Rucaparib (2) – Rubraca®

• Clinical trials
  • The benefit assessment is based on the results of the double-blind, randomised, controlled, parallel-group ARIEL3 trial.
  • In this ongoing trial, rucaparib is being compared with placebo.

Maintenance therapy in adult female patients with platinum-sensitive, recurrent, high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in remission (complete or partial) following platinum-based chemotherapy

• For rucaparib as monotherapy in maintenance treatment for adult female patients with platinum-sensitive, recurrent, high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in remission (complete or partial) following platinum-based chemotherapy, additional benefit is not proven.
• mortality
  • With regard to the endpoint of overall survival, there is no statistically significant difference between rucaparib and watchful waiting.
  • However, due to the limited data available, the result for this endpoint cannot be conclusively assessed.
• Morbidity – Progression-free survival (PFS)
  • With regard to invPFS1, there is a statistically significant difference between the two treatment arms (hazard ratio (HR): 0.365; [95% confidence interval (CI) 0.295; 0.451]; p-value < 0.0001).
  • Median time to this event was 10.8 months in the rucaparib treatment arm, compared with 5.4 months in the control arm.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • The morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures (in accordance with RECIST v1.1).
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint.
• Morbidity – Health status
  • Health status is assessed in the ARIEL3 study using the visual analogue scale (VAS) of the EQ-5D.
  • In the responder analysis, using the underlying MID of 7 points, no statistically significant difference was observed between rucaparib and watchful waiting (HR: 1.26; [95% CI 0.99; 1.60]; p = 0.056).
• Morbidity – Symptoms
  • The data collected using the FOSI-18 DRS-P subscale (Disease-related Symptoms Subscale – physical of the Functional Analysis of Cancer Therapy Ovarian Symptom Index-18) are, contrary to the pharmaceutical manufacturer’s assessment, not classified under the ‘quality of life’ category but under the ‘symptoms’ endpoint.
  • The analyses of the mean difference reveal a statistically significant disadvantage for rucaparib, with the confidence interval of Hedges’ g lying entirely outside the irrelevance range (mean difference –2.3 [3.1; –1.5]; p < 0.001; Hedges’ g: –0.57 [–0.78; –0.37]).
  • Overall, therefore, for the morbidity category, Rucaparib is at a disadvantage compared with a ‘wait-and-see’ approach.
• quality of life
  • No data on quality of life were collected in the ARIEL3 study.
• Side effects – total adverse events (AEs)
  • In the rucaparib arm, every patient experienced an adverse event; in the placebo arm, 96.3% were affected by an adverse event.
• Side effects – Serious adverse events (SAEs)
  • With regard to the SUE endpoint, there was no statistically significant difference between the two treatment arms.
  • In the treatment arm, 22.3% of patients experienced a SAE, compared with 10.6% in the control arm.
• Side effects – Severe side effects (CTCAE grade ≥ 3)
  • There is a statistically significant difference to the detriment of rucaparib (HR: 4.33; [95% CI: 2.93; 6.40]; p < 0.001).
  • Patients in the rucaparib arm experienced a severe AE a median of 36.9 months earlier.
• Side effects – discontinuation due to side effects
  • In the rucaparib arm, there was a statistically significant disadvantage (HR: 5.55; [95% CI: 2.00; 15.40]; p = 0.001) with regard to therapy discontinuation due to adverse events.
• Side effects – Specific AEs
  • With regard to the endpoints ‘General disorders and administration site conditions (AE, SOC)’, ‘Gastrointestinal disorders (AE, SOC)’, ‘Photosensitivity reaction (AE, PT)’, ‘Taste disturbance (AE, PT)’ and ‘Blood and lymphatic system disorders (SOC, CTCAE grade ≥ 3)’, there was a statistically significant difference to the detriment of rucaparib.
  • With regard to the endpoints “Myelodysplastic syndrome (AE, PT)” and “Acute myeloid leukaemia (AE, PT)”, there is no statistically significant difference between the two treatment arms.
  • For the endpoint “Skeletal muscle, connective tissue and bone disorders (AE, SOC)”, there is a significant advantage with rucaparib treatment.
  • In summary, the category of side effects shows overwhelmingly more disadvantages for rucaparib compared with a ‘wait-and-see’ approach.
• Overall assessment / Conclusion
  • With regard to the endpoint of mortality, there is no difference between rucaparib and watchful waiting; however, this endpoint cannot be conclusively assessed on the basis of the available data, which must still be regarded as immature.
  • With regard to the morbidity category, no difference was observed in health status, as assessed using the EQ-5D VAS, between the treatment arms. However, a statistically significant, relevant disadvantage in symptoms was identified as mean differences in the FOSI-18 DRS-P subscale, meaning that, overall, rucaparib is at a disadvantage in the morbidity category.
  • There are disadvantages with regard to severe adverse events (CTCAE grade ≥ 3) and discontinuation due to adverse events. Apart from the endpoint ‘musculoskeletal, connective tissue and bone disorders (AE, SOC)’, the detailed analysis also reveals exclusively disadvantages to the detriment of rucaparib in the side effects category.
  • Overall, therefore, whilst data on quality of life are lacking, there are exclusively disadvantages in the morbidity categories and overwhelmingly so in the side effect category; however, these cannot be conclusively assessed in view of the immature data for the overall survival endpoint.
  • Overall, for rucaparib as maintenance therapy in adult female patients with platinum-sensitive, recurrent, high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in remission (complete or partial) following platinum-based chemotherapy. The additional benefit is not proven.

Courtesy translation only, please refer to the German original.