (suppl; abstr 4551)
16. Smith DC, Smith MR, Sweeney C et al. Cabozantinib in patients with advanced prostate cancer : results of a phase II randomized discontinuation trial. J Clin Oncol 2013; 31(4): 412-419
17. Fizazi K, Carducci M, Smith M et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011; 377(9768): 813-822
18. Ileana E, Loriot Y, Albiges L et al. Abiraterone in patients with metastatic castration-resistant prostate cancer progressing after docetaxel and MDV3100. J Clin Oncol 30, 2012 (suppl; abstr 4554)
19. Pezaro CJ, Le Moulec S, Albiges L et al. Response to cabazitaxel in CRPC patients previously treated with docetaxel and abiraterone acetate. J Clin Oncol 31, 2013 (suppl 6; abstr 155)