Evaluating Radium-223 Combinations and Bone Protection in mCRPC

Despite meaningful advancements, patients with metastatic castration-resistant prostate cancer (mCRPC) face a poor prognosis and are at high risk for progression, necessitating the identification of more effective treatment combinations.

During a Case-Based Roundtable event in Warren, New Jersey moderated by Mark N. Stein, MD, associate professor of medical oncology, Columbia University Medical Center, Stein discussed the potential synergy between the antitumor activity of enzalutamide (Xtandi) and radium-223 dichloride (Xofigo) vs enzalutamide monotherapy. Further, he confirmed the importance of prescribing bone-protecting agents such as bisphosphonates or denosumab in this patient population.

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This is part 2 of 2. Read Part 1 here.

CASE SUMMARY

• A 72-year-old man started androgen deprivation therapy (ADT) and docetaxel75 mg/m² every 3 weeks for 6 cycles. He had tested positive for adenocarcinoma of the prostate; Gleason score 7 (4 + 3), prostate-specific antigen (PSA) 40 ng/mL; T3N1M1 (4 bony lesions in right hip); germline and somatic genetic testing are negative
  • Nadir PSA 0.1 ng/mL
  • Testosterone: 39 ng/dL
• PSA remained steady until 2023:
  • March 2023: 0.4 ng/mL
  • September 2023: 0.5 ng/mL
  • April 2024: 1.6 ng/mL
  • July 2024: 33 ng/mL; testosterone, 43 ng/dL
• Imaging (prostate-specific membrane antigen [PSMA] PET/CT and bone scan): showed 2 new bone lesions and high PSMA uptake in 3 pelvic lymph nodes and intraprostatic lesions
• ECOG performance status: 0
• He is asymptomatic.
• Circulating tumorDNA showed no actionable alterations.

Targeted Oncology: Would you consider prescribing a bone-protecting agent for this patient?

Mark N. Stein, MD: I think most physicians would give this patient a bone-protecting agent. So I tend, if somebody is truly hormone-sensitive before they become castration-resistant, not to pursue bone-saving therapy early on. It’s not clear that the benefit exists early in the disease when the patient is still responding to hormonal therapy. Giving years of bone-protective agents in the hormone-sensitive setting has not been shown to actually improve bone-related outcomes. It’s very tempting because you want to do everything you can to help your patients as much as possible.

But the data from several large trials, including one arm of the STAMPEDE trial [NCT00268476] that specifically looked at this question,¹ did not show a clear benefit in this setting. STAMPEDE was a large European trial that used ADT as a control arm, with multiple additional arms added on over time. It did not show clear benefit in the hormone-sensitive setting.

However, this patient is doing well. He had success with docetaxel. Unfortunately, his PSA subsequently begins to rise. On repeat imaging, he has 2 new lesions. He is feeling well, but repeat CT and circulating tumor DNA testing show no actionable alteration. He has now developed what would be considered castration-resistant prostate cancer. Importantly, he has never received an androgen pathway inhibitor, only docetaxel, so that remains a therapeutic option going forward.

For a patient with CRPC who has progressed on docetaxel, what considerations do you have for the available second-line approaches?

The National Cancer Center Network guidelines are a useful tool, and mutational status is obviously an important consideration, particularly for patients with a BRCA mutation.

One point worth highlighting: for patients with homologous recombination deficiency who are non-BRCA, the data for talazoparib [Talzenna] plus enzalutamide [Xtandi] was positive even in the non-BRCA setting. That said, I do think the strongest signal for PARP inhibitors remains in [patients with a BRCA mutation]. ATM, by contrast, does not show as strong a signal. I would encourage everyone to look at the TALAPRO-2 study [NCT03395197]² and examine the subgroups to decide for yourself whether you would consider a PARP inhibitor for someone with an ATM mutation.

For other patients, radium-223 plus enzalutamide could certainly be considered, assuming the patient has not previously received enzalutamide. For patients with particularly aggressive disease, such as those with extensive liver metastases who have already received abiraterone [Zytiga] or enzalutamide, cabazitaxel [Jevtana] and carboplatin could be an option.

For many patients, however, one of the more common approaches would be [lutetium Lu 177 vipivotide tetraxetan; Pluvicto], particularly for those who have already received abiraterone.

DISCUSSION QUESTIONS

• Have you used enzalutamide in a patient who has received prior abiraterone plus prednisone in your clinical practice?

• What has been your experience with radium-223 for the treatment of prostate cancer?
  • In which specific patient populations do you consider using it?
  • What are the logistical considerations for your patients who receive radium-223?
  • Have you treated patients with radium-223 who were also receiving an ARPI?

Would you consider giving enzalutamide to this patient if his PSA is rising on triple therapy with abiraterone, prednisone, and docetaxel?

