Biochemical Relapse After Lu-177 PSMA — Options for Bone-only mCRPC

My father is 82 and was diagnosed in December 2021 with advanced prostate cancer. MRI at diagnosis showed a PIRADS 5 prostate lesion with pelvic lymphadenopathy and multiple bone metastases. No biopsy done. A PSMA PET in 2022 confirmed diffuse skeletal disease. His PSA was >100 at presentation and ALP was ~300.

In January 2022 he underwent orchiectomy and started abiraterone, which he continued for about 20 months. His PSA fell into the 20–30 range and remained stable during that time. ALP normalized and has stayed normal since. He has been on denosumab 120 mg every 12 weeks throughout.

In late 2023 his PSA began rising (into the 40s), marking transition to castration-resistant disease, and he was switched to enzalutamide. PSA initially dropped to 19 but then gradually increased despite dose escalation. He was on enzalutamide for roughly 12 months. By August 2024 PSA was 58 and by September it reached 130. Around that time he developed intermittent bone pain. A repeat PSMA PET showed more extensive skeletal metastases but resolution of the prostate lesion and pelvic nodes — essentially bone-only disease at that stage.

He then received 4 cycles of Lu-177 PSMA starting September 2024, and hormonal therapy was stopped at that time. He had an excellent response, with PSA declining to a nadir of 2.4 about six months after completing Lu. Bone pain resolved and he returned to his usual routine. He is currently not on any systemic cancer therapy.

Now, about a year after finishing Lu, his PSA has risen gradually from 2.4 to 7.5 over five months. He feels well, walks over a kilometer daily, and continues part-time office work. Hemoglobin is around 12 and ALP remains normal. Due to age and reduced cardiac function (EF ~35–40%, CRT device), he is not considered a candidate for standard chemotherapy.

I am trying to understand realistic next options now that his PSA appears to be rising again. For those who have been in a similar situation after a strong Lu response, what approaches have provided meaningful control? Has anyone had success with Lu rechallenge (2 or 4 more cycles), Actinium-based therapy, Radium-223, or any oral agents in older patients who cannot tolerate chemotherapy? Would appreciate hearing how others have sequenced treatment at this stage.