Study Demonstrates Promise for Olaparib in Metastatic Castration-Resistant Prostate Cancer

In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide (Xtandi) or abiraterone (Zytiga) and who had alterations in genes with a role in homologous recombination repair, olaparib (Lynparza) was found to be associated with longer progression-free survival (PFS) and improved measures of response and patient-reported end points than either enzalutamide or abiraterone, according to results from the phase III PROfound trial published in The New England Journal of Medicine. 

The randomized, open-label clinical trial also found that a benefit was observed in the overall trial population with an alteration in any of the prespecified genes with a direct or indirect role in homologous recombination repair. 

“In men with metastatic castration-resistant prostate cancer who had BRCA1, BRCA2, or ATM mutations and who had disease progression while receiving a new hormonal agent, olaparib led to a significantly longer imaging-based progression-free survival than the physician’s choice of enzalutamide or abiraterone,” the authors wrote. “The physician’s choice of either enzalutamide or abiraterone was selected as the comparator because switching between these agents does occur in practice, despite the lack of randomized evidence to support this approach.”

The primary endpoint for the study was imaging-based PFS, as assessed by an independent review committee, in patients with at least 1 alteration in BRCA1, BRCA2, or ATM. Secondary endpoints included the confirmed objective response rate, the time to pain progression, overall survival, a reduction of at least 50% in the concentration of prostate-specific antigen, and the circulating-tumor-cell conversion rate. 

Patients were assigned in a 2:1 fashion to receive either olaparib or the physician’s choice of either enzalutamide or abiraterone. Moreover, patients who were eligible for the trial were included in 1 of 2 cohorts depending on their qualifying gene alteration. Cohort A, which consisted of 245 patients, had at least 1 alteration in BRCA1, BRCA2, or ATM. Cohort B, which consisted of 142 patients, had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. 

In cohort A, imaging based PFS was found to be significantly longer in the olaparib group compared to the control group (median, 7.4 months vs. 3.6 months; HR, 0.34; 95% CI, 0.25-0.47; P < 0.001). A significant benefit was also observed in regard to the confirmed objective response rate and the time to pain progression. 

The median overall survival in cohort A was 18.5 months in the olaparib group and 15.1 months in the control group. Further, 81% of the patients in the control group who had progression crossed over to receive olaparib. A significant benefit for olaparib was also seen for imaging based PFS in the overall population.

However, the incidence of adverse events (AEs) of grade 3 or higher, regardless of attribution, dose modification, and treatment discontinuation due to AEs, was higher with olaparib than with the control treatment. The most common AEs of any grade were anemia, nausea, and fatigue or asthenia with olaparib and fatigue or asthenia with the physician’s treatment choice. A total of 11 cases of pulmonary embolism (4% of patients) were also reported in the olaparib group, compared to 1 (1%) in the control group, though none were fatal. Additionally, no reports of myelodysplastic syndromes or acute myeloid leukemia were noted. 

“Our findings validate phase 1 and 2 data on the antitumor activity of olaparib in metastatic castration-resistant prostate cancer,” the authors wrote. “It is important that olaparib showed activity in patients with alterations in other prespecified genes with a direct or indirect role in homologous recombination repair; detailed analyses are ongoing.”

References:

de Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. doi: 10.1056/NEJMoa1911440.