TA887 · STA
Source documents
Intervention
Conditions
Comparators
| Name | Type | Established | Committee preferred |
|---|---|---|---|
| cabazitaxel | active drug | Yes | Yes |
| docetaxel | active drug | Yes | — |
| radium-223 dichloride | active drug | Yes | — |
| best supportive care | best supportive care | Yes | — |
| retreatment with abiraterone or enzalutamide | active drug | — | — |
| abiraterone or enzalutamide retreatment | active drug | — | — |
| abiraterone | active drug | — | — |
| enzalutamide | active drug | — | — |
Clinical trials
| Trial | Design | Phase | Pivotal |
|---|---|---|---|
| PROfound | RCT | Phase 3 | Yes |
| CARD | RCT | 3 | Yes |
| TAX327 | RCT | 3 | — |
| TROPIC | RCT | — | — |
Economic model
ICER
Methodological decisions (32)
Company initially limited appraisal to prior taxane group with cabazitaxel as sole comparator. Committee required consideration of both prior taxane and no prior taxane groups with multiple comparators. Prior taxane group: cabazitaxel, docetaxel retreatment, and radium-223. No prior taxane group: docetaxel and best supportive care.
Company: Limited to prior taxane group; cabazitaxel only comparator
Committee: Separate analysis of prior taxane and no prior taxane groups with multiple comparators (cabazitaxel, docetaxel retreatment, radium-223 for prior taxane; docetaxel and best supportive care for no prior taxane)
ICER impact: uncertain_direction
Whether retreating with abiraterone or enzalutamide is an appropriate comparator. Committee noted this is not offered in NHS practice.
Company: Compared olaparib with abiraterone or enzalutamide retreatment in PROfound
Committee: This comparator does not reflect NHS practice and is not offered in the NHS
ICER impact: uncertain_direction
Use of hazard ratios from BRCA-mutation prior taxane subgroup to model comparative effectiveness with cabazitaxel
Company: Initial approach of comparing BRCA-mutation prior taxane subgroup with whole group
Committee: Use hazard ratios from the BRCA-mutation prior taxane subgroup to model cabazitaxel effectiveness, consistent with use of same subgroup data for other model inputs
ICER impact: uncertain_direction
Method for estimating cost of olaparib using relative dose intensity
Company: Used mean relative dose intensity from PROfound
ERG: Preferred median relative dose intensity; later questioned whether costs should be based on packs prescribed rather than tablets consumed
Committee: Preferred costs calculated for each person based on individual dose and duration; acknowledged company approach acceptable for decision making
ICER impact: negligible
Proportion of patients receiving prophylactic G-CSF with cabazitaxel and duration of treatment
Company: Assumed all people having cabazitaxel had prophylactic G-CSF for 14 days, aligned with CARD and marketing authorisation
ERG: Assumed lower proportion based on clinical expert survey and 7 days duration based on clinical opinion
Committee: Agreed ERG's estimate was appropriate; company followed this approach in revised modelling
ICER impact: decreases
Costing of best supportive care after disease progression
Company: Assumed different costs for BSC depending on whether person had active treatment after progression to avoid double counting
ERG: Assumed same BSC costs regardless of whether active treatment received
Committee: Agreed with ERG approach that same BSC costs incurred for everyone
ICER impact: uncertain_direction
Inclusion of BRCA mutation testing costs in cost-effectiveness estimates
Company: Excluded testing costs in initial base case as test is in NHS Genomic Test Directory; included in scenario analysis
ERG: Included testing costs in base case as NHS does not routinely test; calculated cost to identify 1 BRCA-positive person
Committee: Agreed revised company approach to include testing costs in base case was appropriate
ICER impact: increases
Whether costs of testing for BRCA mutations should be included in cost-effectiveness estimates
Company: Excluded BRCA testing costs from initial base case, included in scenario analysis only, arguing that testing is part of standard NHS practice via the NHS Genomic Test Directory
ERG: Included testing costs in base case, based on clinical advice that routine testing is not standard NHS practice
Committee: Testing costs should be included; testing is not standard NHS care despite inclusion in NHS Genomic Test Directory. Committee noted clinical practice varies and at least one clinical expert does not routinely test unless family history is present.
