Prostate carcinoma is an important health problem in Ireland and the number of new cases in Ireland is increasing. In 1999 there were 1,492 cases as compared to 3,014 in 2010. The number of cases has more than doubled in men between the ages of 55 and 64.¹

Screening for prostate carcinoma is not recommended in Ireland currently; however, informal screening is common and this has undoubtedly led to a significant increase in the incidence of prostate cancer. In the US, since the introduction of prostate-specific antigen (PSA) screening more than 1.3 million men have been diagnosed with prostate cancer and one million of these have undergone treatment.²

When cases of non-melanoma skin cancers are excluded, prostate cancer is the most commonly diagnosed cancer overall in males and comprises almost one-third of all cancers in men.¹ In 2010, 533 males died from prostate cancer in Ireland with both prostate and colorectal cancer comprising 12.2% of all cancer deaths, which was second only to lung carcinoma (22.4%) which accounted for the majority of cancer-related deaths in males.¹

Ireland has the fourth-highest incidence of prostate cancer of the 27 European countries, after Norway, France and Sweden, with rates more than 50% higher than the EU average in 2010. With regard to mortality, although still 17% higher than the EU average and ranked 12th highest overall, the mortality/incidence ratios in Ireland however were second-lowest after France – with one death for every 10 men diagnosed. The mortality/incidence ratios tended to be higher in eastern Europe with four or five deaths for every 10 diagnosed cases, for example, Romania, Bulgaria and Greece.¹

Epidemiological risk factors

A variety of risk factors have been shown to be important in defining prostate cancer risk. Dietary factors, lifestyle-related factors and androgens have long been recognised as contributors to the risk of prostate cancer.

Ethnic differences

The highest incidence rates occur among black American men, for whom the age-standardised rates are 50-60% higher than those for white American men. The lowest rates of prostate cancer are typically found in Asian countries.^3,4

Genetic

Apart from age, the most consistent risk factor for prostate cancer found is occurrence of the disease in a close relative. A first-degree relative with prostate cancer increases the risk of the disease by about 2-2.5 times among black, white and Asian men.⁵ Different study groups have supplied evidence for the occurrence of a prostate cancer gene (HPC1 – hereditary prostate cancer 1) located on the short arm of chromosome 1.^6,7 Further research is needed to identify the specific mutated locus within this region, which contains 20 million base pairs. Other candidates have been proposed including several genes on the X chromosome, such as the androgen receptor gene and the vitamin D receptor gene.^8,9,10

Dietary

The total fat intake, especially animal fat intake, has been associated with an increased risk of prostate cancer. Consumption of red meat also correlates with an increased risk of development of prostate cancer.^11,12,13

Oncologic treatment

Importance of androgens in prostate carcinoma

Androgens such as testosterone and dihydrotestosterone are important in growth and differentiation of the prostate gland. Androgen signalling is important in prostate tumour growth and targeting this pathway has been an important treatment strategy in prostate cancer. Huggins and Hodges first showed in the 1940s that surgical orchidectomy could lead to prostate cancer regression.¹⁴ Since then, androgen suppression treatment, through the use of gonadotropin-releasing hormone (GnRH) agents (predominantly agonists and, recently, antagonists), has played a pivotal part in the systemic treatment for metastatic prostate cancer. 

In the majority of cases androgen suppression results in PSA responses, however relapse almost invariably ensues. Relapse usually occurs within 12-24 months, as demonstrated by rising PSA, radiologic worsening or deterioration of a patient’s symptoms.¹⁵ Disease at this juncture has previously been considered to be ‘androgen-independent’, ‘hormone-refractory’ or ‘hormone-resistant’. However, these terms are very misleading, since androgen receptor expression is almost never lost in these cases. Further evidence and observation has shown that, in many cases, the response to residual levels of androgens or other circulating hormones in a particular patient could be amplified due to one of several factors, including mutations of the androgen receptor (AR) and alteration in levels of cofactor proteins, and therefore disease would still be sensitive to further hormonal manipulation.¹⁶ For this reason, the term ‘castration-resistant’ is now widely accepted and preferred in this setting. 

