NIHR Signal Bone-targeting drugs improve quality of life, but not survival in prostate cancer that has spread to bone

Published on 27 September 2016

The drug zoledronic acid delayed the onset of bone complications by two months in men with prostate cancer that had spread to the bone. Though it did not increase overall survival, it improved quality of life by reducing important complications such as fractures and spinal cord compression.

The radioactive drug strontium-89 was also tested and delayed the combined outcome of bone-related complications, pain or death by about one month. It also had no effect on overall survival or the number of bone complications.

Both treatments were compared with chemotherapy alone. Current NICE guidance recommends strontium-89 to treat prostate cancer that has spread to the bone, but not zoledronic acid unless other treatment has failed due to costs. The branded version of zoledronic acid did not give value for money but cheaper generic versions, now available, could be a better use of NHS resources.

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Why was this study needed?

Prostate cancer is the second most common cause of cancer deaths in men in the UK. Just over 10,000 men died from prostate cancer in 2009. The rate has been declining every year, with many more men now living with the disease.

Hormone therapy may be given – alone or alongside other treatments like radiotherapy – to stop the production of testosterone, which causes the cancer cells to grow. If the disease relapses after initial hormone treatment, it’s called castration-refractory prostate cancer (CRPC). The next step for men with CRPC is usually chemotherapy with docetaxel.

CRPC can spread to the bone, causing pain, fractures and other serious complications. There are various options available to treat the bone damage. These include drugs known as bisphosphonates such as zoledronic acid, and radioactive substances such as strontium-89.

Previous studies have suggested that adding the bone-targeting drugs zoledronic acid or strontium-89 to chemotherapy in men with CRPC may improve survival and reduce the risk of bone-related complications. This trial was funded by the NIHR to see if these drugs worked and, if so, if they were good value for money.

What did this study do?

This randomised controlled trial (TRAPEZE) assessed the effects of providing bone-targeting treatment with zoledronic acid or strontium-89 alongside docetaxel chemotherapy in men with CRPC.

A total of 757 men with CRPC that had spread to the bone were recruited from oncology departments across the UK.

Participants were randomly assigned to one of four treatment groups: docetaxel alone; docetaxel plus zoledronic acid; docetaxel plus strontium-89; or docetaxel plus zoledronic acid and strontium-89. The steroid prednisolone was given to all groups.

Participants were followed up for an average of 22 months to look at time to progression of bone-related complications, pain progression or death. The study also considered the cost effectiveness of the treatment combinations.

What did it find?

  • Strontium-89 plus docetaxel and zoledronic acid plus docetaxel both increased time without bone-related complications, pain progression or death by about a month compared with docetaxel alone. This difference was not statistically significant for zoledronic acid, but was just technically significant for strontium-89 when adjusted for cancer score and study centre (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.73 to 0.99).
  • When bone-related complications were considered separately, zoledronic acid increased the time until complications by more than two months compared with docetaxel alone (HR 0.78, 95% CI 0.65 to 0.95). It also reduced the total number of complications.
  • Strontium-89 did not increase the time until bone-related complications compared with docetaxel alone.
  • Neither treatment combination improved overall survival compared with docetaxel alone.
  • Compared with docetaxel, strontium-89 cost an extra £16,590 for each year that the person lived a good quality of life. This cost falls just below the usual NHS willingness-to-pay threshold of £20,000 to £30,000 a year.
  • Zoledronic acid cost an extra £42,047 per year of good quality life if the branded drug was used, but using the generic version brought the cost down to £8,005, suggesting this drug is a reasonable use of NHS resources.

What does current guidance say on this issue?

NICE guidance from 2006 recommends docetaxel for treating men with CRPC that has spread, providing that their cancer is not so serious as to require special or inpatient care.

NICE’s 2014 guideline on diagnosis and management of prostate cancer says that bisphosphonates should not be offered to prevent or reduce the complications of bone metastases in men with CRPC, but may be considered for pain relief when other treatments have failed.

