Targeted Therapy Delays Progression in Advanced Prostate Cancer

The PARP inhibitor olaparib (Lynparza) delayed disease progression and prolonged overall survival (OS) compared with enzalutamide (Xtandi) or abiraterone acetate (Zytiga) in men with heavily pre-treated metastatic prostate cancer and mutations associated with DNA damage repair, according to the results of a new randomized trial.

“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 treatment based on specific genomic alterations in their cancer cells,” said Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago, according to a press release.

Hussain presented results of the PROfound trial at the European Society for Medical Oncology (ESMO) 2019 Congress, held September 27 to October 1 in Barcelona (Abstract LBA12).

The PROfound trial included two cohorts of patients. In cohort A, men with metastatic prostate cancer and alterations to BRCA1, BRCA2, or ATM were randomized to receive either olaparib (162 patients) or physician’s choice of enzalutamide or abiraterone (83 patients). Cohort B included men who had alterations to any of those or 12 other genes associated with DNA damage repair. In total, 256 men received olaparib, and 131 received either enzalutamide or abiraterone acetate. All patients had progressed on prior new hormonal agent (enzalutamide or abiraterone) treatment, and 65.6% had received prior taxane therapy.          

In cohort A, 33.3% had a confirmed objective response to olaparib, compared with 2.3% of the physician’s choice cohort, for an odds ratio (OR) of 20.86 (95% CI, 4.18-379.18; P < 0.0001). In the combined analysis of cohorts A and B, the objective response rate with olaparib was 21.7%, compared with 4.5% with enzalutamide or abiraterone, for an OR of 5.93 (95% CI, 2.01-25.40; P = 0.0006).

The median progression-free survival (PFS) with olaparib in cohort A was 7.39 months, compared with 3.55 with physician’s choice, for a hazard ratio (HR) of 0.34 (95% CI, 0.25-0.47; P < 0.0001). In the combined analysis, the median PFS was 5.82 months with olaparib and 3.52 months with physician’s choice, for an HR of 0.49 (95% CI, 0.38-0.63; P < 0.0001). In cohort A, 28.11% of olaparib patients were progression-free at 12 months, compared with 9.4% of physician’s choice patients; in an analysis of both cohorts, these rates were 22.13% and 13.47%, respectively.

Not enough deaths occurred to conduct a conclusive OS analysis, but an interim analysis still favored olaparib. In cohort A, the median OS was 18.5 months with olaparib and 15.11 months with enzalutamide or abiraterone, for an HR of 0.64 (95% CI, 0.43-0.97; P = 0.0173). In the combined analysis, the median OS was 17.51 months and 14.26 months, respectively, for an HR of 0.67 (95% CI, 0.49-0.93; P = 0.0063).

Several adverse events were more common with olaparib. These included anemia (46.1% vs 15.4%) and nausea (41.4% vs 19.2%) among other symptoms; 16.4% of olaparib patients discontinued treatment due to adverse events, compared with 8.5% of physician’s choice patients.

“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 pretreated patients with prostate cancer,” Hussain said. “We saw the benefits of olaparib in all subgroups 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.”

Eleni Efstathiou, MD, PhD, of MD Anderson Cancer Center in Houston, commenting                                for ESMO, called PROfound a “landmark trial.” She noted that the delay in progression was substantially greater than what has previously been considered a success in prostate cancer trials.          

“We should not ignore that significant adverse events, such as anemia and nausea, were more common with olaparib as these can have an important effect on a patient’s ability to take the drug,” she cautioned. “Overall, these data show that, like breast and lung cancers, prostate cancer is not one, but many different diseases and we need to start identifying different groups of patients and treating them with targeted therapy.”