Understanding the Sequencing Decisions in mCRPC After Progression on ADT/ARPI

During a live event, Matthew Rettig, MD, professor of medicine and urology and medical director of the prostate cancer program at the David Geffen School of Medicine at UCLA, and participants discussed the sequencing of available therapies for patients with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI); these include docetaxel, radium-223 (Xofigo) plus enzalutamide (Xtandi), and lutetium Lu 177 vipivotide tetraxetan (Pluvicto; 177Lu-PSMA-617).

This article is the second of 2 parts from a Case-Based Roundtable event. Read part 1.

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CASE SUMMARY

• A 72-year-old man presented initially with progressive urinary hesitancy and intermittent discomfort in the lower back.
• Medical history: hypertension and hyperlipidemia, well controlled on medication
• Prostate biopsy reveals adenocarcinoma with a Gleason score of 9 [4+5] involving 9/12 cores. Initial prostate-specific antigen (PSA) level is 52 ng/mL, hemoglobin 11.2 g/dL, and ANC 2.1
• Staging with PSMA (prostate-specific membrane antigen) PET imaging demonstrates multiple pelvic lymph nodes, including an external iliac lymph node measuring 3.0 cm in short-axis diameter, and several osseous metastases (pelvis, lumbar spine, and ribs)
• Diagnosis: metastatic hormone-sensitive prostate cancer (mHSPC)
• Molecular testing: BRCA negative
• He undergoes robotic radical prostatectomy for local control, followed by initiation of ADT plus darolutamide (Nubeqa).
• Eighteen months later: despite continued castrate levels of testosterone, his PSA rises progressively over several months
• Patient reports increasing fatigue and persistent lower back and hip pain, requiring intermittent NSAID use
• Laboratory findings: hemoglobin 9.8 g/dL and absolute neutrophil count 1700 cells/μL
• Repeat PSMA PET/CT imaging reveals progressive disease with an increased number and size of bone metastases and new lesions in the femur and sacrum
• ECOG performance status of 1
• Patient is referred for further management and treatment options are discussed.
• Patient expresses a desire to maintain quality of life and is open to escalating treatment but has concerns about toxicity and preserving independence.

EVENT RECAP

This patient had progressed through what is now a standard frontline doublet, leaving the group to weigh several mechanistically distinct options for mCRPC, each supported by phase 3 data but with meaningfully different toxicity profiles, access barriers, and prior-exposure considerations.

Rettig reviewed NCCN guidelines for mCRPC, which stratify recommendations by prior hormone therapy exposure, chemotherapy status, and biomarker results such as PSMA expression.¹ Before presenting the trial data, a brief polling question on bone-protective agents generated a striking result: 78% of attendees said they would prescribe a bone-protecting agent at initiation of ADT plus ARPI. Rettig clarified that the approved bone-protective agent indications divide into 2 settings: prevention of skeletal-related events in mCRPC (using denosumab or zoledronic acid), and prevention of bone mineral density loss in patients newly starting ADT. He monitors bone density with a dual-energy X-ray absorptiometry scan and initiates treatment only if T-scores fall below his threshold; he noted that answers could be responding to the mCRPC skeletal indication with the ADT bone-loss setting.

For a patient with mCRPC with progression after receiving darolutamide, Rettig made clear that crossover to another ARPI such as abiraterone (Zytiga) offers less than 5% PSA response, making it an unfavorable choice. The discussion focused on 3 remaining options: docetaxel, the enzalutamide plus radium-223 combination, and 177Lu-PSMA-617.

Rettig reviewed the PEACE-3 trial (NCT02194842), which evaluated enzalutamide plus 6 cycles of radium-223 vs enzalutamide alone in asymptomatic or mildly symptomatic patients with bone-dominant mCRPC who had not previously received an ARPI. Final overall survival (OS) results confirmed a median OS of 38.2 months with the combination vs 32.6 months with enzalutamide alone (HR, 0.76; 95% CI, 0.60-0.96; P =.0096).² Rettig highlighted a critical safety lesson embedded in the trial’s history: when a similar combination of radium-223 and abiraterone was tested in the ERA 223 study (NCT02043678), fracture rates increased sharply in the combination arm.³ PEACE-3 responded by mandating bone-protective agent coadministration for all subsequently enrolled patients, which brought fracture rates down substantially. Rettig said he applies this lesson broadly: patients receiving radium-223 should be on a bone-protective agent.

