Targeting DNA Repair Pathways With Lynparza May Delay Prostate Cancer Progression

Phase 3 trial findings showed that treatment with Lynparza delayed disease progression by about four months compared with newer hormonal agents in pre-treated patients with metastatic castration-resistant prostate cancer and faulty DNA repair genes.

Treatment with Lynparza (olaparib) delayed prostate cancer progression by about four months compared with newer hormonal agents in pre-treated patients with faulty DNA repair genes, according to findings from the phase 3 PROfound trial.

Moreover, the PARP inhibitor also prolonged overall survival by over three months, according to preliminary data from the study.

“Prostate cancer has lagged behind all other common solid tumors in the use of molecularly targeted treatment so it is very exciting that now we can personalize an individual’s treatment based on specific genomic alterations in their cancer cells,” study author Dr. Maha Hussain, from the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago, said in a press release.

Loss-of-function alteration in homologous recombination repair genes, such as BRCA1, BRCA2 and ATM mutations, are associated with PARP inhibition. Since targeting DNA repair pathways with PARP inhibitors is already used to treat breast and ovarian cancer, the researchers compared Lynparza with Xtandi (enzalutamide) or Zytiga (abiraterone acetate) — the latest forms of hormonal treatment in patients with metastatic castration-resistant prostate cancer.

Treatment was evaluated in two groups of men: those who had alterations in BRCA1, BRCA2 or ATM genes (cohort A) and those who had alterations in any one of 12 other genes known to be involved in DNA repair (cohort B).

In cohort A, median progression-free survival (the time from the start of treatment to disease progression or worsening) was 7.4 months with Lynparza, compared with 3.6 months in those who received treatment with hormonal therapy. Among both cohorts of patients, median progression-free survival was 5.8 months, compared with 3.5 months, respectively.

An interim analysis showed that median overall survival was 18.5 months with Lynparza, compared with 15.1 months in the hormonal treatment arm of cohort A. In the overall population, median overall survival was 17.5 months, compared with 14.3 months, respectively.

Treatment duration was also longer in men who received Lynparza versus hormonal therapy

(7.4 months vs. 3.9 months).

Side effects occurred more frequently in the Lynparza arm, compared with hormonal therapy, an included anemia (46.1% vs. 15.4%, respectively), nausea (41.4% vs. 19.2%), decreased appetite (30.1% vs. 17.7%) and fatigue (26.2% vs. 20.8%). Treatment discontinuation was also higher with Lynparza (16.4% vs. 8.5%, respectively).

“We saw the benefits of olaparib in all sub-groups of patients, regardless of country, age, prior therapy and severity of disease, including in those with worse disease that had spread to their liver or lungs,” Hussain said. “To see such a significant effect on disease progression and other clinically relevant effects such as pain progression and objective response rate is a remarkable achievement in such heavily pre-treated patients with prostate cancer.”