Rucaparib improves progression-free survival in metastatic, castration-resistant prostate cancer with BRAC alteration compared to usual care
Rucaparib in men with metastatic, castration-resistant prostate cancer and BRAC alteration improved progression-free survival compared to physician’s choice of treatment according to the findings of a randomised trial by the TRITON3 investigators.
The five-year survival of men diagnosed with metastatic prostate cancer has been estimated to be around 28%. Moreover, the presence of inherited mutations in DNA-repair genes such as BRCA2, increase the risk of the cancer being lethal with one analysis finding that such mutations were detected in nearly 12% of metastatic prostate cancers. In fact, the presence of BRAC 1 and 2 mutations are associated with poor survival outcomes in men with prostate cancer. The enzyme poly(ADP-ribose) polymerase facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Furthermore, use of PARP inhibitors to selectively kill a tumour, represents a new concept in cancer treatment.
In a phase 2 trial (TRITON2), the use of oral rucaparib, which is a PARP inhibitor, showed that the drug had anti-tumour activity in men with metastatic, castration-resistant prostate cancer and a deleterious BRAC alteration. In the current study, researchers sought to be build on the success of TRITON2. They undertook a phase 3 trial in men with metastatic, castration-resistant prostate cancer and a BRCA1, BRCA2, or ataxia telangiectasia mutated (ATM) alteration, whose disease had progressed after use of a second-generation androgen-receptor pathway inhibitor. Participants were randomised 2:1 to oral rucaparib (600 mg twice daily) or a physician’s choice control which was docetaxel or abiraterone acetate or enzalutamide. They set the primary outcome as the median duration of imaging-based progression-free survival according to independent review.
Rucaparib and progression-free survival
A total of 405 men with a median age of 70.5 years were randomised to rucaparib (270) or control. In the rucaparib arm, 201 patients had a BRAC alteration.
After 62 months, the median duration of progression-free survival in those with a BRAC alteration was 11.2 months compared to 6.4 months in the control arm (Hazard ratio, HR = 0.50, 95% CI 0.36 – 0.69, p < 0.001). Similarly, among the intention-to-treat group, survival was also significantly longer (HR = 0.61, 95% CI 0.47 – 0.80, p < 0.001). However, in an exploratory analysis, the median duration of progression-free survival in the ATM subgroup was not significantly lower (HR = 0.95, 95% CI 0.59 – 1.52).
Fizazi K et al. Rucaparib or Physician’s Choice in Metastatic Prostate Cancer. N Eng J Med 2023