Androgen deprivation therapy

Androgen deprivation therapy (ADT) is the initial gold standard therapy in metastatic prostate carcinoma. Luteinising hormone-releasing hormone (LHRH) agonist or antagonist (medical castration) as compared to bilateral orchidectomy (surgical castration) are equally efficacious. Anti-androgen therapy should precede or be administered for at least seven days along with an LHRH agonist in patients with metastatic disease who are at an increased risk of developing symptoms associated with their metastatic disease, as an initial flare of testosterone is seen with use of an LHRH agonist alone. These flare symptoms include exacerbation of pain, increase in uraemia, development of neurological sequelae, and possibly death. Adverse effects associated with ADT include hot flashes, loss of libido, detrimental effect on bone health and adverse cardiovascular risk. Screening and intervention for osteoporosis and adverse cardiovascular risk factors is recommended for patients on ADT. 

Once primary ADT fails the treating physician may consider second-line hormonal manipulation. This is based on performance status and patient symptoms. If patients are asymptomatic and chemotherapy naïve, one can consider using a different anti-androgen (for example, flutamide, bicalutamide), or use of an androgen synthesis inhibitor such as ketoconazole. If patients have failed ADT and have metastatic disease and are symptomatic, then they must be considered for systemic therapy.

Metastatic castrate-resistant prostate carcinoma

Chemotherapy

Despite the proven success of hormonal therapy for prostate cancer using chemical or surgical castration, most patients eventually will progress to a phase of the disease that is metastatic and shows resistance to further hormonal manipulation. This has been termed metastatic castrate-resistant prostate cancer (mCRPC). However, as previously mentioned, evidence suggests that androgen receptor mediated signalling and gene expression can persist in mCRPC, even in the face of castrate levels of androgen. This can be due to several different reasons: upregulation of enzymes involved in androgen synthesis, the overexpression of AR, or the emergence of mutant ARs with promiscuous recognition of various steroidal ligands and molecular cross-talk with other signalling pathways and co-regulators that lie downstream of the AR.¹⁷ Studies have suggested that even in the presence of castrate levels of androgen, androgen levels in the prostate of men with CRPC remain nearly equivalent to those in non-castrated patients.¹⁷

Previously, treatment options were severely limited in this setting and treatment of patients with mitoxantrone with prednisone or hydrocortisone was aimed only at alleviating pain and improving quality of life, but no benefit was seen in terms of patients’ overall survival.¹⁸ However, in 2004 docetaxel chemotherapy was shown to significantly improve survival. Two randomised phase III studies have evaluated docetaxel chemotherapy in this setting – TAX 327 and SWOG 9916.^19,20

In TAX 327, a 24% relative reduction in death for men with mCRPC was observed with a three-weekly docetaxel with prednisone regimen (hazard ratio [HR] for death = 0.76; 95% confidence interval [CI], 0.62 to 0.94), and the benefit in survival rate compared with patients receiving mitoxantrone and prednisone was significant (p = 0.009).¹⁹ Docetaxel was also effective in providing symptom control, with 35% of patients reporting reduction in pain versus 22% with mitoxantrone (p = 0.01). Results of extended follow-up again showed persistence of the survival benefit seen with docetaxel in the TAX 327 study.²⁰ Median survival time was 19.2 months (95% CI, 17.5 to 21.3 months) in the three-weekly docetaxel arm versus 17.8 months (95% CI, 16.2 to 19.2 months) in the weekly docetaxel arm, and 16.3 months (95% CI, 14.3 to 17.9 months) in the mitoxantrone arm (all arms received prednisolone).²⁰ In SWOG 9916, a regimen of docetaxel plus estramustine was compared with mitoxantrone and prednisone.²¹ In this study, the docetaxel regimen also conferred a significant survival benefit (HR for death = 0.80; 95% CI, 0.67 to 0.97), with an increased median survival seen (17.5 versus 15.6 months; p = 0.02).²⁰ These results helped to establish first-line docetaxel as the standard of care for mCRPC. 

