Prostate cancer: treatment options

Patients with pros
tate cancer can be diagnosed with locally advanced disease, which over time will progress to metastatic disease, or present with distant bone metastases. Treatment of early stage prostate cancer and locally advanced disease can involve surveillance, radical treatment (e.g. prostatectomy), or androgen deprivation therapy (ADT). As the disease progresses, treatment options may change. Patients can expect a number of years of ADT but many eventually progres
s to advanced metastatic disease.

Surveillance

Watchful waiting is sometimes used to monitor the disease with no planned intervention, as it is likely the patient will die from other comorbidities (e.g. cardiovascular disease) before they die of prostate cancer.

Active surveillance is used for low-risk patients who have a limited life expectancy (<10–15 years) on account of age at diagnosis or comorbidities. It is an important treatment option as it is more likely that these patients will die of a condition other than prostate cancer. Around 25–30% of these patients will require definitive therapy as their prostate cancer progresses. It is currently unknown whether deferred active therapy results in worse outcomes for men compared with immediate therapy; however, as definitive therapy has associated complications, active surveillance remains a valid choice. The National Institute for Health and Care Excellence (NICE) has produced a protocol for active surveillance (see ‘NICE protocol for active surveillance’)^[1]
.

Radical treatment

NICE recommends radical prostatectomy or radical radiotherapy for men with intermediate-risk localised prostate cancer and men with high-risk localised prostate cancer when there is a realistic prospect of long-term disease control^[1]
. There is a variety of surgical options, including open surgery or robotic-assisted laparoscopic prostatectomy (RALP) to treat localised prostate cancer. Prostatectomy is associated with complications such as urinary incontinence or sexual dysfunction. Where possible, nerve-sparing radical pr
ostatectomy is performed, as it offers a greater chance of sexual recovery. However, patient suitability for this treatment depends on the size and position of the tumour.

Radiotherapy can be administered using radical external beam radiotherapy (EBRT) for localised prostate cancer, given as daily fractions over a number of weeks. NICE recommends a minimum dose of 74 Gy to the prostate, at no more than 2 Gy per daily fraction^[1]
. An alternative to radical radiotherapy is to use high-dose rate brachytherapy in combination with EBRT. Brachytherapy is the implantation of radioactive material directly into the tumour. Two radioactive seed isotopes have been used: iodine (I-125), with a half-life of 60 days, and palladium (Pd-103), with a shorter half-life (17 days) and higher dose rate. The advantage of brachytherapy is that a substantial dose can be delivered to the prostate with minimal effect on the surrounding tissue.

One of the main concerns of men undergoing surgery and radiotherapy is the potential loss of sexual function; it is estimated that as many as 50% of patients may not recover erections sufficient for intercourse^[1]
. In those who do undergo surgery and radiotherapy, the quality (rigidity and duration) of erections is poorer compared with preoperative erections. Potency may return anywhere from two to 24 months following surgery. Sensation of the penis is not changed after nerve sparing radical prostatectomy, and men still experience orgasm. ADT can result in a reduction in libido and loss of sexual function.

Early use of phosphodiesterase type-5 inhibitors (e.g. sildenafil, tadalafil) should be offered to patients who are experiencing loss of sexual function; if these fail to restore erectile function, alternatives such as vacuum devices or intracavernosal injections of vasoactive treatments (e.g. papaverine, intraurethral inserts) can be considered^[1]
.

Androgen deprivation therapy

ADT has been the mainstay of advan
ced prostate cancer management for many years. Recently, there has been a move towards the use of hormonal treatment in younger men with earlier disease (i.e. non-metastatic) or recurrent disease after definitive treatment (e.g. radiotherapy or surgery)

^[2]
. 
NICE recommends ADT, together with radiotherapy, as a treatment option for men with intermediate- and high-risk localised prostate cancer^[1]
. 
ADT can be used before, during or after radical EBRT, and is often continued for up to three years in patients with high-risk localised prostate cancer^[1]

.

The ‘gold standard’ ADT is bilateral orchiectomy (castration). However, the negative psychological effect of castration has led to a preference for therapies offering reversible testosterone suppression.