However, because the trial enrolled primarily patients whose mCRPC had developed on ADT alone, and now most patients will have received an ADT plus ARPI doublet in the hormone-sensitive setting, it is less relevant. One attendee said he uses the PEACE-3 regimen for “patients who are frail progressing after ADT and ARPI, and then you don’t want to put them on just docetaxel.” Rettig agreed he would consider enzalutamide plus radium-223 mainly in patients with bone-dominant disease who had received ADT only or possibly in a patient with abiraterone in the mHSPC setting.

The PSMAfore trial (NCT04689828) enrolled a population of patients with PSMA-positive mCRPC who had progressed on 1 prior ARPI without taxane exposure, investigating whether to switch ARPIs or escalate to 177Lu-PSMA-617. PSMAfore demonstrated a 51% reduction in the risk of radiographic progression or death with 177Lu-PSMA-617 vs ARPI change (HR, 0.49; 95% CI, 0.36–0.67).⁴ OS was not statistically different, but Rettig noted that this could be attributed to more than 80% of patients on the comparator arm crossing over to 177Lu-PSMA-617 at progression.

He flagged an important practical consideration from an Australian randomized phase 2 study of 177Lu-PSMA-617: patients who received docetaxel before 177Lu-PSMA-617 had better outcomes than those who reversed the sequence, likely because patients who received the radioligand first were less willing or able to tolerate chemotherapy afterward.⁵

Rettig also reviewed the RALU retrospective study, which examined outcomes with 177Lu-PSMA-617 in 198 heavily pretreated patients who had previously received radium-223; 58% had received 4 or more prior life-prolonging therapies.⁶ PSA declines of 50% or greater were seen in 37% of patients, and the treatment was reasonably well tolerated, with most treatment-emergent adverse events grade 1 or 2. Rettig noted that he has used radium-223 followed by 177Lu-PSMA-617 in practice without encountering problematic toxicity.

For the case patient, the group converged on docetaxel and 177Lu-PSMA-617 as the primary options. Before the data presentation, 56% of participants selected docetaxel and 33% selected 177Lu-PSMA-617; after reviewing the data, 44% chose docetaxel and 33% 177Lu-PSMA-617. In an alternate scenario posing the question for a patient who had received abiraterone in the mHSPC setting rather than darolutamide, 67% selected docetaxel and 22% selected enzalutamide plus radium-223. No participants chose ARPI crossover in either scenario. Rettig’s own inclination for this patient would be 177Lu-PSMA-617 first, with a strong recommendation to plan for docetaxel subsequently; ongoing trials DORA (NCT03574571) and RADIANT (NCT04597125) are continuing to refine where radium-223 fits in the post-ARPI sequencing landscape.

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_{DISCLOSURES: Rettig previously reported receiving speaking honoraria or consulting fees from Ambrx, Amgen, AVEO, Clovis Oncology, Roivant, Iimmune Bio, Johnson & Johnson, and Bayer; and research funding from Merck, Pfizer, Immune Bio, Novartis, and Fibrogen.}

REFERENCES

1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer; version 5.2026. Accessed July 17, 2026. https://tinyurl.com/3tfnmh9x

2. 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

3. Smith M, Parker C, Saad F, 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;20(3):408-419. doi:10.1016/S1470-2045(18)30860-X

4. Morris MJ, Castellano D, Herrmann K, et al. ¹⁷⁷Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. Lancet. 2024;404(10459):1227-1239. doi:10.1016/S0140-6736(24)01653-2

5. Azad AA, Bressel M, Tan H, et al. Sequential [¹⁷⁷Lu]Lu-PSMA-617 and docetaxel versus docetaxel in patients with metastatic hormone-sensitive prostate cancer (UpFrontPSMA): a multicentre, open-label, randomised, phase 2 study. Lancet Oncol. 2024;25(10):1267-1276. doi:10.1016/S1470-2045(24)00440-6

6. Rahbar K, Sarfaty M, Peer A, et al. Lutetium-177–prostate-specific membrane antigen (177Lu-PSMA) therapy in patients (pts) with prior Radium-223 (223Ra). Ann Oncol. 2024;35(suppl 2):S983-S984. doi:10.1016/j.annonc.2024.08.1710