ICER impact: increases
Cost of best supportive care relative to active treatment receipt
Company: Initially differed cost of best supportive care depending on whether active treatment had been received
Committee: Cost of best supportive care should be the same regardless of whether people had active treatment after progression
ICER impact: uncertain_direction
Use of prophylactic G-CSF (granulocyte-colony stimulating factor) with cabazitaxel
Company: Initially assumed all people on cabazitaxel received prophylactic G-CSF
Committee: Only a proportion of people having cabazitaxel should be assumed to have prophylactic G-CSF, for an average of 7 days
ICER impact: decreases
Whether to adjust for treatment switching in PROfound using RPSFTM and recensoring
Company: Used RPSFTM with recensoring to adjust for treatment switching in PROfound; inappropriate to adjust for CARD as trial followed NHS practice
ERG: Agreed RPSFTM was most appropriate; preferred to consider results with and without recensoring as both can bias results
Committee: Company's method for adjusting for treatment switching in PROfound is appropriate including recensoring. Inappropriate to adjust for CARD but uncertainty remains in effect estimate.
ICER impact: uncertain_direction
Whether mitoxantrone plus prednisone from TAX327 and TROPIC is equivalent to abiraterone/enzalutamide control arms in PROfound and CARD
Company: Used mitoxantrone as anchor for indirect comparison assuming equivalence to PROfound control
Committee: Mitoxantrone similar to control arms but TROPIC population had not received abiraterone/enzalutamide making it incomparable
ICER impact: increases
Company used indirect treatment comparison between PROfound (olaparib vs abiraterone/enzalutamide) and CARD (cabazitaxel vs abiraterone/enzalutamide) to compare olaparib with cabazitaxel. Multiple differences between trials identified.
Company: Used RPSFTM for indirect comparison; BRCA mutation status and prior cabazitaxel do not affect comparability; TROPIC should be excluded
ERG: Highlighted differences in BRCA mutation status, prior cabazitaxel exposure, blinding status between PROfound and CARD. Noted some studies suggest BRCA status modifies treatment effect.
Committee: Differences between PROfound and CARD create uncertainty in indirect comparison; TROPIC population not comparable and unlikely to reduce uncertainty
ICER impact: increases
Validity and composition of network meta-analysis for treatment comparisons
Company: Conducted indirect treatment comparison for prior taxane and no prior taxane subgroups
ERG: Participated in network meta-analysis; noted concerns about generalisability of no prior taxane subgroup
Committee: Significant uncertainty in network meta-analyses, particularly for no prior taxane group; this should reduce the maximum acceptable ICER threshold
ICER impact: increases
Whether to use hazard ratios from whole licensed population or BRCA prior-taxane subgroup when modelling cabazitaxel arm
Company: Initially used hazard ratios from licensed population (larger sample size) rather than prior taxane subgroup
Committee: Should use hazard ratios from BRCA prior-taxane subgroup to match population and other model inputs; committee preferred this revised approach
ICER impact: uncertain_direction
PROfound trial included some people with both abiraterone and enzalutamide prior treatment, which does not reflect NHS practice. Baseline characteristics otherwise generalisable.
Committee: Results should be interpreted with caution; some prior treatment patterns not reflective of NHS practice
ICER impact: uncertain_direction
Whether baseline characteristics in PROfound BRCA-mutation prior taxane subgroup are generalisable to NHS patients. Committee noted some prior treatment regimens (both abiraterone and enzalutamide) did not reflect NHS practice.
Company: Baseline characteristics are generalisable to NHS
Committee: Baseline characteristics generalisable except for some patients having had both enzalutamide and abiraterone before trial
ICER impact: uncertain_direction
Whether post-progression treatments in PROfound and CARD reflect NHS practice. PROfound and CARD included abiraterone/enzalutamide after progression (no clinical benefit in NHS); NHS would use radium-223 dichloride instead.
Company: Excluded abiraterone and enzalutamide from post-progression treatments. Did scenario analyses varying hazard ratio by 5% and 10%.
Committee: Differences in post-progression treatments affect validity of indirect comparison and generalisability to NHS practice
ICER impact: uncertain_direction
Representativeness of PROfound trial population to NHS practice, particularly for no prior taxane subgroup
Company: Used PROfound data for both prior taxane and no prior taxane groups
ERG: Clinical advice suggested PROfound participants without prior taxane were unlikely to represent people who cannot or should not have docetaxel in NHS practice
Committee: Significant concern that no prior taxane group in PROfound does not reflect NHS patients who cannot or should not have docetaxel; no modelling specifically for this clinical scenario
ICER impact: increases
PROfound primary endpoint was radiographic progression-free survival; overall survival secondary. Company compared olaparib with retreatment with abiraterone or enzalutamide, which has no clinical benefit and is not offered in NHS practice.
