Radium-223, Prolonging Survival in Combination with Enzalutamide at an Earlier Disease State

The world of genitourinary oncology is and should be quite enamored with radioligand therapy for men with prostate cancer.  The recent regulatory approvals that followed ¹⁷⁷Lu-PSMA-617 after the positive survival results from the VISION trial,¹ and the recent radiographic progression-free survival results from the PSMAfore trial in the earlier chemotherapy-naive metastatic castration-resistant prostate cancer disease state are compelling.²  This data is recently followed with data from the SPLASH trial, where ¹⁷⁷Lu-PNT2002 has shown a significant radiographic progression free survival benefit in the chemotherapy-naïve metastatic castration-resistant prostate cancer disease state.³  We will await to see what regulatory agencies do with the data from both the PSMAfore and SPLASH trials and whether radioligand therapy use moves earlier in the treatment paradigm.

At ESMO 2024, we were reminded of an older radiopharmaceutical, radium-223, when the PEACE-3 trial data was presented.⁴  This trial accrued 446 men with asymptomatic or mildly symptomatic bone metastatic castration resistant prostate cancer to be randomized to either radium-223 for 6 cycles with enzalutamide or enzalutamide alone.  The primary endpoint revealed a median radiographic progression-free survival of 19.4 vs. 16.4 months (HR 0.69, 95% CI 0.54, 0.87; log-rank p-value 0.0009) for the combination vs. monotherapy, respectively.  The interim overall survival analysis at 80% of events revealed median overall survival of 42.3 vs. 35.0 months (HR 0.69, 95% CI 0.52, 0.90; p-value <0.0034), respectively.  Secondary endpoints were also positive for time to next systemic treatment for the combination therapy arm, but time to pain progression and time to symptomatic skeletal event was not significantly different between the arms.  The adverse events data was quite benign with hypertension in about a 1/3 of patients in both treatment arms, attributable to enzalutamide. However, drug related grade 3 or greater events occurred in 28% of the combination arm compared to 19% for enzalutamide monotherapy.

One key take-home message from the PEACE-3 trial is that bone protective agents must be administered.  We previously saw the early unblinding of the ERA-223 trial, where radium-223 was combined with abiraterone acetate, due to a significant increase in osteoporotic fractures, and it was likely due to the fact that 60% of the patients were not receiving bone protective agents.⁵  In the PEACE-3 trial, prior to a safety update, only 46.1% of patients were using bone protective agents.  At one year of treatment, patients not taking bone-protective agents had a fracture risk of 15.6% in the enzalutamide only arm and 37.1% for those in the enzalutamide plus radium-223 arm.  Therefore, the trial was amended to mandate the use of bone protective agents e.g. denosumab or zoledronate.  After the amendment, the fracture risk in the enzalutamide arm decreased to 2.6% and to 2.7% in the enzalutamide plus radium-223 arm.⁶

Although radium-223 monotherapy offers an overall survival, symptomatic skeletal event, and multiple pain benefits for patients with bone metastatic castration-resistant prostate cancer patients, the use of radium-223 is somewhat limited.  The regulatory label has always been restricted to patients with symptomatic disease, as that was the population accrued to the original ALSYMPCA trial.⁷  This has had challenges in practical patient care, often relegating the use of radium-223 to patients with very advanced, severely symptomatic disease, where it is unlikely for radium-223 to provide clinical benefit and also unlikely for administration of all 6 doses to be completed.  This more advanced disease state is also more likely to harbor restrictive challenges with bone marrow disease infiltration and/or prior chemotherapy-induced bone marrow suppression, further limiting the ability to administer radium-223.  Additionally, visceral prostate cancer metastasis also is contraindicated in the label, appears more frequently in more advanced late-stage disease, and can appropriately limit the use of radium-223.  Another pragmatic issue with the utilization of radium-223 is that prostate-specific antigen (PSA) levels frequently do not decline and have no association with clinical outcomes with Radium-223. 

The key advantage to the delivery of radium-223 in the PEACE-3 trial is that we now know overall survival benefit can be contributed in patients who have asymptomatic bone metastases, and the concern of rising PSA is abrogated with enzalutamide-induced PSA decline.  As a result, 87.9% of patients on the PEACE-3 trial were able to complete all 6 cycles of radium-223.

The downside to the data from PEACE-3 is that the patients were first-line metastatic castration-resistant prostate cancer patients and only around 2% had received prior abiraterone.  With treatment intensification for patients who had metastatic castration-sensitive prostate cancer, this first-line androgen receptor pathway inhibitor naïve patient population is certainly shrinking.  This could limit the opportunity to use the enzalutamide plus radium-223 combination, should regulatory approval follow in the near future.

We now have evidence from multiple clinical disease states that radium-223 offers significant overall survival benefits, and we should work hard to find opportunities to provide the agent for appropriate patients.  While we await the potential for regulatory approval for this earlier disease state, we should note that there are still a few ongoing, accruing clinical trials using radium-223.  Some of these trials, displayed below, offer opportunities to refine the use of radium-223 and optimize patient selection, and there is significant value to our patients for us to learn what we can from these trials.

Actively accruing clinical trials with Radium-223

• Impact of DNA repair alterations on sensitivity to radium-223 (NCT04480719)
• PSMA PET selection of patients for radium-223 (NCT05924672)
• Phase 2 trial of darolutamide combinations for metastatic castration-resistant prostate cancer, including radium-223 (NCT06401980)
• Phase 1/2 trial of radium-223 vs. radium-223 plus the DNA pk inhibitor peposertib vs. radium-223 plus peposertib plus avelumab (NCT04071236)

References

1. Sartor O, et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2021; epub June 23, 2021.
2. Sartor O, et al. Phase III trial of [177Lu]Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (PSMAfore). Ann Oncol, Volume 34, S1324-S1325; LBA13.
3. Sartor O, et al. Efficacy of 177Lu-PNT2002 in PSMA-positive mCRPC following progression on an androgen-receptor pathway inhibitor (ARPI) (SPLASH). Ann Oncol (2024) 35 (suppl_2): 1-72; LBA65.
4. Gillessen S, et al. Adding metformin to androgen deprivation therapy (ADT) for patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC): Overall survival (OS) results from the multi-arm, multi-stage randomised platform trial STAMPEDE. Ann Oncol (2024) 35 (suppl_2): 1-72; LBA1.
5. Smith M, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019; 220:408-19.
6. Gillessen S, et al. Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACEIII trial combining Ra223 with enzalutamide versus enzalutamide alone: An updated safety analysis. J Clin Oncol. Volume 39, Number 15_suppl; abstr 5002.
7. Parker C et al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. N Engl J Med 2013; 369:213-23.