Olaparib Plus Radium-223 Doubles rPFS vs Radium-223 Alone in mCRPC

Rana R. McKay, MD

Findings from the phase 2 COMRADE trial (NCT03317392) demonstrated a significant improvement in radiographic progression–free survival (rPFS) with the addition of the PARP inhibitor olaparib (Lynparza) to the targeted alpha-emitting radiopharmaceutical radium-223 (Xofigo) vs radium-223 monotherapy in men with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases, according to Rana R. McKay, MD.

These data, which were presented at the 2025 ASCO Annual Meeting, showed that among all treated patients, the median rPFS was 8.9 months in the combination arm vs 4.7 months with radium-223 alone (HR, 0.47; 90% CI, 0.34-0.65; 1-sided P = .0013).1

“We seemed to see the most pronounced effect [of the combination] in patients who had not received prior docetaxel and who had a low burden of bone metastases,” McKay said in an interview with OncLive®.

Stratified analyses revealed the most pronounced rPFS benefit with the combination vs the monotherapy in patients with 20 or fewer bone metastases (median, 13.4 months vs 4.2 months; HR, 0.21; 1-sided 90% CI, 0.13-0.33) and in those without prior docetaxel exposure (median rPFS, 13.7 vs 5.7 months; HR, 0.24; 1-sided 90% CI, 0.15-0.40).1

In the interview, McKay discussed unmet needs for patients with mCRPC that led to the development of the COMRADE trial, key efficacy and safety findings from this study, and how these data may affect the mCRPC treatment paradigm going forward.

McKay is a professor in the Departments of Medicine and Urology at the University of California (UC) San Diego School of Medicine, as well as a medical oncologist with UC San Diego Health.

OncLive: What was the rationale for conducting the phase 2 COMRADE study?

McKay: Patients with mCRPC essentially have lethal prostate cancer. Most of those patients have bone metastases. Approximately 80% of those patients have bone metastases. Those are a source of great morbidity and an increased risk of mortality related to the disease.

There are several agents that are approved to manage this disease, one of which is radium-223. Radium-223 is a targeted radionuclide that targets the bone microenvironment, where there’s a vicious cycle of bone turnover that causes cancer cell growth and affects the disease progression within the bone.

Radium-223 is a life-prolonging radionuclide that is FDA approved to treat patients who have advanced prostate cancer.2 The rationale for the COMRADE study stems from strategies to sensitize tumors to radionuclide therapy. This trial compares the combination of radium-223 plus olaparib vs radium-223 alone.1 We believe that the olaparib can potentially work as a radiosensitizer to the radium-223, which is already an FDA-approved agent.

[Radium-223 is] an alpha-emitting radionuclide. The reason for that effect may be related to [its capacity for] synthetic lethality, chromatin remodeling, and arresting the cell in its most radiosensitive state, [which all may] potentially affect tumor hypoxia.

How was this phase 2 study designed?

We have previously reported on the phase 1 [portion of the COMRADE] study, which had a primary end point of defining the recommended phase 2 dose [RP2D] of olaparib. [This] was [identified as] 200 mg by mouth twice daily plus fixed-dose radium-223.

Here [at ASCO 2025], we reported on the results of the phase 2 trial. This was a randomized study where patients were randomly assigned 1 to 1 to receive the combination of radium-223 with olaparib vs radium-223 alone. The eligibility criteria for the trial included patients who had mCRPC with bone metastases. Patients should have received an androgen receptor pathway inhibitor [ARPI], and [the trial] mandated that patients be receiving a bone-protecting agent, unless there was a contraindication.

The primary end point for the study was rPFS with key stratification factors including prior docetaxel use and extent of bone metastases. There were many key secondary end points, including PSA response, alkaline phosphatase response, time to SSE, overall survival, etc.

