Key points from the evidence

The content of this evidence summary was up-to-date in January 2016. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

Randomised controlled trial (RCT) data suggest that docetaxel improves overall survival and time to disease progression in men with hormone‑sensitive metastatic prostate cancer. Two RCTs found that, compared with androgen deprivation therapy (ADT) alone, docetaxel combined with ADT statistically significantly improved overall survival by around 10–15 months in this population. No statistically significant difference was seen between the groups in another, smaller RCT. Time to disease progression was statistically significantly longer with docetaxel plus ADT compared with ADT alone in all 3 RCTs. These findings are reinforced by a meta‑analysis of the RCTs.

The toxicity of docetaxel is well‑established. Nevertheless, most participants in the RCTs tolerated the planned number of docetaxel treatment cycles.

Regulatory status: Docetaxel is licensed for treating men with hormone‑resistant metastatic prostate cancer. Use of docetaxel for treating men with hormone‑sensitive metastatic prostate cancer is off‑label.

Effectiveness

In open‑label RCTs in men with hormone‑sensitive prostate cancer, compared with ADT alone, docetaxel plus ADT statistically significantly improved overall survival:

  • by 10 months in men with metastatic or non‑metastatic disease in STAMPEDE (n=1776, median follow‑up: 43 months, p=0.006)

  • by 15 months in a subgroup of men with metastases in STAMPEDE (n=1086, median follow‑up: 43 months, p=0.005)

  • by 13.6 months in men with metastases in CHAARTED (n=790, median follow‑up: 29 months, p<0.001)

  • no statistically significant difference was seen between the groups in a smaller RCT GETUG-AFU 15, although overall survival was 4.7 months longer with docetaxel (n=385, median follow‑up: 50 months).

In men with hormone‑sensitive metastatic prostate cancer at 4 years, estimates based on a meta‑analysis of the 3 RCTs (STOpCaP, n=2992) found:

  • a 9% absolute improvement in overall survival with docetaxel compared with ADT alone (49% compared with 40%, p<0.0001, number needed to treat [NNT] 12)

  • a 16% absolute improvement in time to disease progression with docetaxel compared with ADT alone (treatment failure 64% compared with 80%, p<0.0001, NNT 7).

Safety

  • Four deaths in GETUG-AFU 15, 1 death in CHAARTED and 8 deaths in STAMPEDE (1 with docetaxel plus ADT and 7 with docetaxel, zoledronic acid and ADT) were considered possibly or probably related to docetaxel treatment.

  • In men taking docetaxel plus ADT, severe, life‑threatening or disabling adverse events or death (grade 3–5 adverse events) were reported in 38.1% of men in GETUG-AFU 15, 29.5% of men in CHAARTED and 52.4% of men in STAMPEDE. 32.5% of men taking ADT alone in STAMPEDE reported grade 3–5 adverse events.

  • According to the summary of product characteristics, the adverse effects most commonly reported with docetaxel 75 mg/m2 when used for prostate cancer are neutropenia (32%), anaemia (4.9%), fatigue (3.9%) and infection (3.3%).

Patient factors

  • In STAMPEDE and GETUG-AFU 15 respectively, 13.1% and 20.6% of men taking docetaxel plus ADT discontinued treatment due to adverse events. This outcome was not reported in CHAARTED.

  • In the 3 RCTs, half to three quarters of men tolerated the study dosage of docetaxel for the planned treatment duration (75 mg/m2 3‑weekly, usually for 6 cycles). However, the toxicity of docetaxel means some men (particularly those with poor performance status or comorbidities) may prefer other treatment options.

  • Little information is available on quality of life. GETUG-AFU 15 reported that, although quality of life was statistically significantly impaired during docetaxel treatment, global scores were generally similar between the combination and ADT alone groups at 12 months.

Resource implications

  • Docetaxel concentrate for solution for infusion costs £162.75 for 0.5 ml and £534.75 for 2 ml of the 40 mg/ml strength (MIMS, December 2015).

  • The cost of 6 cycles of docetaxel 75 mg/m2 3‑weekly is approximately £6138 per person (see below).

  • These are the costs of docetaxel only (excluding VAT) and do not include any procurement discounts or other costs incurred, such as dilution and administration, or the cost of standard supportive therapy.

Introduction and current guidance

Prostate cancer is the most common cancer in men. Over 40,000 cases were registered in 2013, accounting for 27% of new cancers in males. Up to 25% of men diagnosed with prostate cancer present with metastases. The average 5‑year survival rate for men with metastatic prostate cancer is 30%; 10% will survive for at least 10 years.