ADT has been based on luteinising hormone-releasing hormone (LHRH) agonists, which act to reduce testosterone levels by blocking the production and release of gonadotrophins, exerting a negative feedback control on hypothalamic luteinising hormone (LH) secretion and reducing follicle-stimulating hormone (FSH) in the medium- to long-term. If prostate cells are deprived of androgenic stimulation, they undergo apoptosis. LHRH agonists include goserelin^[3]
, triptorelin^[4]
and buserelin, with the choice of treatment based on local formulary and cost, rather than any significant differences in clinical effectiveness.

Side effects of ADT include hot flushes, weight gain, loss of libido, loss of peripheral hair growth, gynaecomastia, an elevated risk of diabetes, loss of bone mineral density and raised risk of fracture, and an increased risk of cardiovascular complications. Hot flushes can be managed with medroxyprogesterone or cyproterone acetate. Gynaecomastia caused by ADT can be treated with tamoxifen or prophylactic radiotherapy to the breast buds.

ADT initially results in an increase in testosterone levels, producing a testosterone surge, prior to down-regulation of testosterone production. This elevation in testosterone levels can result in a ‘tumour flare’ in some patients, who experience a temporary deterioration in their condition. It is common practice to pre-treat patients with anti-androgen therapy prior to starting LHRH therapy and for the first two weeks of LHRH therapy. Anti-androgen therapy reduces the testosterone surge symptoms by blocking the action of testosterone, rather than lowering serum testosterone levels. The most commonly used anti-androgens include nonsteroidal agents (e.g. flutamide, bicalutamide) and steroidal agents (e.g. cyproterone, megestrol).

LHRH antagonists (e.g. cetrorelix, ganirelix, degaralix), in contrast to LHRH agonists, bind immediately and competitively to LHRH receptors in the pituitary gland. The effect is a rapid decrease in LH, FSH and testosterone levels without tumour flare. This seemingly more desirable mechanism of action has made LHRH antagonists appear to have an advantage over LHRH agonists, but so far they remain in limited use. 
Degaralix is currently being reviewed by NICE; draft guidance recommends it as an option only for advanced hormone-dependent prostate cancer patients with spinal metastases who present with signs or symptoms of spinal cord compression (because the tumour flare when starting an LHRH agonist would be dangerous for these patients)^[5]

.

LHRH antagonists are more expensive than LHRH agonists and less cost-effective for all patients; NICE reported it costs £12,306 (excluding VAT) per course of treatment. Clinical trials have compared degarelix with leuprorelin or goserelin with or without bicalutamide, with the primary outcome being prostate-specific antigen (PSA) suppression. These trials were powered for non-inferiority, so improvement in overall survival or tumour reduction was not studied^[6]
.

Treatment of advanced disease

Advanced disease that is initially responsive to androgen blockade can become resistant to blockade with LHRH agonists and antagonists or castration. Previously, this was called ‘hormone refractory’ or ‘androgen independent’ prostate cancer, but is now more accurately known as metastatic castrate resistant prostate cancer (mCRPC). The reason for this change in terminology is a result of greater understanding of the disease, with clinical evidence showing that the androgen receptor axis remains functional, even when patients become ‘hormone refractory’.

Historically, patients with metastatic disease showed disease progression to mCRPC within 12–18 months of diagnosis and androgen ablation, despite having castrate levels of serum testosterone (traditionally defined as <50ng/dL), with a median survival of two to three years^[6]
. Many patients progress while on ADT and experience an increase in PSA without any physical symptoms.

Until a few years ago, the only viable treatment option for metastatic disease after failure of ADT was chemotherapy, typically with docetaxel. In recent years, several new effective treatments for metastatic prostate cancer have become available, all of which have been shown to improve overall survival in large-scale, randomised phase III trials.

Patients with prostate cancer should be managed by a urology team until they develop mCRPC; at this point they should be referred to an oncology team.

Docetaxel

Since its approval by NICE in 2006, docetaxel has been the mainstay of chemotherapy treatment in the UK^[7]
. The phase III trial that established docetaxel as standard practice was TAX 327, which compared two different schedules of docetaxel and prednisone (weekly and three-weekly) with mitoxantrone and prednisone^[8]
. The primary endpoint was overall survival, with secondary endpoints including quality of life, PSA changes and pain evaluation.

