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Carl Booth MPhil MRPharmS
Lead Pharmacist for Cancer Services,
Airedale NHS Foundation Trust, UK
Prostate cancer is one of the most common of male cancers, accounting for nearly a quarter (24%) of all new male cancer diagnoses in England.(1) Approximately one in nine men in the UK will be diagnosed with prostate cancer. The incidence varies widely between countries, but is much higher in developed countries, such as those in Western Europe and in the USA. This increased incidence can be attributed to the higher rate of prostate-specific antigen (PSA) testing and subsequent biopsy in these countries.(2) Risk factors for developing prostate cancer include advancing age, genetic predisposition, hormonal influences and environmental factors as toxins, chemicals and industrial products.
In the early stages, prostate cancer causes few, if any, symptoms and is often detected only on routine PSA testing.
In more advanced cases, patients might experience difficulty urinating as the prostate gland enlarges. Prostate cancer will eventually metastasise, usually to the lymph nodes and to the bones of the pelvis and lower back, and patients with metastatic prostate cancer often first present with the resultant back pain that this can cause.
Localised prostate cancer without evidence of metastases is usually treated radically by surgery (radical prostatectomy or transurethral resection of the prostate) or radiotherapy, with the aim of a cure. The first-line treatment of symptomatic advanced prostate cancer usually relies on hormone-deprivation therapy, and when the disease progresses despite hormone deprivation (as it almost inevitably will) it is termed castration-resistant metastatic prostate cancer (CRPC).
The treatment of metastatic CRPC
There is no curative therapy available for metastatic CRPC. Treatment is aimed at improving symptoms, slowing progression of the disease and prolonging life. Docetaxel with a steroid (prednisone or prednisolone) is the standard first-line chemotherapy agent for metastatic CRPC. There is no generally accepted standard care for patients who fail first-line chemotherapy and patients are likely to receive a combination of treatments that can include:
Rationale for the development of abiraterone
Clinical data have indicated that metastatic CRPC frequently remains hormone-dependent, which is why it is no longer described as ‘hormone refractory’ prostate cancer. In the 1990s scientists at the Institute of Cancer Research and The Royal Marsden in London began to hypothesise that prostate cancers that became resistant to hormonal deprivation therapy were able to receive androgens from elsewhere in the body, including perhaps the tumour itself, and began to investigate compounds that inhibited the production of male androgens.
Androgenic steroids (such as testosterone and dihydrotestosterone) are the most potent known androgen receptor agonists, and research suggests that high intratumoural levels can be maintained in the castrate state either by the conversion of serum adrenal androstenedione to testosterone or by the intratumoural synthesis of androgens from substrates such as cholesterol or progesterone.(3)
Steroid hormone synthesis is dependent on cytochrome P (CYP)17, which is critical in the generation of both androgens and oestrogens. Inhibition of CYP17 can be induced by ketoconazole, which is a non-specific, weak, inhibitor of several CYP enzymes. However, owing to low specificity for CYP17, the doses required for CYP17 blockade are several times higher than those used for antifungal treatment, are hepatotoxic, and result in up to 30% of patients stopping treatment because of toxicity.(4)
This lack of potency and the excess adverse effects of ketoconazole led to the development of a much more potent and specific inhibitor of CYP 17, that is, abiraterone.4 The US Food and Drug administration (FDA) approved the use of abiraterone (Zytiga) in men with CRPC in April 2011, and European approval followed in September 2011.
Mechanism of action and efficacy
Abiraterone acetate is converted in vivo to abiraterone, which is a potent, selective, and orally available inhibitor of 17a-hydroxylase/C17,20-lyase (CYP17). Abiraterone decreases serum testosterone to undetectable levels when administered with luteinising hormone releasing hormone (LHRH) agonists or orchiectomy.(5)
A small phase I study of abiraterone in patients with advanced prostate cancer was first carried out at the Institute of Cancer Research and the Royal Marsden. The study involved 21 men and showed significant tumour shrinkage and dramatic falls in PSA levels in the majority of advanced prostate cancer patients who received abiraterone, as well as demonstrating the safety of the drug in humans.(6)
The results of a larger phase I/II study (54 patients) were reported in 2009, confirming the phase I results. Up to 70% of the participants responded to abiraterone.(7) About two-thirds of men experienced significant benefits for an average of eight months, with scans showing their tumours decreased in size and their PSA levels dropped substantially. There were differences in response; not all men responded to abiraterone and some experienced more benefit than others. The majority of patients whose tumours shrank significantly had a rearrangement in the ERG gene. A test for the ERG gene was developed and additional studies are being carried out to determine which men are most likely to benefit from treatment with abiraterone.