It adds that strontium-89 should be considered for men with CRPC and painful bone metastases, especially those men who are unlikely to receive chemotherapy that suppresses bone marrow function.

What are the implications?

Though zoledronic acid was not effective at improving overall survival, it did prolong the time to any bone-related events. It was cost effective if using the non-branded version, and therefore may have some value in preventing bone-related complications and improving quality of life.

This study also supports the use of strontium-89 alongside docetaxel chemotherapy, in line with current NICE guidance, to improve quality of life for men with CRPC that has spread to the bone.

This study does not consider new radioactive treatments that have recently become available, such as radium-223. Further research may find these newer alternatives to be more clinically and cost effective for improving survival in men with metastatic prostate cancer.

Citation and Funding

James N, Pirrie S, Pope A et al. TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer. Health Technol Assess 2016;20(53).

This project was funded by the National Institute for Health Research Health Technology Assessment (HTA) programme (project number 06/303/205).

Bibliography

Cancer Research UK. Prostate cancer incidence statistics. London: Cancer Research UK; 2015.

James ND, Pirrie SJ, Pope AM, et al. Clinical outcomes and survival following treatment of metastatic castrate-refractory prostate cancer with docetaxel alone or with strontium-89, zoledronic acid, or both: the TRAPEZE randomized clinical trial. JAMA Oncol. 2016;2(4):493-9.

National Cancer Intelligence Network. Mortality from prostate cancer. South West Public Health Obsevatory; 2012.

NICE. Docetaxel for the treatment of hormone-refractory metastatic prostate cancer. TA101. London: National Institute for Health and Care Excellence; 2006.

NICE. Prostate cancer: diagnosis and management. CG175. London: National Institute for Health and Care Excellence; 2014.

Prostate Cancer UK. Advanced prostate cancer. London: Prostate Cancer UK; undated.

Why was this study needed?

Prostate cancer is the second most common cause of cancer deaths in men in the UK. Just over 10,000 men died from prostate cancer in 2009. The rate has been declining every year, with many more men now living with the disease.

Hormone therapy may be given – alone or alongside other treatments like radiotherapy – to stop the production of testosterone, which causes the cancer cells to grow. If the disease relapses after initial hormone treatment, it’s called castration-refractory prostate cancer (CRPC). The next step for men with CRPC is usually chemotherapy with docetaxel.

CRPC can spread to the bone, causing pain, fractures and other serious complications. There are various options available to treat the bone damage. These include drugs known as bisphosphonates such as zoledronic acid, and radioactive substances such as strontium-89.

Previous studies have suggested that adding the bone-targeting drugs zoledronic acid or strontium-89 to chemotherapy in men with CRPC may improve survival and reduce the risk of bone-related complications. This trial was funded by the NIHR to see if these drugs worked and, if so, if they were good value for money.

What did this study do?

This randomised controlled trial (TRAPEZE) assessed the effects of providing bone-targeting treatment with zoledronic acid or strontium-89 alongside docetaxel chemotherapy in men with CRPC.

A total of 757 men with CRPC that had spread to the bone were recruited from oncology departments across the UK.

Participants were randomly assigned to one of four treatment groups: docetaxel alone; docetaxel plus zoledronic acid; docetaxel plus strontium-89; or docetaxel plus zoledronic acid and strontium-89. The steroid prednisolone was given to all groups.

Participants were followed up for an average of 22 months to look at time to progression of bone-related complications, pain progression or death. The study also considered the cost effectiveness of the treatment combinations.

What did it find?

