Clinical Pearls & Morning Reports
The PROfound trial, conducted by de Bono et al., was a randomized, open-label, phase 3 trial that evaluated olaparib in men with metastatic castration-resistant prostate cancer who had had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes that are involved in homologous recombination repair. Read the NEJM Original Article here.
Q: What percentage of patients with metastatic castration-resistant prostate cancer harbor deleterious aberrations in genes involved in the repair of DNA damage?
A: Metastatic castration-resistant prostate cancer is a heterogeneous disease with poor outcomes. Tumors in up to 30% of patients harbor deleterious aberrations in genes involved in repairing DNA damage.
Q: What are some of the genes that have a role in homologous recombination repair?
A:BRCA1 and BRCA2 are well-characterized genes involved in homologous recombination repair, and ATM functions as a DNA-damage checkpoint and indirectly activates homologous recombination repair. Loss-of-function alterations in these and other genes with a direct or indirect role in homologous recombination repair are associated with more aggressive prostate cancers. Such gene alterations confer sensitivity to poly(adenosine diphosphate–ribose) polymerase (PARP) inhibition in prostate and other cancers.
A: Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician’s choice of enzalutamide or abiraterone (control). Patients with at least one alteration in BRCA1, BRCA2, or ATM were assigned to cohort A, regardless of co-occurring qualifying alterations in any of the other genes. Patients with alterations in any of the other 12 prespecified genes were assigned to cohort B. The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review. The median imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval [CI], 0.25 to 0.47; P<0.001). The confirmed objective response rate among patients who could be evaluated was 33% (28 of 84 patients) in the olaparib group and 2% (1 of 43 patients) in the control group (odds ratio for an objective response, 20.86; 95% CI, 4.18 to 379.18; P<0.001). The median time to pain progression was significantly longer in the olaparib group than in the control group. The most common adverse events of any grade were anemia, nausea, and fatigue or asthenia with olaparib and fatigue or asthenia with the control treatment.
A: Olaparib was also associated with a significantly longer duration of imaging-based progression-free survival than the control treatment in the overall population (patients with an alteration in any of the 15 prespecified genes), although this finding may also reflect the benefit seen in a subgroup of patients including the population with BRCA1 or BRCA2 alterations.