The androgen receptor is involved in the growth and spread of prostate cancer. Prostate cancer can, therefore, be treated hormonally using androgen deprivation therapy (ADT). This includes surgical castration (bilateral orchidectomy) and medical castration (usually with luteinising‑hormone‑releasing hormone [LHRH] agonists, also known as gonadotropin‑releasing hormone [GnRH] agonists or analogues). As a prostate cancer progresses, further genetic mutations can affect the androgen receptors and allow increasing numbers to function without androgen. ADT then becomes less effective. This is known as hormone‑resistant (castration‑resistant, hormone‑relapsed or hormone‑refractory) prostate cancer.

For men with hormone‑sensitive metastatic prostate cancer, the NICE guideline on prostate cancer recommends bilateral orchidectomy or continuous LHRH agonist therapy, anti‑androgen therapy with bicalutamide (in men who are willing to accept the adverse effects; off‑label) or combined androgen blockade (not first‑line).

NICE recommends docetaxel as a possible treatment for men with hormone‑resistant metastatic prostate cancer if the man is well enough to care for himself with occasional assistance. This evidence summary considers the efficacy and safety of docetaxel (in combination with ADT) for treating men with hormone‑sensitive prostate cancer.

Full text of introduction and current guidance.

Product overview

Docetaxel is an antineoplastic agent in the taxane class. As well as other non‑prostate cancer indications, docetaxel (in combination with prednisone or prednisolone) is licensed for treating men with hormone‑resistant metastatic prostate cancer (see the summary of product characteristics for Taxotere).

Use of docetaxel for treating men with hormone‑sensitive metastatic prostate cancer is off‑label.

Full text of product overview.

Evidence review

  • This evidence review includes 3 open‑label randomised controlled trials (RCTs) that compared the effects of docetaxel in combination with ADT with ADT alone in men with hormone‑sensitive prostate cancer. GETUG-AFU 15 and CHAARTED included only men with metastases: in STAMPEDE, 61% of men had metastases. A meta-analysis (STOpCaP) on docetaxel for men with hormone‑sensitive metastatic and non‑metastatic prostate cancer, which includes the 3 RCTs, is also outlined. In STOpCaP, analyses for docetaxel also include men from another treatment group in STAMPEDE who received a treatment regimen of docetaxel, zoledronic acid and ADT (which was not found to improve overall survival statistically significantly better than docetaxel plus ADT and is not discussed in any detail in this evidence summary).

  • STAMPEDE and CHAARTED found that docetaxel (75 mg/m2 3‑weekly for 6 cycles) combined with ADT statistically significantly improved overall survival compared with ADT alone in men with hormone‑sensitive metastatic prostate cancer. However, no statistically significant difference was seen between the groups in GETUG-AFU 15 (docetaxel 75 mg/m2 3‑weekly, median 8 cycles).

  • In STAMPEDE, in the docetaxel plus ADT group compared with the ADT alone group, median overall survival was 10 months longer in the total population of men with and without metastases (n=1776; 81 months compared with 71 months; hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.66 to 0.93, p=0.006) and 15 months longer in the subgroup of men with metastases (n=1086; 60 months compared with 45 months; HR 0.76, 95% CI 0.62 to 0.92, p=0.005). In men using docetaxel plus ADT compared with ADT alone, median overall survival was 13.6 months longer in CHAARTED (n=790; 57.6 months compared with 44.0 months; HR 0.61, 95% CI 0.47 to 0.80, p<0.001) and 4.7 months longer in GETUG-AFU 15 (n=385; 58.9 months compared with 54.2 months; p=0.955). In GETUG-AFU 15, the authors suggest that overall survival may not have reached statistical significance because of insufficient statistical power or confounding caused by crossover use of docetaxel in the ADT alone group when prostate cancer became hormone‑resistant. A meta‑analysis of men with metastatic prostate cancer (3 RCTs [STAMPEDE, CHAARTED and GETUG-AFU 15], n=2992) in STOpCaP found overall survival was statistically significantly increased at 4 years in the docetaxel group compared with the ADT alone group (estimated overall survival 49% compared with 40% respectively; HR 0.77, 95% CI 0.68 to 0.87, p<0.0001; number needed to treat [NNT] 12).

  • CHAARTED and GETUG-AFU 15 found that treatment with docetaxel and ADT statistically significantly improved median time to clinical progression (including death and clinical signs and symptoms of worsening disease) compared with ADT alone (33.0 months compared with 19.8 months; HR 0.61, 95% CI 0.50 to 0.75, p<0.001 and 23.5 months compared with15.4 months; HR 0.75, 95% CI 0.59 to 0.94, p=0.015 respectively). Median time to biochemical progression (including death, clinical progression and deterioration in biological markers) was statistically significantly improved with docetaxel plus ADT compared with ADT alone in STAMPEDE (total population: 37 months compared with 20 months; HR 0.61, 95% CI 0.53 to 0.70, p<0.0001 and metastatic population: months to progression not reported; HR 0.61, 95% CI 0.53 to 0.71, p<0.0001) and GETUG-AFU 15 (22.9 months compared with12.9 months; HR 0.72, 95% CI 0.57 to 0.91, p=0.005). The STOpCaP meta‑analysis found that, in men with metastatic prostate cancer at 4 years, time to disease progression was statistically significantly longer in men taking docetaxel plus ADT compared with ADT alone (estimated treatment failure 64% compared with 80%; HR 0.64, 95% CI 0.58 to 0.70, p<0.0001; NNT 7).