Committee: Comparison with abiraterone/enzalutamide retreatment not reflective of NHS practice; indirect comparison needed with relevant comparators
ICER impact: uncertain_direction
In TAX327, company assumed docetaxel's relative treatment effect on progression-free survival equals that on overall survival, as progression-free survival was not reported
Company: Assumed same relative effect size for progression-free and overall survival in docetaxel
Committee: This assumption increased uncertainty in analyses
ICER impact: increases
Choice of parametric curve to extrapolate overall survival in prior taxane group. Committee noted none of the curves fitted observed hazard rates well.
Company: Initially chose log-logistic, then exponential citing best fit, then changed to Weibull after committee discussion
ERG: Chose Rayleigh distribution based on best statistical and visual fit; noted Weibull was second preferred
Committee: Both Weibull and Rayleigh appear reasonable but possibly pessimistic; little difference between them; both equally plausible and equally uncertain
ICER impact: uncertain_direction
Choice of parametric curve to extrapolate overall survival in no prior taxane group for comparisons with docetaxel and best supportive care
Company: Used log-logistic distribution for both arms
ERG: Preferred Rayleigh distribution
Committee: Both log-logistic and Rayleigh appear plausible; similar extrapolations for docetaxel and best supportive care arms but some differences in olaparib arms
ICER impact: uncertain_direction
Choice of parametric curve for extrapolating overall survival in prior taxane group
Company: Initially chose log-logistic, then changed to exponential for best fit; after committee feedback, chose Weibull distribution
ERG: Chose Rayleigh distribution based on best statistical and visual fit
Committee: Agreed both Weibull and Rayleigh extrapolations were equally plausible and equally pessimistic; took both into account
ICER impact: uncertain_direction
Choice of parametric curve for extrapolating overall survival in no prior taxane group
Company: Selected log-logistic distribution for both arms; stated it had best visual fit and statistical match to Kaplan-Meier data
ERG: Preferred Rayleigh distribution; considered log-logistic may overestimate long-term olaparib survival
Committee: Concluded both log-logistic and Rayleigh distributions showed good visual and statistical fit with plausible long-term survival predictions
ICER impact: uncertain_direction
Choice of parametric curves for extrapolating overall survival beyond trial follow-up
Company: Used Weibull curve in updated base case for prior taxane group; log-logistic for no prior taxane group
ERG: Preferred Rayleigh curve for both groups
Committee: Both Weibull and Rayleigh curves were considered plausible; both predicted at least 3-month survival benefit. However, given uncertainty in network meta-analyses, specific curve choice was not determinative.
ICER impact: uncertain_direction
Data source for modelling olaparib treatment duration and costs
Company: Used time until disease progression from PROfound to model treatment duration, as consistent with cabazitaxel trial data
ERG: Preferred to use time to stopping treatment data from PROfound, as curve was above progression-free survival curve and aligned with relative dose intensity
Committee: Agreed that time to stopping treatment better estimates treatment duration and costs of olaparib than progression-free survival
ICER impact: increases
Duration of olaparib treatment and timing of dose adjustments
Company: Used time to stopping treatment data from PROfound to model treatment duration
Committee: Time to stopping treatment data is appropriate for modelling duration
ICER impact: negligible
Modelling of post-progression treatments after olaparib and cabazitaxel
Company: Model allowed only 1 active treatment after progression; assumed different treatments depending on first treatment; included abiraterone/enzalutamide retreatment; provided scenario analyses excluding cabazitaxel retreatment and all post-progression costs
ERG: Noted company approach did not reflect NHS practice; noted PROfound data showed more than 1 active treatment on average; used trial proportions but acknowledged limitations
Committee: Acknowledged both approaches did not reflect NHS practice but acceptable for decision making as minimal effect on cost-effectiveness
ICER impact: negligible
Modelling of post-progression treatments available after olaparib or cabazitaxel failure
Company: Initially included retreatment with abiraterone or enzalutamide after progression
ERG: Challenged the assumption of retreatment with hormonal agents
Committee: Post-progression treatments should not include retreatment with abiraterone or enzalutamide
ICER impact: increases
Source of utility values for health states
Company: Used utility values from PROfound; mapped EQ-5D-5L to EQ-5D-3L; included quality of life decrement for IV administration of cabazitaxel
Committee: Concluded company's utility values were appropriate
ICER impact: uncertain_direction
Source and appropriateness of health-state utility values
Company: Used utility values from PROfound trial, mapped EQ-5D-5L to EQ-5D-3L values; modelled worse quality of life with cabazitaxel than olaparib with additional decrement for intravenous administration
Committee: Utility values from PROfound are appropriate
ICER impact: negligible
Evidence gaps
Commercial arrangement
Special considerations
Cross-references