A total of 1,006 patients were recruited and the arms of the trial evenly balanced. A survival advantage was shown with the three-week docetaxel and prednisone schedule versus mitoxantrone and prednisone; 18.9 months medium overall survival versus 16.5 months medium overall survival (P=0.009; hazard ratio (HR) 0.76). No significant survival advantage over mitoxantrone and prednisone was seen in patients receiving the weekly dosing schedule; however, the trial demonstrated a significant improvement in pain response and improved quality of life scores. Docetaxel is associated with a high rate of neutropenia in practice; however, in the TAX 327 trial, only 3% of patients had febrile neutropenia. This might have been because the trial protocol allowed treatment with granulocyte colony-stimulating factor for neutropenia patients, which is not common practice in the UK^[8]
.

To date, three trials have examined the use of docetaxel chemotherapy at earlier stages of prostate cancer, either for high-risk, localised disease or metastatic hormone sensitive prostate cancer (mHSPC). The GETUG-AFU 15 trial was a randomised, open-label, phase III trial that enrolled 385 patients with newly diagnosed mHSPC^[9]
. Patients received ADT alone (orchiectomy or LHRH agonists) or ADT with docetaxel 75mg/m² every 21 days for nine cycles. The trial did not demonstrate a statistically significant overall survival benefıt by adding docetaxel to ADT; 58.9 months for the docetaxel arm versus 54.2 months for the ADT arm (P=0.95; HR 1.01). The trial had a relatively small sample size and included a substantial percentage of patients with good prognostic factors. High levels of toxicity were reported, with more than a 10% incidence of grade 3 neutropenia and four deaths in the ADT plus docetaxel arm; 21% of men who received docetaxel plus ADT discontinued treatment because of toxicity^[9]
.

CHAARTED, a larger phase III American
clinical trial conducted in 790 patients with hormone-naive mHSPC, compared ADT alone to ADT plus docetaxel chemotherapy at 75mg/m
² every three weeks, for a maximum of six cycles^[10]

. Patients were stratifıed as having high-volume or low-volume metastatic disease. 
The primary endpoint was overall survival, and the trial showed a median overall survival of 57.6 months for the early docetaxel arm, compared with 44 months for ADT alone (P=0.0003; HR 0.61). In the subset of patients with high-volume disease, a 17-month improvement in overall survival was observed in the ADT plus docetaxel arm^[10]
.

The UK-led STAMPEDE trial is a complex multi-centre, randomised controlled trial for patients with locally advanced or metastatic prostate cancer who are about to commence ADT^[11]

. The trial randomises patients to receive a variety of medicines in combination with ADT, including zoledronic acid, docetaxel, celecoxib, abiraterone and enzalutamide. In June 2005, the first results of four of the trial’s arms were presented, with data from 2,962 men randomised at a 2:1:1:1 ratio to receive ADT; ADT plus six
cycles given e
very three weeks of docetaxel; ADT with zoledronic acid; or ADT with docetaxel and zoledronic acid^[11]

. In total, 61% of participants had metastatic disease and 39% had locally advanced, non-metastatic prostate cancer. Patients assigned to the docetaxel arm had a significantly improved median overall survival of 77 months compared with 67 months for patients in the ADT-only arm (P=0.003; HR 0.76). The subset of patients with metastatic disease had an even better 22-month improvement in overall survival, compared with ADT alone (65 months versus 43 months, P=0.002; HR 0.73). The trial is ongoing.
 

Cabazitaxel

After standard docetaxel, cabazitaxel has been used as second-line chemotherapy for mCRPC. In the UK, cabazitaxel has been rejected by NICE and the Scottish Medicines Consortium (SMC) because they do not consider it to be cost-effective, but it has been made available for patients in England through the Cancer Drugs Fund (CDF).

The TROPIC phase III study randomised a total of 755 patients with mCRPC, previously treated with a docetaxel-containing regimen to receive cabazitaxel 25mg/m² plus prednisone every three weeks versus mitoxantrone 12mg/m² plus prednisone every three weeks^[12]

. The primary end point was overall survival, which increased with cabazitaxel treatment (15.1 months versus 12.7 months, respectively, a difference of 2.4 months [P<0.0001; HR 0.70]). The secondary end point of progression-free survival (PFS) was also significantly prolonged with cabazitaxel (2.8 months versus 1.4 months, respectively). However, patients in the cabazitaxel arm experienced greater toxic effects, including diarrhoea
, vomiting, neutropenia and febrile neutropenia^[12]
.

