Apalutamid (3) – Erleada®

• Clinical trials
  • The SPARTAN trial is a randomised, double-blind, placebo-controlled, parallel-group trial.

Adult men with non-metastatic castration-resistant prostate cancer (nmCRPC) who are at high risk of developing metastases

• Consequently, the G-BA has determined that apalutamide, for the treatment of adult men with non-metastatic castration-resistant prostate cancer who are at high risk of developing metastases, compared with the appropriate comparator therapy – a watch-and-wait approach whilst continuing existing conventional ADT – has determined that there is a minor additional benefit.
• Consequently, the certainty of the evidence for the established additional benefit is classified as ‘indication’.
• mortality
  • Overall survival was defined in the SPARTAN study as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, a statistically significant difference was observed between the treatment arms in favour of apalutamide.
  • The median overall survival at the third data cut-off was 66.10 months in the apalutamide arm and 58.68 months in the control arm.
  • Although apalutamide leads to an improvement in overall survival, the extent of apalutamide’s effect compared with a watch-and-wait approach, taking into account the patients’ remaining life expectancy in the current treatment context, is assessed as a relevant, but no more than a minor improvement.
• Morbidity – Metastasis-Free Survival (MFS)
  • In the SPARTAN study, the endpoint MFS was defined as the time from randomisation to the first occurrence of a confirmed radiographically detectable bone or soft-tissue distant metastasis, or until death.
  • MFS was statistically significantly prolonged in the apalutamide arm compared with the control arm.
  • In this study, the morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures (radiographic detection of metastases) and thus solely on the basis of primarily asymptomatic findings that are not directly relevant to the patient.
  • Consequently, there are major uncertainties regarding the interpretability of the results for this endpoint in terms of patient-relevant benefit; for this reason, the MFS endpoint is not taken into account in the present assessment.
• Morbidity – time to initiation of cytotoxic chemotherapy
  • In the SPARTAN study, the endpoint ‘time to initiation of cytotoxic chemotherapy’ was defined as the time from randomisation to the start of a new course of cytotoxic chemotherapy for prostate cancer.
  • Notwithstanding the fundamental question of whether the endpoint ‘time to initiation of cytotoxic chemotherapy’ should also be reflected in other relevant endpoints in order to be assessed as patient-relevant, in the present case there are significant uncertainties regarding the interpretability of the results for this endpoint, which mean that no conclusions regarding additional benefit can be drawn from the available data.
• Morbidity – Symptomatic progression
  • The composite endpoint of symptomatic progression assessed in the SPARTAN study, defined as the time from randomisation to first documentation, comprises the following components: • Development of a skeletal-related event (pathological fractures, spinal cord compression or the need for surgical intervention or radiotherapy to the bone), • Progression of pain or worsening of disease-related symptoms requiring the initiation of a new systemic cancer therapy, • Development of clinically significant symptoms due to locoregional tumour progression requiring surgical intervention or radiotherapy.
  • The endpoint of symptomatic progression, for which apalutamide demonstrates a statistically significant advantage over a watch-and-wait approach, is therefore considered to be clinically relevant.
  • Based on the available data, this effect is interpreted as a moderate improvement in disease-related symptoms that has not been achieved previously.
• Quality of life – FACT-P
  • Health-related quality of life was self-reported by patients in the SPARTAN study and assessed using the FACT-P questionnaire.
  • There is no statistically significant difference in the total score between the treatment arms.
  • Only the total score is included in the assessment of additional benefit, as this provides a comprehensive view of the data on patients’ health-related quality of life.
• Side effects – Total adverse events (AEs)
  • Adverse events (AEs) occurred in almost all study participants.
  • The results are presented here for supplementary information only.
• Overall assessment
  • For the re-assessment of the benefits of apalutamide for the treatment of adult men with non-metastatic castration-resistant prostate cancer (nmCRPC) who are at high risk of developing metastases, results are available for the endpoint categories of mortality, morbidity, health-related quality of life and side effects from the SPARTAN trial.
  • The improvement achieved by apalutamide in the mortality endpoint category compared with a watch-and-wait approach is assessed, taking into account the patients’ remaining life expectancy in the current treatment situation, as a relevant improvement, but no more than a minor one.
  • In the morbidity endpoint category, only some of the available endpoints or study results allow for valid conclusions. Here, a patient-relevant advantage from treatment with apalutamide is evident only for the symptomatic progression endpoint. Based on the available data, this effect is assessed as a previously unachieved moderate improvement in symptoms.
  • With regard to health-related quality of life, treatment with apalutamide shows neither positive nor negative effects.
  • With regard to side effects, too, neither an advantage nor a disadvantage can be identified for apalutamide compared with a watch-and-wait approach. Statistically significant differences are observed only in the specific adverse events. In detail, both advantages and disadvantages are evident.
  • In the overall assessment of the available results on patient-relevant endpoints, the advantages in terms of overall survival and the improvement in clinical symptoms are not offset by any disadvantages in health-related quality of life or side effects.
• Overall assessment
  • Overall, there is an indication of a minor additional benefit of apalutamide compared with a watch-and-wait approach, whilst maintaining existing conventional androgen deprivation therapy.

Courtesy translation only, please refer to the German original.