Post-docetaxel options

Although docetaxel has been shown to improve survival in mCRPC it became clear that identifying different treatment agents in patients who progress after docetaxel systemic therapy would be imperative. Patients in the post-docetaxel era have provided a great challenge in the treatment of prostate carcinoma, however with continuing research different agents have now been developed to provide treatment options for this subgroup of patients. 

Cabazitaxel

This is a novel tubulin-binding taxane cytotoxic agent with poor affinity for P-glycoprotein that has shown efficacy in model system tumours which are resistant to paclitaxel and docetaxel.^22,23 In a randomised, multicentre, phase III trial, the efficacy and safety of cabazitaxel plus prednisone 10mg daily was compared with mitoxantrone plus prednisone 10mg daily in the treatment of mCRPC that had progressed following docetaxel-based chemotherapy.²⁴ This study, known as the TROPIC trial, had 755 patients who were randomly assigned to treatment with cabazitaxel (n = 378) or mitoxantrone (n = 377). Patients received either 12mg/m² mitoxantrone intravenously or 25mg/m² cabazitaxel intravenously every three weeks along with prednisolone. A maximum of 10 cycles was allowed, due to the risk of mitoxantrone-induced cardiotoxicity. A significant benefit in overall survival was seen for patients assigned to cabazitaxel, with a significant (p < 0.0001) 30% reduction in death (HR = 0.70). Median overall survival was 15.1 months with cabazitaxel as compared with 12.7 months with mitoxantrone.²⁴ Median progression-free survival also favoured the cabazitaxel arm (2.8 versus 1.4 months; p < 0.0001). Tumour response (14.4% versus 4.4%; p = 0.0005) and PSA response (39.2% versus 17.8%; p = 0.0002) significantly favoured cabazitaxel, as did the median time to tumour progression (8.8 versus 5.4 months; p < 0.0001) and the median time to PSA progression (6.4 versus 3.1 months; p = 0.001). 

The most common toxicity seen with cabazitaxel therapy was neutropaenia. Grade 3 or higher neutropaenia occurred in 82% of cabazitaxel patients versus 58% in the mitoxantrone group. Non-haematological toxicities observed in the cabazitaxel arm included diarrhoea, fatigue, asthenia and peripheral neuropathy.²⁴ Severe hypersensitivity reactions have been reported with cabazitaxel; thus, premedication with H2-antagonists and corticosteroids is recommended along with granulocyte-colony stimulating factor (G-CSF) agents to reduce the risk of febrile neutropaenia. Given the above results it was concluded that cabazitaxel plus prednisone is clinically efficacious and improves overall survival in patients with mCRPC whose cancer has progressed during or after docetaxel therapy. Therefore, in June 2010 the US Food and Drug Administration (FDA) approved cabazitaxel as a new therapeutic treatment option for patients with mCRPC resistant to docetaxel.

Abiraterone

This is a selective oral inhibitor of androgen biosynthesis by inhibiting cytochrome P450 17alpha-hydroxylase-17,20-lyase, which is the key enzyme involved in androgen biosynthesis. By targeting CYP17A, abiraterone decreases the production of androgens in the adrenal glands, prostate and tumour tissues.^25,26,27,28 A study was carried out involving 1,195 patients who previously had received docetaxel systemic therapy; they received 5mg of prednisone twice daily with either 1,000mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary endpoint in this study was overall survival.²⁹ Updated results showed that the median overall survival in the abiraterone group was longer than that seen in the placebo group (15.8 months [95% CI 14.8 to 17.0] versus 11.2 months [10.4 to 13.1]; HR 0.74, 95% CI 0.64 to 0.86; p < 0.0001).³⁰ The main toxicity seen and associated with abiraterone includes hypertension, hypokalaemia and oedema, which appear to be manageable with mineralocorticoid antagonists or low-dose corticosteroids.³¹ Therefore, steroids are required alongside abiraterone to reduce adverse effects. Abiraterone acetate in conjunction with prednisone received approval in April 2011 for mCRPC after docetaxel failure based on this COU-AA-301 trial.