This trial enrolled patients who had bone metastases. The bulk of the patients who were enrolled on the trial had been heavily pretreated. [Nearly] all [enrolled] patients had received a prior ARPI. Approximately 50% of patients had received prior docetaxel, and approximately 50% of patients had greater than 20 bone metastases on imaging. This was a heavily pretreated population, [and] approximately 85% of patients were receiving a bone-protecting agent.

What efficacy outcomes were reported in this analysis?

This was a positive trial resulting in a statistically significant improvement in rPFS with the combination compared with radium-223 alone. The median rPFS in the treatment arm was 8.9 months compared with 4.7 months in the control arm, with a hazard ratio of 0.47, which was statistically significant.

We also conducted an exploratory analysis using ctDNA to dissect the effect of homologous recombination repair [HRR] alterations on outcomes. We saw a benefit [with the combination vs the monotherapy] in the group that was HRR negative. Regarding the group that was HRR positive, only 23 patients [in this study] had HRR mutations, and [only 4] of those mutations were in the BRCA1/2genes. We saw [an efficacy] signal [with the combination] in [the HRR-negative] group with a HR of 0.49, but it wasn’t statistically significant and is probably related to the small sample sizes.

We didn’t see any effect [of the combination on] PSA response or alkaline phosphatase response. However, we saw an approximately 50% reduction in the rates of 12-month skeletal-related events between the 2 arms.

rPFS data were not reported out in the original phase 3 ALSYMPCA trial that led to the approval of radium-223; that trial reported out overall survival [OS]. The median OS in that trial was 14.9 months with radium-223 alone.2

In the COMRADE study, we observed a median OS of approximately 20 months in both the treatment arms.1 It was 20.2 months and 21.1 months in [the combination vs monotherapy arms, respectively], which is dramatically longer than what was seen in the ALSYMPCA trial. [The reason for these OS outcomes is] probably multifactorial in nature. Our trial allowed for crossover [from the monotherapy arm to the investigational arm], and 23 patients [from the control arm crossed] over to the combination arm, so that could have [affected these findings]. Additionally, approximately 70% of patients enrolled on our trial went on to receive subsequent therapies, including chemotherapy and lutetium PSMA–based treatments, which probably also affected the increased median OS.

What safety findings were reported in this analysis?

We saw increased grade 3 and 4 toxicity with the combination compared with the radium-223 monotherapy. We saw slightly increased rates of grade 3 or higher anemia, from 16.3% with radium-223 alone compared with 22.0% [with the combination].

We also saw an increased rate of lymphopenia in the investigational arm, at 31.0% compared with 9.1% in the radium-223 alone arm. The delta of lymphopenia rates between the arms may have driven the [bulk of the] difference between the adverse effects in the 2 groups. Otherwise, this was a fairly well-tolerated regimen with radium-223 and reduced-dose olaparib.

Based on these findings, where do you see this combination positioned within the current treatment paradigm for mCRPC?

The prostate cancer field is rapidly evolving, [and] there are lots of radioligands that are under development for this disease. There are beta emitters, alpha emitters, and different targets being evaluated, including PSMA, STEAP1, and, KLK2. We’re constantly asking the question of how we can enhance the efficacies of the therapies we have, and this trial opens up that foray of how a PARP inhibitor can serve as a radiosensitizer to a radioligand therapy.

References

1. McKay RR, Xie W, Ajmera A, et al. A multicenter, randomized, phase 2, investigator-initiated ETCTN trial of olaparib + radium-223 vs. radium-223 in men with castration-resistant prostate cancer (CRPC) with bone metastases (BM) (COMRADE): initial efficacy and biomarker analysis. J Clin Oncol. 2025;43(suppl_16):5007-5007. doi:10.1200/jco.2025.43.16_suppl.5007
2. Radium-223 Improves Survival in Patients with Advanced Prostate Cancer. National Cancer Institute. Posted August 2, 2013. Accessed June 10, 2025. https://www.cancer.gov/types/prostate/research/radium-223-improves-survival