Abiraterone and enzalutamide

For the treatment of adult men with mCRPC whose disease has progressed during, or after, docetaxel therapy, abiraterone and enzalutamide are approved by NICE^[13],[14]
.

Abiraterone acetate is an androgen biosynthesis inhibitor that blocks biosynthesis of extragonadal androgens. Abiraterone leads to a rebound increase in LH and in adrenocorticotropic hormone (ACTH), and so it is given with low-dose corticosteroids to normalise mineralocorticoid levels and reduce side effects. Abiraterone is taken as a 1g oral dose, in combination with prednisolone 5mg twice daily, on a 28-day cycle. It is available in 250mg tablets, which must not be taken with food. Patients should be advised that taking the dose at night can often minimise the lethargy that is a potential side effect. If toxicity occurs, treatment should be suspended and restarted with the advice of the treating oncologist; there is no evidence to support reducing the dose. The most commonly observed side effects are hypokalaemia, hypertension, lower limb oedema, diarrhoea and lethargy^[15]
.

Enzalutamide acts on three steps in the androgen receptor signalling pathway; as an androgen receptor antagonist (no agonist activity); by inhibiting translocation of the androgen-receptor complex to the cell nucleus; and by inhibiting receptor binding to DNA in the nucleus and therefore preventing cell replication and instigating apoptosis.

Enzalutamide is taken as a 160mg oral dose once daily, on a 28-day cycle. It is available as 40mg capsules, which should be swallowed whole with water and can be taken with or without food. If a patient experiences serious toxicity or an intolerable adverse reaction, they will require interruption of abiraterone therapy and dosing should be withheld for one week, or until symptoms improve, then resumed at the same or a reduced dose (120mg or 80mg) if warranted. The most common side effects are hypertension, hot flushes and headache.

Although they have slightly different mechanisms of action, clinically both treatments are considered interchangeable, with evidence of clinical benefits similar between the two^[13],[14]
. Clinicians can use one or the other, but not both. Currently there are no published phase III trials of either drug where patients had previously received the other treatment. There is also emerging evidence of cross resistance among abiraterone, enzalutamide and taxane chemotherapy, although the implications for the order of treatment are not yet known^[16]
.

The COU-AA-301 phase III trial for abiraterone post-chemotherapy examined 1,195 patients who had previously received docetaxel and randomised them to receive 5mg of prednisone twice daily, with either 1g of abiraterone (797 patients) or placebo (398 patients)^[17]
. The primary end point was overall survival, which was longer in the abiraterone plus prednisone group than in the placebo plus prednisone group, at 14.8 months versus 10.9 months, respectively (P<0.001; HR 0.65). All secondary end points, including time to PSA progression (10.2 months versus 6.6 months; P<0.001) and PFS (5.6 months versus 3.6 months P<0.001), favoured the treatment group. However, the side effect profile was worse in the abiraterone prednisone group, with more mineralocorticoid-related adverse events, including fluid retention, hypertension and hypokalaemia^[17]
.

The AFFIRM phase III trial of enzalutamide post-docetaxel randomised 1,199 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily at a 2:1 ratio and patients were allowed, but not required, to take up to 10mg prednisone a day^[18]
. Enzalutamide demonstrated a 4.8 month improvement in the primary outcome of overall survival compared with placebo, at 18.4 months versus 13.6 months, respectively (P<0.001; HR 0.631). The benefit of enzalutamide was demonstrated by the secondary end points, including the time until the initiation of cytotoxic chemotherapy, the time until the first skeletal-related event and the time until PSA progression. Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment^[18]
.

Both abiraterone and enzalutamide can interact with other drugs. Abiraterone may increase exposure of other medicines metabolised by cytochrome P450 (CYP) 2D6, which include metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol.

Enzalutamide is a strong CYP3A4 enzyme inducer. Interactions with medicines that are eliminated via CYP3A4 metabolism are expected, including fentanyl, clarithromycin, cabazitaxel, warfarin, anti-epileptics and calcium channel blockers. The clinical significance of these interactions is unknown.

Similarly to docetaxel, the focus of abiraterone and enzalutamide treatment in metastatic disease is shifting towards a preference for earlier treatment. Soon after abiraterone and enzaluatmide demonstrated their efficacy in the post-chemotherapy metastatic setting, both reported trial data on their efficacy in the pre-chemotherapy setting and have been approved in England by the CDF based on their pre-chemotherapy trial data^[19],[20]
.

