Findings from the phase 2 COMRADE trial (NCT03317392)were recently shared at the 2025 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.1
Overall, data showed that the combination of olaparib (Lynparza) plus radium-223 (Xofigo) led to improved radiographic progression-free survival (rPFS) vs radium-223 alone in patients with castration-resistant prostate cancer (CRPC) with bone metastases.This finding was consistent across both HRR-positive and HRR-negative subgroups.
In a recent interview with Urology Times®, presenting author Rana R. McKay, MD, FASCO, walked through the key findings and notable takeaways from the study. McKay noted that although it is unlikely that the combination of olaparib plus radium-223 will advance to a phase 3 trial, these results open the door for more combination DNA damaging agents in this setting.
McKay is a genitourinary medical oncologist at the University of California, San Diego.
Could you describe the background/rationale for this study?
As a way of background, CRPC really represents a lethal disease. Over 90% of patients develop bone metastases, which are associated with morbidity and diminished quality of life. Radium-223 is a targeted radionuclide that has demonstrated significant improvements in overall survival for patients with CRPC with bone metastases, and olaparib, we know, is a potent PARP inhibitor that has shown clinical efficacy in mCRPC patients harboring HRR alterations.
The rationale for the combination of olaparib with radium-223 is built on 4 complementary mechanisms: that of synthetic lethality; leveraging the G2/M cell cycle arrest period that is the most radiosensitive part of the cell cycle; leveraging the chromatin remodeling effects that are associated with PARP inhibition, which can delay chromatin opening and accessibility, making it harder for cells to repair damaged DNA that’s elicited by radium-223; and reduced tumor hypoxia. So, PARP inhibition decreases cellular oxygen consumption, reducing the hypoxic tumor environment that typically provides radio-resistance. Those complementary mechanisms are why we decided to investigate the combination of these 2 agents.
How was this trial designed? What were the key findings?
The COMRADE study was a phase 1/2 study that enrolled patients with an ECOG [score] of 0 to 1 and progressive mCRPC with at least 2 or more bone metastases without visceral metastases. Patients with adenopathy that was less than or equal to 4 cm were eligible. Patients weren’t permitted to have received prior radium or olaparib, [but] prior docetaxel was permitted. They were required to be on a bone-protecting agent unless contraindicated.
We had previously conducted the phase 1 study, which had demonstrated the recommended phase 2 dose of olaparib at 200 mg by mouth twice daily with 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], with a primary end point of radiographic progression-free survival. There were stratification factors based off prior docetaxel utilization and the extent of bone metastases. Crossover was permitted.
This was a positive trial, resulting in a statistically significant improvement in the primary end point of radiographic progression-free survival in the intent-to-treat population. The median rPFS was 8.9 months in the combination, compared with 4.7 months in the radium-223 alone arm with a stratified hazard ratio of 0.47, which was statistically significant. When we look at the benefit based off prior docetaxel utilization, we demonstrate that the greatest effect was observed in patients who had not received prior docetaxel, with a hazard ratio of 0.24. When we looked at the pre-specified subgroup analysis by bone metastases, the greatest effect was among those who had 20 or less bone metastases with a hazard ratio in that subgroup of 0.21.
So, this was a positive trial that met its primary end point of improved radiographic progression-free survival with combination therapy.
What did the safety data from this trial show?
With regards to the safety data, the study demonstrated that there was a higher rate of grade 3 treatment-related adverse events that were observed in the combination arm, 56% compared to 33%. The most common events included anemia (22% vs 16%) and lymphocyte count decrease (31% vs 9%). Most of these were well-managed. For the lymphocyte counts, we largely monitored the symptoms. Drug discontinuation rates were about 24% with [olaparib] in arm A and around 12% with radium-223 in arm A.
Where do you see a radium-223 plus PARP inhibitor combination fitting into the treatment landscape for mCRPC?
This trial really opens up the landscape for combination DNA damaging agents in prostate cancer. Although the combination of olaparib and radium-223 is unlikely to move forward into a large phase 3 trial, there are other radiopharmaceuticals and other PARP inhibitors and DNA-damaging agents. We demonstrated that we could safely and feasibly complete a 145-patient trial with a combination radiopharmaceutical strategy.
What are some of the next steps for this study?
Additional next steps are subgroup analyses based off the molecular findings. All patients on the trial underwent a baseline bone biopsy, and we’re working at dissecting out those results right now. [Patients also underwent] serial ctDNA testing, so we’ll be dissecting out the efficacy data based off biomarker status.
Is there anything else that you wanted to add?
The only other thing to add is that this study was really conducted through the [Experimental Therapeutics Clinical Trials Network] ETCTN as an investigator-initiated trial at 9 different centers across the US, with support from the NCI [National Cancer Institute], PCF [Prostate Cancer Foundation], and other funding agents [such as] Padres Pedal the Cause. We thank all of the patients and the community for supporting this study.
REFERENCE
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 17):5007. doi:10.1200/JCO.2025.43.16_suppl.5007