The efficacy of abiraterone was reported in a randomised placebo-controlled multicentre phase lll clinical study of patients with metastatic CRPC who had received prior docetaxel-based chemotherapy.(8) Patients were randomised to receive either 1000mg abiraterone daily or placebo (both with prednisone 5mg twice daily) daily. Patients were also using a LHRH agonist or had previously undergone orchiectomy (n=1195). The primary efficacy endpoint was overall survival.
The median overall survival for patients treated with abiraterone was 14.8 months versus 10.9 months for patients receiving placebo (hazard ratio (HR): 0.65; 95% Cl: 0.54,0.77, p<0.001). At all evaluation time points after the initial few months of treatment, a higher proportion of patients treated with abiraterone remained alive compared with the placebo group.
All subgroup survival analyses, for example, baseline Eastern Cooperative Oncology Group status, presence of pain at baseline, one or two prior chemotherapy regimens, type of progression, baseline PSA score above median, and presence of visceral disease at entry, showed a consistent favourable survival effect for treatment with abiraterone.
Patients receiving abiraterone demonstrated a significantly higher total PSA response rate (defined as >50% response from baseline) compared with patients receiving placebo (38% vs 10%, p<0.001).
The median time to PSA progression was 10.2 months for patients treated with abiraterone and 6.6 months for patients treated with placebo (HR: 0.58; 95% Cl: 0.462, 0.728, p< 0.001).
Patients treated with abiraterone also showed statistically significant improvements in pain palliation scores, time-to-pain progression and reduction in risk for skeletal-related events. The proportion of patients with a baseline pain score ≥4 and at least one post-baseline pain score who had a pain response was significantly higher in patients treated with abiraterone compared with patients treated with placebo (44% vs 27%, p=0.002).
Treatment with abiraterone resulted in a 36% reduction in the risk of skeletal-related events compared with placebo treatment. The time to first skeletal-related event at the 25th percentile in the abiraterone group was twice that of the placebo group (9.9 months vs 4.9 months, respectively).(8)
Scher et al presented data from the COU-AA-301 study at the 2011 ASCO meeting.9 A preplanned interim analysis of the COU-AA-301 trial showed that abiraterone acetate significantly improved overall survival in mCRPC. This was the first phase III study to prospectively assess circulating tumour cells (CTC) as a surrogate biomarker. A total of 1195 patients with mCRPC post-docetaxel were randomised 2:1 to abiraterone acetate (1ooomg od) + prednisolone (5mg bid) (n = 797) or placebo (n = 398). CTCs post-baseline at weeks 4, 8 and 12 were enumerated and CTC (as part of a biomarker panel of lactate dehydrogenase (LDH), PSA, alkaline phosphatase) was examined as a surrogate for overall survival. At median follow up of 20.2 months, the difference in median overall survival between the two groups improved from 3.9 to 4.6 months (15.8 months for abiraterone acetate vs 11.2 months for placebo; HR = 0.74; p < 0.0001). CTC counts were evaluated in 972 patients at screening and baseline, in 838 patients at four weeks, 783 patients at eight weeks and 723 patients at 12 weeks. High concordance between screening and baseline values was observed (r = 0.83). CTC conversion using standard definition for unfavourable (CTC ≥ 5) and favourable (CTC < 5) counts was predictive of OS as early as four wks after treatment and its inclusion significantly reduced the treatment effect at all post-treatment time points (HR 0.74–0.97).