The COU-AA-302 trial^[19]

 randomised 1,088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer randomly in a 1:1 ratio to receive either abiraterone acetate (1g once daily) plus prednisone (5mg twice daily), or placebo plus prednisone. Co-primary end points were radiographic PFS and overall survival. Median overall survival was significantly longer in the abiraterone acetate group than in the placebo group at 34.7 months versus 30.3 months, respectively (P=0.0033; HR 0.81). The most common grade 3–4 adverse events were cardiac disorders (8% of patients in the abiraterone acetate group versus 4% in the placebo group), increased alanine aminotransferase (6% versus <1%, respectively) and hypertension (5% versus 3%, respectively)^[19]
.

PREVAIL was a randomised phase III trial of enzalutamide versus placebo in 1,717 patients with a primary end point of median radiographic PFS^[20]
. The rate of radiographic PFS at 12 months was 65% among patients treated with enzalutamide versus 14% among patients receiving placebo (P<0.001; HR 0.19), and showed a median overall survival of 32.4 months compared with 30.2 months (final overall survival rates have not been published). The time prior to starting chemotherapy was significantly longer with enzalutamide (28 months compared with 10.8 months) and quality of life was improved.

Sipuleucel-T and ipilimumab

The autologous cellular immunotherapy vaccine Sipuleucel-T stimulates the patient’s own immune cells to identify and attack prostate cancer cells. It is generated from a patient’s own peripheral immune cells, obtained via leukopheresis, which are then exposed to a fusion peptide of granulocyte macrophage colony stimulating factor (serving as immune adjuvant) and pulmonary alveolar proteinosis
^[21]
. 

The IMPACT trial was a randomised placebo-controlled trial of 512 asymptomatic or minimally symptomatic men with mCRPC, and provides the main evidence for Sipuleucel-T^[21]
. The trial demonstrated a 4.1-month improvement in median overall survival in the Sipuleucel-T arm compared with the placebo arm (25.8 months versus 21.7 months; P=0.03, HR 0.78). No difference in time to progression or PSA response was reported, which may be a reflection of the late onset of benefit of immune therapy. Sipuleucel-T is not recommended by NICE on cost-effectiveness grounds^[22]
.

Ipilimumab is an immune checkpoint inhibitor used for the treatment of metastatic melanoma. Its use in prostate cancer was evaluated in a phase III study in patients previously treated with chemotherapy^[23]
. Patients received a single dose of radiation followed by either ipilimumab 10mg/kg or placebo, every three weeks, for up to four doses. The study did not meet its primary end point of improved overall survival, so ipilimumab remains investigational and is not used. However, there is renewed interest in immune therapy in oncology, so further trials are expected.

Bone metastases

One important part of the treatment of metastatic prostate cancer involves the prevention and treatment of the complications of bone metastases. Patients are at substantial risk of skeletal complications from bone metastases, often referred to as skeletal-related events (SREs), and include fracture, skeletal instability or loss of skeletal integrity, spinal cord compression, the need for surgery or radiation therapy for a symptomatic bone metastasis and hypercalcaemia. NICE recommends that bisphosphonates should not be used for prevention, but only for pain relief for men with mCRPC when other treatments (including analgesics and palliative radiotherapy) have failed^[1]
. NICE also recommends the use of strontium-89 as a treatment option for men with painful bone metastases. Denosumab is licensed for preventing SREs and has shown superiority to bisphosphonates^[24]
; however, it is not recommended by NICE for men with bone metastases from prostate cancer.

Radium-223 is a radioactive isotope that emits low levels of alpha particle radiation, which causes double-strand breaks in DNA, killing cells. It acts as a ‘calcium mimetic’ that, like calcium, accumulates preferentially in areas of bone that are undergoing increased turnover, and therefore acts against bone metastases. The ALSYMPCA trial targeted men with symptomatic bone metastases in the absence of visceral disease^[25]
. Radium-223 was administered at a dose of 50 kBq/kg once every four weeks, for six cycles. Radium-223 improved overall survival by 3.6 months: 14.9 months for Radium-223 versus 11.3 months for placebo (P=0.001; HR 0.7). Patients receiving radium-223 also reported a better quality of life than patients in the placebo group^[25]
.