  • Strontium-89 plus docetaxel and zoledronic acid plus docetaxel both increased time without bone-related complications, pain progression or death by about a month compared with docetaxel alone. This difference was not statistically significant for zoledronic acid, but was just technically significant for strontium-89 when adjusted for cancer score and study centre (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.73 to 0.99).
  • When bone-related complications were considered separately, zoledronic acid increased the time until complications by more than two months compared with docetaxel alone (HR 0.78, 95% CI 0.65 to 0.95). It also reduced the total number of complications.
  • Strontium-89 did not increase the time until bone-related complications compared with docetaxel alone.
  • Neither treatment combination improved overall survival compared with docetaxel alone.
  • Compared with docetaxel, strontium-89 cost an extra £16,590 for each year that the person lived a good quality of life. This cost falls just below the usual NHS willingness-to-pay threshold of £20,000 to £30,000 a year.
  • Zoledronic acid cost an extra £42,047 per year of good quality life if the branded drug was used, but using the generic version brought the cost down to £8,005, suggesting this drug is a reasonable use of NHS resources.

What does current guidance say on this issue?

NICE guidance from 2006 recommends docetaxel for treating men with CRPC that has spread, providing that their cancer is not so serious as to require special or inpatient care.

NICE’s 2014 guideline on diagnosis and management of prostate cancer says that bisphosphonates should not be offered to prevent or reduce the complications of bone metastases in men with CRPC, but may be considered for pain relief when other treatments have failed.

It adds that strontium-89 should be considered for men with CRPC and painful bone metastases, especially those men who are unlikely to receive chemotherapy that suppresses bone marrow function.

What are the implications?

Though zoledronic acid was not effective at improving overall survival, it did prolong the time to any bone-related events. It was cost effective if using the non-branded version, and therefore may have some value in preventing bone-related complications and improving quality of life.

This study also supports the use of strontium-89 alongside docetaxel chemotherapy, in line with current NICE guidance, to improve quality of life for men with CRPC that has spread to the bone.

This study does not consider new radioactive treatments that have recently become available, such as radium-223. Further research may find these newer alternatives to be more clinically and cost effective for improving survival in men with metastatic prostate cancer.

Citation and Funding

James N, Pirrie S, Pope A et al. TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer. Health Technol Assess 2016;20(53).

This project was funded by the National Institute for Health Research Health Technology Assessment (HTA) programme (project number 06/303/205).

Bibliography

Cancer Research UK. Prostate cancer incidence statistics. London: Cancer Research UK; 2015.

James ND, Pirrie SJ, Pope AM, et al. Clinical outcomes and survival following treatment of metastatic castrate-refractory prostate cancer with docetaxel alone or with strontium-89, zoledronic acid, or both: the TRAPEZE randomized clinical trial. JAMA Oncol. 2016;2(4):493-9.

National Cancer Intelligence Network. Mortality from prostate cancer. South West Public Health Obsevatory; 2012.

NICE. Docetaxel for the treatment of hormone-refractory metastatic prostate cancer. TA101. London: National Institute for Health and Care Excellence; 2006.

NICE. Prostate cancer: diagnosis and management. CG175. London: National Institute for Health and Care Excellence; 2014.

Prostate Cancer UK. Advanced prostate cancer. London: Prostate Cancer UK; undated.

TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer

Published on 1 July 2016

James N, Pirrie S, Pope A, Barton D, Andronis L, Goranitis I, Collins S, McLaren D, O'Sullivan J, Parker C, Porfiri E, Staffurth J, Stanley A, Wylie J, Beesley S, Birtle A, Brown J, Chakraborti P, Russell M, Billingham L.