  • There is currently no evidence that the effect of docetaxel varies significantly in subgroups of men with hormone‑sensitive prostate cancer. The STOpCaP meta‑analysis found that, in men with metastases, overall survival was statistically significantly increased at 4 years with docetaxel compared with ADT alone, but there was no significant difference between the groups in men with non‑metastatic prostate cancer. However, the smaller number of deaths in men without metastases means this analysis was probably underpowered to detect a difference between the groups when it was undertaken, but it is possible that the results may change with longer follow‑up. The meta‑analysis found that time to disease progression was statistically significantly longer in men taking docetaxel compared with ADT alone in subgroups of men both with and without metastatic prostate cancer.

  • Little information is available on the effect of these regimens on quality of life. GETUG-AFU 15 reported that, although quality of life was statistically significantly impaired during docetaxel treatment, global scores were generally similar between the combination and ADT alone groups at 12 months. STAMPEDE is expected to report on patient‑reported outcomes in due course.

  • There are differences between the RCTs that make it difficult to compare the results; for example, the numbers of men with high volume compared with low volume metastases, the proportions of men with metastatic disease at diagnosis or following treatment for localised disease, definitions of outcomes, use of newer treatments for prostate cancer, and the length of follow‑up. The number of men with metastases at diagnosis was high in all 3 RCTs (60–70% compared with 25% in the general population). The evidence for using docetaxel in men with non‑metastatic or recurrent metastatic hormone‑sensitive prostate cancer is less robust.

  • In STAMPEDE and CHAARTED, 77% and 74% of men respectively received the planned 6 cycles of docetaxel. In GETUG-AFU 15, 48% of men received the maximum 9 cycles of treatment: the median number of cycles was 8. This suggests that treatment was tolerated.

  • Four deaths in GETUG-AFU 15, 1 death in CHAARTED and 8 deaths in STAMPEDE (7 in the docetaxel, zoledronic acid and ADT arm and 1 in the docetaxel plus ADT arm) were considered possibly or probably related to docetaxel treatment. Grade 3–5 adverse events (severe, life‑threatening or disabling adverse events or those resulting in death) were reported in 38.1% of men taking docetaxel plus ADT in GETUG-AFU 15 (72/189 compared with 0/1228 with ADT alone), 29.5% of men in CHAARTED (115/390; results for ADT alone not reported) and 52.4% of men in STAMPEDE (288/550 compared with 399/1288 [32.5%] with ADT alone). Statistical analyses were not reported.

  • According to the summary of product characteristics for Taxotere, the originator brand of docetaxel, the adverse effects most commonly reported with docetaxel 75 mg/m2 when used for prostate cancer (in combination with prednisone or prednisolone) are neutropenia (32%), anaemia (4.9%), fatigue (3.9%), infection (3.3%), nausea (2.4%), vomiting (1.2%), diarrhoea (1.2%) and peripheral sensory neuropathy (1.2%).

  • Although the adverse event profile of docetaxel is well‑established, caution should be used in men with comorbidity and poor performance status (who were generally excluded from the RCTs), and men should be monitored carefully for toxicity.

Full text of evidence review.

Context and estimated impact for the NHS

In the 3 RCTs included in this evidence summary, docetaxel 75 mg/m2 was administered every 3 weeks, usually for 6 cycles. Assuming the average body surface area of a man with cancer is 1.91 m2 (Sacco et al. 2010), the approximate dose of docetaxel is 140 mg, which costs £1023 if 1 x 2 ml vial plus 3 x 0.5 ml vials containing 40 mg/ml are used. The cost of 6 cycles of docetaxel treatment is, therefore, approximately £6138 per person (MIMS, November 2015).

This is the cost of docetaxel only (excluding VAT) and does not include any procurement discounts or other costs incurred, such as dilution and administration or standard supportive therapy.

Full text of context and estimated impact for the NHS.

About this evidence summary

'Evidence summaries: unlicensed or off‑label medicines' summarise the published evidence for selected unlicensed or off‑label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision‑making and support the construction and updating of local formularies.

The summaries support decision‑making on the use of an unlicensed or off‑label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.

The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance.