COMRADE: Olaparib plus radium-223 improves rPFS in mCRPC

In the phase 2 COMRADE trial (NCT03317392), reduced-dose olaparib (Lynparza) combined with radium-223 (Ra-223, Xofigo) significantly improved radiographic progression-free survival (rPFS) over Ra-223 alone in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases, particularly among those without prior docetaxel and with limited bone involvement.¹

Rana R. McKay, MD, FASCO

“Reduced-dose olaparib plus radium-223 resulted in significant improvements in radiographic progression-free survival compared with radium-223 alone. This benefit was most pronounced in those without prior docetaxel and with 20 or less bone metastases. Additionally, we demonstrated that ctDNA tumor fraction at cycle 1, day 1 and cycle 2, day 1 were prognostic of rPFS in both treatment arms,” reported Rana R. McKay, MD, FASCO, a professor in the department of medicine and department of urology at the University of California, San Diego, at the 2025 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.

Discussing the background for the study, McKay explained, “The rationale for the combination of olaparib and radium-223 is built on 4 complementary mechanisms. First, synthetic lethality. The DNA damage created by radium-223 cannot be repaired by PARP due to olaparib inhibition, resulting in increased burden of double strand DNA breaks that accumulate and lead to cell death. Second, G2/M cell cycle, arrest. Olaparib traps cells in the G2/M phase, which is the most radio-sensitive portion of the cell cycle. Third, chromatin remodeling effects. PARP inhibition delays chromatin opening and accessibility, making it harder for cells to access and repair DNA that is damaged by radium. And lastly, reduced tumor hypoxia. PARP inhibition decreases cellular oxygen consumption, reducing the hypoxic tumor environment. That typically leads to radio resistance. It is this rationale that brings us to our hypothesis, which is that the combination of olaparib with radium-223 will be feasible, safe, and demonstrate anti-tumor activity in patients with CRPC with bone metastases.”^2-4

Patients were eligible for inclusion in the phase 1-2 COMRADE study if they had an ECOG Performance Status of 0-1, had progressive metastatic CRPC, had at least 2 bone metastases, had no visceral metastases, adenopathy of 4 cm or less, had not received prior Ra-223, and had a bone-protecting agent unless contraindicated. Prior docetaxel use was permitted. Circulating tumor DNA was collected at cycle 1, day 1; on treatment; and end of treatment.

“The phase 1 study, which has been previously reported,⁵ established the recommended phase 2 dose of olaparib at 200 mg by mouth, twice daily and fixed-dose radium-223 at 55 kBq/kg every 4 weeks for up to 6 doses. The phase 2 study randomized patients 1:1 to the combination of olaparib plus radium vs radium alone,” McKay said.

The primary end point was rPFS as assessed by Prostate Cancer Working Group 3 and RECIST. Secondary end points included rPFS by disease extent, prior docetaxel, HRR gene mutation status, 50% reduction in PSA level from baseline (PSA50), decline of alkaline phosphatase by 30% from baseline (ALK30), objective response rate, PSA progression, time to ALK progression, time to first subsequent treatment, time to symptomatic skeletal event (SSE), and overall survival (OS). Patients were stratified by prior receipt of docetaxel (yes or no) and extent of bone metastases (fewer than 20 or 20 or more bone lesions).

A total of 133 patients were enrolled in the phase 2 portion of the study. “The first 13 patients were inadvertently assigned to the combination treatment arm due to an error in the electronic randomization algorithm, resulting in non-randomized enrollment. Following identification of this issue, the protocol was amended to expand enrollment to 133 patients, to ensure that 120 patients would be properly 1:1 for the primary efficacy analysis,” McKay explained.

Regarding baseline characteristics, 28 (45.9%) patients in the olaparib plus Ra-223 arm had more than 20 bone lesions on bone scan compared with 28 (47.5%) patients in the Ra-223–alone arm. Fifty-nine (96.7%) patients in the olaparib plus Ra-223 arm had received a prior androgen receptor pathway inhibitor compared with 56 (94.9%) patients in the Ra-223–alone arm. In addition, 32 (52.5%) patients in the olaparib plus Ra-223 arm had received prior docetaxel compared with 30 (50.8%) patients in the Ra-223–alone arm. Fifty-four (88.5%) patients in the olaparib plus Ra-223 arm reported current bone-modifying agent use compared with 54 (91.5%) patients in the Ra-223–alone arm.

“This was a positive study, resulting in a statistically significant improvement in the primary end point of rPFS in the intent-to-treat population. Median rPFS was 8.9 months in the combination arm, compared to 4.7 months in the radium-223-alone arm, with a stratified hazard ratio of 0.47,” McKay reported.

In patients who had not received prior docetaxel, median rPFS was 13.7 months for the olaparib plus Ra-223 arm vs 5.7 months in the Ra-223–alone arm (HR 0.24; 1-sided 90% CI: 0.15-0.40). In patients who had received prior docetaxel, median rPFS was 6.6 months in the olaparib plus Ra-223 arm vs 3.3 months in the Ra-223–alone arm (HR 0.73; 1-sided 90% CI: 0.48-1.11).

For patients with 20 or fewer bone metastases, median rPFS was 13.4 months in the olaparib plus Ra-223 arm vs 4.2 months in the Ra-223–alone arm (HR 0.21; 90% CI:0.13-0.33). For patients with more than 20 bone metastases, median rPFS was 4.7 months in the olaparib plus Ra-223 arm vs 4.8 months in the Ra-223–alone arm (HR 1.17; 95% CI: 0.75-1.84).

Confirmed PSA50 was observed in 9 (14.8%) patients in the olaparib plus Ra-223 arm vs 9 (15.3%) patients in the Ra-223–alone arm. Confirmed ALK30 was observed in 30 (49.2%) patients in the olaparib plus Ra-223 arm and 30 (50.8%) patients in the Ra-223–alone arm.

“With regards to key secondary time to event end points, we observed a numerically longer time to first SSE in the combination arm compared to radium-223, with a 1-year cumulative rate of 12.7% vs 22.9% respectively. We did not observe differences in time to PSA progression, time to alkaline phosphatase progression, time to initiation of subsequent treatment, and overall survival,” McKay said.

Median OS was 20.2 months (95% CI: 13.8-25.7) in the olaparib plus Ra-223 arm vs 21.1 months in the Ra-223–alone arm (95% CI: 14.4-23.7). “This may be reflected by the fact that 23 patients crossed over to the combination,” McKay said.

Grade 3-5 adverse events were reported in 56.0% of the olaparib plus Ra-223 arm vs 33.0% of the Ra-223–alone arm.

“The main driver behind this difference was increased rate of lymphopenia, which was largely managed with observation. Rates of anemia were slightly higher in the combination arm, at 22% compared to 16%. For drug discontinuation due to toxicity in [the olaparib plus Ra-223 arm], olaparib discontinuation was observed in 23.7% of patients, and radium-223 discontinuation in 11.9% of patients. For the [Ra-223–alone arm], discontinuation was 5.4%,” McKay said.

The investigators also conducted an exploratory ctDNA biomarker analysis. Fifty-three (86.9%) patients in the olaparib plus Ra-223 arm had available cycle 1, day 1 ctDNA vs 49 (83.1%) patients in the Ra-223–alone arm. Ten (18.9%) patients in the olaparib plus Ra-223 arm were considered HRR positive compared with 13 (26.5%) patients in the Ra-223–alone arm.

“Of the 102 patients with available cycle 1, day 1 ctDNA testing, the benefit of the combination of olaparib plus radium-223 was most pronounced in patients without an HRR alteration identified on ctDNA at baseline, with a hazard ratio of 0.49, which was statistically significant,” McKay said.

REFERENCES

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