Health Technology Assessment Volume 20 Issue 53 , 2016

Background Bony metastatic castration-refractory prostate cancer is associated with a poor prognosis and high morbidity. TRAPEZE was a two-by-two factorial randomised controlled trial of zoledronic acid (ZA) and strontium-89 (Sr-89), each combined with docetaxel. All have palliative benefits, are used to control bone symptoms and are used with docetaxel to prolong survival. ZA, approved on the basis of reducing skeletal-related events (SREs), is commonly combined with docetaxel in practice, although evidence of efficacy and cost-effectiveness is lacking. Sr-89, approved for controlling metastatic pain and reducing need for subsequent bone treatments, is generally palliatively used in patients unfit for chemotherapy. Phase II analysis confirmed the safety and feasibility of combining these agents. TRAPEZE aimed to determine the clinical effectiveness and cost-effectiveness of each agent. Methods Patients were randomised to receive six cycles of docetaxel plus prednisolone: alone, with ZA, with a single Sr-89 dose after cycle 6, or with both. Primary outcomes were clinical progression-free survival (CPFS: time to pain progression, SRE or death) and cost-effectiveness. Secondary outcomes were SRE-free interval (SREFI), total SREs, overall survival (OS) and quality of life (QoL). Log-rank test and Cox regression modelling were used to determine clinical effectiveness. Cost-effectiveness was assessed from the NHS perspective and expressed as cost per additional quality-adjusted life-year (QALY). An additional analysis was carried out for ZA to reflect the availability of generic ZA. Results Patients: 757 randomised (median age 68.7 years; Eastern Cooperative Oncology Group scale score 0, 40%; 1, 52%; 2, 8%; prior radiotherapy, 45%); median prostate-specific antigen 143.78 ng/ml (interquartile range 50.8–353.9 ng/ml). Stratified log-rank analysis of CPFS was statistically non-significant for either agent (Sr-89, p = 0.11; ZA, p = 0.45). Cox regression analysis adjusted for stratification variables showed CPFS benefit for Sr-89 [hazard ratio (HR) 0.845, 95% confidence interval (CI) 0.72 to 0.99; p = 0.036] and confirmed no effect of ZA (p = 0.46). ZA showed a significant SREFI effect (HR 0.76; 95% CI 0.63 to 0.93; p = 0.008). Neither agent affected OS (Sr-89, p = 0.74; ZA, p = 0.91), but both increased total cost (vs. no ZA and no Sr-89, respectively); decreased post-trial therapies partly offset costs [net difference: Sr-89 £1341; proprietary ZA (Zometa®, East Hanover, NJ, USA) £1319; generic ZA £251]. QoL was maintained in all trial arms; Sr-89 (0.08 additional QALYs) and ZA (0.03 additional QALYs) showed slight improvements. The resulting incremental cost-effectiveness ratio (ICER) for Sr-89 was £16,590, with £42,047 per QALY for Zometa and £8005 per QALY for generic ZA. Conclusion Strontium-89 improved CPFS, but not OS. ZA did not improve CPFS or OS but significantly improved SREFI, mostly post progression, suggesting a role as post-chemotherapy maintenance therapy. QoL was well maintained in all treatment arms, with differing patterns of care resulting from the effects of Sr-89 on time to progression and ZA on SREFI and total SREs. The addition of Sr-89 resulted in additional cost and a small positive increase in QALYs, with an ICER below the £20,000 ceiling per QALY. The additional costs and small positive QALY changes in favour of ZA resulted in ICERs of £42,047 (Zometa) and £8005 for the generic alternative; thus, generic ZA represents a cost-effective option. Additional analyses on the basis of data from the Hospital Episode Statistics data set would allow corroborating the findings of this study. Further research into the use of ZA (and other bone-targeting therapies) with newer prostate cancer therapies would be desirable. Funding This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 53. See the NIHR Journals Library website for further project information.

Bone related complications included: pathological fracture (due to the metastases), spinal cord compression, requirement for radiotherapy to the bone, hypercalcaemia (high blood calcium level) and change in anticancer treatment to treat bone pain.

Expert commentary

Recent trials have shown that adding docetaxel to first-line hormone treatment improves survival and should be standard therapy; and that second-line hormone treatment with enzalutamide and abiraterone also increase survival. Other new strategies targeting the immune response and structural variants of the androgen receptor are likely to impact treatment of prostate cancer.

The TRAPEZE trial showed that agents targeting bone such as zoledronic acid or strontium-89 improved quality of life, but not survival. The relative costs (generic zoledronic acid less than strontium-89) against benefit (slightly better QoL for strontium-89 and fewer skeletal related events for zoledronic acid) suggest that funding the addition of generic zoledronic acid to docetaxel should be considered by NHS commissioners in men with this stage of the disease.

David E Neal, Senior Visiting Fellow and Professor Emeritus of Surgical Oncology, University of Cambridge