The androgen receptor pathway inhibitor (ARPI) switch has actually been used as the control arm in several larger phase 3 clinical trials, and the FDA has been fairly critical of that approach, as there is no clear survival benefit. It works somewhere between 20% to 30% of the time, and to some extent the response can depend on the nature of the particular resistance pattern.

Generally, the results are fairly transient. The FDA has actively discouraged clinical trials from incorporating the switch going forward. That said, if a patient either cannot tolerate other options or is experiencing slow progression, it does come up as a consideration. I would say it is generally the less preferred option in this setting, though several trials have examined it across different clinical scenarios.

What are the highlights from PEACE-3 (NCT02194842)?

The PEACE-3 trial enrolled patients with castration-resistant prostate cancer and bone metastases, with no prior radium therapy and no visceral metastases.³ Lymph node involvement was permitted. All patients were required to receive a bone-protecting agent, and this trial used enzalutamide rather than abiraterone.

It is worth noting that the combination of radium with abiraterone, which requires prednisone, was problematic in a prior trial, as the prednisone appeared to contribute to increased fractures and that combination did not perform well. Radium plus enzalutamide, by contrast, appears to be well tolerated.

PEACE-3 was conducted primarily in Europe and compared enzalutamide alone to enzalutamide plus radium. The trial demonstrated a positive overall survival benefit with the combination.

In some ways, this trial renewed interest in radium, which had somewhat fallen off people’s radar. Seeing that radium-223 can be given earlier in the disease course in combination with enzalutamide, with a demonstrated overall survival benefit, has prompted clinicians to think about it more seriously again. It is also worth noting that this combination may be particularly relevant for younger patients, generally those under 75 years old.

Can you walk us through the PEACE-3 data, including which patients seem to benefit most, and how you think about radium in the context of PSMA expression and tolerability?

Data presented at 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium examined PEACE-3 to identify which patients tend to benefit most.⁴ The profile that emerged was a patient who has received ADT but not docetaxel, has good performance status, and potentially has fewer bone lesions. In that population, the combination of radium plus enzalutamide demonstrated an overall survival benefit. The combination may not perform as well in older men, potentially due to greater marrow toxicity.

There was also a clear progression-free survival [PFS] benefit, which is worth highlighting. Radium-223 has traditionally been recognized for its overall survival benefit, but this trial demonstrated a meaningful PFS benefit with respect to bone metastases as well, which is conceptually important.

Another noteworthy aspect of radium-223 is that, unlike lutetium, it does not depend on PSMA expression. Radium-223 functions as a calcium mimetic, a divalent cation that is taken up by bone regardless of the degree of PSMA avidity. This raises the possibility that a PEACE-3 type approach could be particularly relevant in patients with low PSMA expression, and there is hope that a trial will ultimately be designed to examine the combination specifically in that population.

In terms of safety, the combination generally reflects the expected profile of each individual drug, including hypertension and fatigue from enzalutamide. Overall, it was reasonably well tolerated, with a drug discontinuation rate due to toxicity of less than 10%, which speaks to the promise of this combination.

One important consideration is that in this trial, most patients had received ADT alone prior to enrollment, and the benefit was demonstrated in that context. For a patient who has already been exposed to enzalutamide, or who is on apalutamide [Erleada] and is now progressing, that represents a somewhat different population from what we typically see in the US.

The question becomes whether you can extrapolate these results, where patients were on ADT alone and then received either enzalutamide or enzalutamide plus radium, to someone who has already become resistant to an ARPI. There may be a biological difference between adding both agents upfront versus adding radium after ARPI resistance has developed. This was, again, largely a European-style trial in which patients were not on any prior hormonal therapy before starting the combination regimen. That said, if someone had been on abiraterone and I was planning to switch them to enzalutamide, I would certainly consider switching them to enzalutamide plus radium in that setting, which would be a quite reasonable approach.

DISCLOSURES: Dr Stein owns stock and other ownership interests in Rafael Holdings; Consulting or Advisory Role: Exelixis, Johnson & Johnson/Janssen, and GI Innovation.

REFERENCES

1. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163-1177. doi:10.1016/S0140-6736(15)01037-5

2. Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023;402(10398):291-303. doi:10.1016/S0140-6736(23)01055-3

3. Gillessen S, Gallardo E, Choudhury A, et al. Final overall survival results from EORTC 1333/PEACE-3 trial of enzalutamide plus radium-223 in metastatic castration-resistant prostate cancer. Ann Oncol. 2026;37(5):736-742. doi:10.1016/j.annonc.2026.02.009

4. Gallardo E. Final overall survival results from the EORTC 1333/PEACE-3 trial: Enzalutamide with or without radium-223 in metastatic castration-resistant prostate cancer. J Clin Oncol. 2026;44(suppl 7):15-15. doi:10.1200/JCO.2026.44.7_suppl.15