Building on a prior Phase 1 trial that established a recommended dose, new results from a Phase 2, multicenter trial (NCT03317392) provide evidence that combining the PARP inhibitor olaparib with radium-223 can significantly improve outcomes. The study enrolled 120 patients with mCRPC and bone metastases across 9 centers. Patients were randomized 1:1 to receive either olaparib plus radium-223 (Arm A) or radium-223 alone (Arm B). Eligibility required patients to have at least two bone metastases, with at least one that hadn’t received prior radiation. Patients with visceral metastases or large lymph nodes were excluded.

The primary goal of the trial was to evaluate radiographic progression-free survival (rPFS). The results showed a significant benefit for the combination therapy. Patients receiving olaparib + radium-223 (Arm A) had a median rPFS of 8.6 months, compared to just 4.0 months for those receiving radium-223 alone (Arm B). This difference was statistically significant (HR 0.51, 80% CI 0.37-0.70, 2-sided p=0.005).
Importantly, the study found that the addition of olaparib improved rPFS regardless of the patient’s homologous recombination repair (HRR) gene status. While HRR gene alterations, particularly BRCA1/2 mutations, are known to predict response to PARP inhibitors alone , the combination benefit was seen in both groups:
• In patients with HRR alterations, median rPFS was 5.5 months in Arm A vs. 3.8 months in Arm B (HR 0.52).
• In patients without HRR alterations, median rPFS was 8.8 months in Arm A vs. 4.5 months in Arm B (HR 0.54).

Beyond the primary endpoint, some secondary measures also favored the combination. While PSA and alkaline phosphatase response rates and time to progression were comparable, the time to next treatment was notably longer for patients in the combination arm (12.0 months) compared to the radium-223 alone arm (7.7 months). The combination also appeared to reduce the rate of 1-year symptomatic skeletal events (11.0% vs. 22.1%). The 12-month overall survival rates were similar between the two arms (74% vs. 71%).
Regarding safety, the combination of olaparib and radium-223 demonstrated a manageable side effect profile, although the rate of severe (Grade ≥3) treatment-related adverse events was higher with the combination.

In summary, this Phase 2 trial indicates that combining olaparib with radium-223 significantly delays radiographic progression in mCRPC patients with bone metastases. This benefit extends to patients both with and without detectable HRR gene alterations. While the combination increased some side effects, these were considered manageable. The results support further investigation of this combination as a potential strategy to improve outcomes in this patient population, and analyses of tissue and serial ctDNA are currently underway.

Source.