The magnitude of the treatment effect of abiraterone acetate on overall survival increased with longer follow-up. Using standard definition of CTC conversion, the biomarker panel demonstrated a level of surrogacy for overall survival by correlating well with survival and in a model-adjusted analysis dramatically attenuating the treatment effect. Baseline CTCs and CTC conversion, along with LDH, were key predictors of OS. Future trials will further evaluate the CTC-based surrogate developed from COU-AA-301.
Reduction in morbidity and clinical sequelae of bone metastases is a significant unmet medical need in mCRPC patients. Logothetis et al(10) presented further data from the COU-AA-301 study on the effect of abiraterone acetate on pain control and skeletal-related events post-docetaxel.
A total of 797 patients were randomised to abiraterone acetate and 398 to placebo; median treatment duration was eight and four months, respectively. The time to skeletal-related events for abiraterone acetate (pathological fracture, spinal cord compression or palliative radiation/bone surgery) was 301 days vs 150 days for placebo). Abiraterone acetate produced significantly improved pain outcomes, including better and faster palliation of pain intensity and pain interference (Table 1). Fewer patients treated with abiraterone acetate had progression of pain intensity and interference at 6, 12 and 18 months and the pain profile of abiraterone acetate was superior to placebo from cycles1–10. There might be potential for integrating bone-targeting therapy with abiraterone to further improve symptom-free survival of patients with mCRPC.
Safety issues and adverse events
Abiraterone is well absorbed following oral ingestion, with a time to maximum plasma concentration of approximately two hours. Concurrent or recent ingestion of food may increase absorption up to 14-fold and so abiraterone must be taken on an empty stomach.(5)
Several adverse events were seen more commonly in patients treated with abiraterone than in the placebo arm. Those of particular interest included those related to elevated mineralcorticoid levels such as fluid retention (31% vs. 22%) and hypokalaemia (17% vs. 8%). There was a slightly higher incidence of cardiac category events in the abiraterone arm vs. placebo. However, there was no increase in fatal cardiac events (1.1% vs. 1.3% respectively).
Blood pressure, serum potassium and fluid retention should be monitored monthly. Hypokalaemia should be corrected before treatment with abiraterone is initiated. Serum transaminases and bilirubin should be measured before initiating abiraterone, then every two weeks for the first three months of treatment, and monthly thereafter.(5)
Abiraterone has been associated with rises in aminotransferase levels and, for patients who develop hepatotoxicity during treatment (alanine aminotransferase (ALT) increased more than five-times the upper limit of normal), treatment should be withheld immediately. Retreatment following return of liver function tests to the patient’s baseline can be given at a reduced dose. For patients undergoing retreatment, serum transaminases should be monitored at a minimum of every two weeks for three months and monthly thereafter. If hepatotoxicity recurs at the reduced dose of 500mg daily, treatment should be discontinued. If patients develop severe hepatotoxicity (ALT 20-times the upper limit of normal) while undergoing therapy, abiraterone should be discontinued and patients should not be retreated.(5)
Impact of abiraterone on the treatment of CRPC
New therapies were desperately needed for CRPC. Much more is now known about the role of androgens in metastatic CRPC, and this has led to the development of a steady stream of potential new therapies. Abiraterone is just the first of several similar agents that will be available over the next few years. Other novel agents, such as MDV3100, are currently in development, and there are other novel therapies with differing mechanisms of action in development, or recently licensed, which are also challenging for a place in the treatment of this common disease.(11)
Following its approval in the US and in Europe, abiraterone has quickly established itself as a useful subsequent line of treatment in patients with metastatic CRPC who have progressed on or after docetaxel and steroid therapy.
Further clinical trials are underway to look at the efficacy of abiraterone in an earlier setting, after failure of traditional hormone-deprivation therapy but prior to chemotherapy, and these results are awaited with interest.(12)
Advancements in understanding the molecular mechanisms underlying disease progression in CRPC have led to the development of agents that target androgen synthesis and signalling. One such drug is abiraterone acetate, which is an irreversible and specific inhibitor of CYP17, a rate-limiting enzyme in androgen biosynthesis.
Abiraterone in combination with prednisone is indicated for the treatment of patients with metastatic CRPC who have received prior docetaxel-based chemotherapy and represents a groundbreaking development in the treatment of this aggressive and highly lethal disease.