Given the benefits of abiraterone in the post-docetaxel setting, it was evaluated in docetaxel-naive patients. Evaluation in this patient population was performed and approval of abiraterone from the FDA in the pre-docetaxel setting came in December 2012 following the double-blind study, in which 1,088 patients were randomised to receive abiraterone acetate (1,000mg) plus prednisone (5mg twice daily) or placebo plus prednisone. The co‑primary endpoints were radiographic progression-free survival and overall survival. Median radiographic progression-free survival was 16.5 months with abiraterone plus prednisone and 8.3 months with prednisone alone (hazard ratio for abiraterone-prednisone versus prednisone alone, 0.53; 95% CI, 0.45 to 0.62; p < 0.001).²⁹ Over a median follow-up period of 22.2 months, overall survival was improved with abiraterone-prednisone (median not reached, versus 27.2 months for prednisone alone; HR, 0.75; 95% CI, 0.61 to 0.93; p = 0.01) but did not cross the efficacy boundary.³² Improvements with respect to time to cytotoxic chemotherapy initiation, opiate use for cancer-related pain and PSA progression were seen in the abiraterone subgroup. Grade 3 or 4 mineralocorticoid-related adverse events and abnormalities on liver-function testing were more commonly seen with abiraterone than placebo. Of note, none of the patients had visceral metastatic disease in this study.³²

Enzalutamide

Known previously as MDV3100, enzalutamide is an oral, second-generation androgen receptor (AR) signalling inhibitor or antagonist that was approved by the FDA in 2012 for the treatment of mCRPC post-docetaxel therapy. This AFFIRM trial was an international double-blind placebo controlled trial in men with mCRPC who had failed prior docetaxel-containing chemotherapy.³³ The 1,199 men with mCRPC were randomised in a 2:1 manner to receive either enzalutamide 160mg daily (n = 800) or placebo (n = 399). Glucocorticoids were not a prerequisite but were allowed and seen in both groups in about 30% of patients. Median overall survival was 18.4 months (95% CI, 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (HR for death in the enzalutamide group, 0.63; 95% CI, 0.53 to 0.75; p < 0.001).³³ A subgroup analysis demonstrated enzalutamide was superior to placebo, even in poor-risk categories including those with lower haemoglobin, higher alkaline phosphatase, poor Eastern Cooperative Oncology Group (ECOG) performance status, presence of pain and visceral disease. The patients who did not seem to obtain benefit from enzalutamide were those who had received two or more prior chemotherapy regimens. The rates of fatigue, diarrhoea and hot flashes seen were higher with enzalutamide, and seizures were seen in five patients (0.6%) receiving enzalutaimide.³³

The use of enzalutamide upfront in mCRPC pre-docetaxel was explored in a pivotal phase III trial – the PREVAIL study. Recent reports have shown that after an interim analysis, overall survival with enzalutamide was significantly better compared with placebo. The independent data monitoring committee recommended that the trial be stopped and that patients who were receiving placebo should be offered the active drug. This will provide another important treatment option for patients and provide another option in the ever-changing landscape of prostate cancer treatment. 

Immunotherapy – sipuleucel-T

The use of immunotherapy as part of the armamentarium in the treatment of cancer has gained a higher profile over recent years. Immunotherapy utilisation has been most notably highlighted more recently in melanoma by agents such as ipilimumab and anti-PD1 showing how exploitation of the body’s immune system can be exploited to help in cancer control. In prostate cancer immunotherapy has been evaluated with the use of sipuleucel-T, an autologous active cellular immunotherapy.³⁴

