The United Kingdom’s National Institute for Health and Care Excellence will not recommend olaparib for the treatment of patients with hormone-relapsed, metastatic prostate cancer that harbors BRCA1 or BRCA2 mutations that has progressed on abiraterone acetate or enzalutamide.
The United Kingdom’s National Institute for Health and Care Excellence (NICE) will not recommend olaparib (Lynparza) for the treatment of patients with hormone-relapsed, metastatic prostate cancer that harbors BRCA1 or BRCA2 mutations that has progressed on abiraterone acetate (Zytiga) or enzalutamide (Xtandi).
Although clinical trial data have demonstrated that patients who receive olaparib have extended progression-free survival (PFS) and overall survival (OS) over those who receive re-treatment with either abiraterone or enzalutamide, evidence is unclear because re-treatment with those agents is not considered to be effective and is not standard of care in the National Health Service (NHS).
The committee also noted that the efficacy of olaparib vs cabazitaxel, radium-223 (Xofigo), or docetaxel is also unclear, because there is no evidence directly comparing them. Although an indirect comparison has indicated that olaparib may extend how long patients live vs cabazitaxel, this still remains unclear.
“The cost-effectiveness estimates are uncertain because of the limitations in the clinical evidence and economic model,” NICE stated in its appraisal consultation document. “They are higher than what NICE normally considers an acceptable use of NHS resources. Therefore, olaparib is not recommended.”
To make this decision, the committee reviewed data from the open-label, multicenter, phase 3 PROfound trial (NCT02987543), which compared olaparib with investigator’s choice of enzalutamide or abiraterone in patients with hormone-relapsed, metastatic prostate cancer who experienced disease progression on abiraterone, enzalutamide, or both.
Notably, patients with homologous recombination repair gene mutations, including BRCA1, BRCA1, ATM, among other mutations, were permitted for inclusion on the trial. Participants were stratified based on whether they previously received taxane treatment. The primary end point of the trial was time to radiographic disease progression. Overall survival was among the secondary end points evaluated.
Results from the trial indicated that olaparib resulted in an improvement in both PFS and OS vs investigator’s choice of abiraterone or enzalutamide (hazard ratio [HR], 0.39; 95% CI, 0.29-0.53) in the overall patient population. Notably, the agent increased PFS in patients who had previously received docetaxel vs those who had not (HR, 0.77; 95% CI, 0.50-1.22). However, the committee did not observe any clinical data for patients with BRCA mutations who had not previously received a taxane.
“The committee concluded that olaparib was effective compared with enzalutamide or abiraterone in PROfound, but the results should be interpreted with caution,” according to the appraisal document. “The committee also concluded that any comparison of olaparib with cabazitaxel or other relevant comparators would need to use other sources of data and an indirect treatment comparison.”
Because a direct comparison between olaparib and cabazitaxel has not been done, the company performed an indirect treatment comparison to look at PFS and OS benefit with the agents.
To do this, they identified the open-label, multicenter, phase 3 CARD trial (NCT02485691) as a source for evidence of cabazitaxel use. In this trial, cabazitaxel plus prednisone was compared with enzalutamide or abiraterone in patients with hormone-relapsed, prostate cancer. Here, the primary end point was radiographic PFS. Key secondary end points comprised OS and skeletal-related effects.
Notably, all participants had prior docetaxel and either enzalutamide or abiraterone. “Clinical experts explained that the comparator in CARD was very similar to PROfound: people who already had abiraterone would be offered enzalutamide and vice versa,” according to the appraisal document. Results from this indirect comparison indicated that olaparib resulted in improved PFS and OS over cabazitaxel.
However, there were several differences noted between the trials that might give reason for uncertainty in interpreting the data. For example, all patients in the BRCA-mutated, prior-taxane population of the PROfound trial had BRCA mutations by definition, whereas mutational status of those in the CARD trial was unknown. Additionally, in the BRCA-mutated, prior-taxane population of the PROfound study, some of the patients received prior cabazitaxel; those in the CARD trial had not received prior cabazitaxel.
Additionally, the company did not adjust for treatment switching in the CARD trial, as they had with the PROfound trial, according to the committee. “The committee considered that OS in the cabazitaxel arm in CARD may be underestimated because 33% of people in the abiraterone or enzalutamide arm switched to cabazitaxel after disease progression,” the committee noted in the appraisal document. “…This suggests that the relative efficacy of olaparib compared with cabazitaxel based upon the indirect comparison is likely overestimated.”
To estimate the cost effectiveness of olaparib in its chosen population, patient-level data from the BRCA-mutation prior-taxane subgroup of the PROfound trial was utilized to model the absolute rates of PFS and OS in those who were given olaparib.
HRs for PFS and OS from the indirect treatment comparison were applied to that data to model the efficacy for patients receiving cabazitaxel, but the HRs from the licensed population rather than the prior-taxane subgroup were utilized. The committee disagreed with this approach of comparing a subgroup with a whole group. They concluded that HRs from the prior-taxane population should be used to model survival with cabazitaxel.
Moreover, the committee concluded that it is unclear whether olaparib meets NICE’s criteria for life-extending treatments at end of life. They noted that they need to be satisfied that the estimates of extension to life are adequately robust and be shown from PFS or OS and the assumptions used in reference case economic modelling are plausible, objective, and robust.
“The committee could not determine whether olaparib offers an extension to life of at least an additional 3 months compared with NHS standard care,” according to the appraisal document. “The committee concluded it is unclear whether olaparib meets NICE’s criteria for life-extending treatments for people with a short life expectancy.”
Olaparib for previously treated BRCA-mutation positive hormone-relapsed metastatic prostate cancer. National Institute for Health and Care Excellence. February 2021. Accessed March 8, 2021. https://bit.ly/30olHzn