Sipuleucel-T is a cellular immunotherapy that consists of autologous peripheral blood mononuclear cells (PBMCs) which are obtained by leukapheresis and cultured (activated) with a recombinant human protein (PAP-GM-CSF) consisting of prostatic acid phosphatase linked to granulocyte-macrophage colony-stimulating factor. Sipuleucel-T is a vaccine-type immunotherapy designed to stimulate an immune response to prostate cancer cells.³⁴

In a multicentre phase III trial, 512 patients were randomised in a 2:1 ratio to receive either sipuleucel‑T (341 patients) or placebo (171 patients), administered intravenously every two weeks, for a total of three infusions, to patients with mCRPC, and showed that in the sipuleucel-T group, a relative reduction of 22% in the risk of death was seen compared with the placebo group (HR, 0.78; 95% CI, 0.61 to 0.98; p = 0.03). This represented a 4.1-month improvement in median survival (25.8 months in the sipuleucel-T group versus 21.7 months in placebo group). 

Despite survival extension no effects were evident on either tumour response or time to tumour progression.³⁰ The treatment was well tolerated with predominantly fever and chills more likely grade 1 and 2 in nature. Of note, patients in this IMPACT study were asymptomatic or minimally symptomatic and the majority of patients were docetaxel naive (> 85%), therefore its use in the post-docetaxel setting requires further investigation.³⁴

How best to use these agents?

How best to sequence these new agents now provides a conundrum for treating physicians. Since the approval of docetaxel in 2004, five new agents have shown to improve survival in mCRPC. These include sipuleucel-T, cabazitaxel, abiraterone, radium-223 and enzalutamide. Enzalutamide is the second oral hormonal agent (after abiraterone) that has shown to prolong survival in patients with mCRPC who have been treated previously with docetaxel. Patient-related factors may influence which one the treating physician may prescribe. The use of steroids is required with abiraterone, however it is not with enzalutamide. Therefore, patients susceptible to having comorbidities exacerbated by steroid use now have an active alternative. Similarly, a patient history of seizures may be an important factor in deciding between abiraterone and enzalutamide – there are no head-to-head studies of both agents currently. 

The exact role of the sequencing of these agents and their use in combination remains under assessment. Various research is underway assessing the role of combinations of these active agents. The utility of combining enzalutamide with a vaccine, or combination with abiraterone, or using it in an earlier setting, has been shown in the enzalutamide monotherapy for hormone-naive prostate cancer.^35,36 The Alliance A03121 trial may allow physicians further insight into the optimum treatment schedule for patients by its assessment of the combination of abiraterone acetate with enzalutamide versus abiraterone monotherapy in the pre-chemotherapy mCRPC setting.

The development of resistance in cancer treatment is the inherent pitfall of systemic treatment. Similarly with these prostate cancer agents, the emergence of resistance is of paramount relevance – such that response to these therapies may be effected by prior use of the other active agents. Emerging retrospective data have shown lower clinical activity, as well as briefer duration of responses with the use of abiraterone after failure of prior docetaxel and enzalutamide therapy. This highlights the inherent heterogeneity of cancer treatment and the identification of the appropriate use and sequencing of these agents so that patients can best avail of these active agents and obtain the most efficient response.^37,38

For example, patients who would have received abiraterone and subsequently switched to enzalutamide may not experience the same benefit as was seen in the AFFIRM trial. Subgroup analyses of the AFFIRM trial also showed that those who had received two or more prior chemotherapy treatments did not do as well on enzalutamide therapy therefore hypothesising that an earlier use of this agent in treatment sequencing of these agents may be more appropriate, however this needs to be defined.³⁹

Various mechanisms of resistance have been proposed. One mechanism suggests that treatment with enzalutamide or abiraterone can lead to an adaptive shift towards an AR-splice-variant signalling, which gives rise to an increase in the constitutively active AR-splice variants that lack the AR-binding domain in prostate cancer. Another potential mechanism postulates an association with cellular Fas-associated death domain-like interleukin 1-converting enzyme inhibitory protein expression, which plays a key role in mediating therapeutic resistance and maintaining viability of prostate cancer cells.^40,41

References