Evaluation of [²²⁵Ac]Ac‐PSMA‐617 vis‐a‐vis Rechallenge [¹⁷⁷Lu]Lu‐PSMA‐617 PRLT Versus Cabazitaxel or Oral Metronomic Chemotherapy in mCRPC: An Observational Analysis of Outcome and Toxicity Profiles in a Real‐World Clinical Scenario

1. Introduction

Prostate cancer is the second most commonly diagnosed malignancy among men worldwide. Even with adequate first‐line treatments such as radical prostatectomy or medical/surgical castration, approximately 10% to 20% of the patients experience progression to metastatic castration resistant prostate carcinoma (mCRPC), a condition associated with high morbidity and a poor overall prognosis [1]. Standard treatment options for mCRPC include androgen receptor pathway inhibitors (ARPIs), taxane‐based chemotherapy such as docetaxel and cabazitaxel, and more recently introduced [¹⁷⁷Lu]Lu‐based PSMA‐targeted‐radioligand therapy (PRLT). Even with multiple therapeutic options, disease control rate (DCR) remains limited [2, 3]. Alpha‐emitting radionuclides like actinium‐225 [²²⁵Ac]Ac demonstrate high therapeutic efficacy owing to their high linear energy transfer, oxygen‐independent killing, and double‐strand DNA breaks, leading to increased tumor cell damage. Early clinical experiences demonstrated promising outcomes of [²²⁵Ac]Ac‐PSMA‐617 in the treatment of mCRPC patients [4, 5, 6, 7, 8]. Nevertheless, a real‐world evaluation of these therapeutic approaches in the management of mCRPC remains lacking. Therefore, we aimed to evaluate and analyse the therapeutic outcomes and toxicity profiles of [²²⁵Ac]Ac‐PSMA‐617, rechallenge [¹⁷⁷Lu]Lu‐PSMA‐617, cabazitaxel, and oral metronomic cyclophosphamide chemotherapy in postdocetaxel mCRPC patients with progressive disease (PD) following an initial course of [¹⁷⁷Lu]Lu‐PSMA‐617 or without previous [¹⁷⁷Lu]Lu‐PSMA‐617.

2. Materials and Methods

3. Treatment Protocol

All patients underwent a standardized institutional work‐up prior to therapy initiation, which included [⁶⁸Ga]Ga‐PSMA‐11PET/CT, [¹⁸F]F‐FDG PET/CT, and documentation of clinical symptoms and serum PSA measurement. Health‐related quality of life (HR QoL) assessments were performed at baseline and at each follow‐up using the Eastern Cooperative Oncology Group (ECOG) performance status, Karnofsky performance score, and visual analog scale (VAS) for pain. The granulocyte colony‐stimulating factor (G‐CSF) was not administered prophylactically in our cohort; however, it was used as per medical oncologist discretion wherever required, and was used in almost all patients with grade 1 or worse hematotoxicity.

Cohort 1:

• 1.

  Arm A: [ ²²⁵ Ac]Ac‐PSMA‐617

  A standardized therapy protocol was followed for all patients, with premedication with intravenous dexamethasone 8 mg and ondansetron 8 mg in 100 mL of normal saline followed by infusion of 92.5–100 KBq/kg (2.5–2.7 uCi/kg) of [²²⁵Ac]Ac‐PSMA‐617 per cycle in 100 mL of normal saline over 30 min as per institutional protocol. Then 1000 mL of saline were infused over 6.5–7 h. A posttherapy whole body planar imaging and regional single photon emission computed tomography (SPECT)/CT image was performed at 24 h posttherapy using large field of view γ camera. Treatment was administered in cycles, typically repeated every 8–10 weeks.

• 2.

  Arm B: Rechallenge [ ¹⁷⁷ Lu]Lu‐PSMA‐617

  Patients were offered rechallenge PRLT after a minimum period of 4 months from the last PRLT cycle. A standardized therapy protocol was followed for all patients, with standard dosing of 7.4 GBq (200 mCi) per cycle at 6 weeks (± 1 week) intervals as per the European Association of Nuclear Medicine/Society of Nuclear Medicine and Molecular Imaging (EANM/SNMMI) procedure guidelines, however, dose reduction by 20% (or even 30%–40% after discussion with multi‐disciplinary team includes nuclear medicine physician, hematologists and treating oncologists) was considered in cases with significantly reduced bone marrow reserves. Premedication with intravenous dexamethasone 8 mg and ondansetron 8 mg in 100 mL of normal saline was followed by followed infusion of 5.55–6.29 GBq (150–170 mCi) of [¹⁷⁷Lu]Lu‐PSMA‐617 per cycle in 100 mL of normal saline over 30 min. The 1000 mL of normal saline was infused over 6.5–7 h. A posttherapy whole body planar imaging and regional SPECT/CT image was performed at 24 h posttherapy using large field of view γ camera. Further cycles were offered at an interval of 8–10 weeks, depending on patient response and tolerance.

• 3.

  Arm C: Chemotherapy with cabazitaxel

  Patients were treated with intravenous cabazitaxel at a dose of 25 mg/m² administered intravenously over 1 h every 21 days, in combination with oral prednisone 10 mg daily, as per the institutional protocol. All patients received appropriate premedication prior to infusion, including antihistamines, corticosteroids, and H₂ antagonists to reduce the risk of hypersensitivity reactions. Prophylactic G‐CSF was administered at the discretion of the treating physician based on baseline risk factors. Treatment was administered with regular monitoring of hematologic, hepatic, and renal function parameters. Therapy was continued until evidence of disease progression, unacceptable toxicity, or withdrawal of consent.

• 4.

  Arm D: Oral metronomic chemotherapy with cyclophosphamide (OMCT)

Patients who could not tolerate cabazitaxel or other treatments in view of deranged hematological parameters, or poor clinical status, or nonavailability of PRLT were treated with oral metronomic chemotherapy with cyclophosphamide with continuous monitoring of hematologic, hepatic, and renal parameters. Oral cyclophosphamide was administered orally at a continuous low dose of 50 mg once daily, combined with oral dexamethasone (1 mg daily), without planned treatment breaks. Therapy was continued until evidence of disease progression, unacceptable toxicity, or withdrawal of consent.

Cohort 2:

Arm E: Chemotherapy with cabazitaxel (no prior [ ¹⁷⁷ Lu]Lu‐PSMA‐617 therapy)

Patients in Arm E received cabazitaxel administered intravenously at a dose of 25 mg/m² every 3 weeks, in combination with daily oral prednisone (5–10 mg). All patients received appropriate premedication prior to infusion, including antihistamines, corticosteroids, and H₂ antagonists to reduce the risk of hypersensitivity reactions. Prophylactic G‐CSF was administered at the discretion of the treating physician based on baseline risk factors. Treatment was continued until documented disease progression, unacceptable toxicity, or patient preference for discontinuation. Dose delays or reductions were implemented according to toxicity severity and standard clinical practice.

Arm F: Oral metronomic chemotherapy with cyclophosphamide (no prior [ ¹⁷⁷ Lu]Lu‐PSMA‐617 therapy)

Patients in Arm F received oral metronomic cyclophosphamide at a dose of 50 mg once daily, combined with oral dexamethasone (1 mg daily), without planned treatment breaks. Treatment was continued until documented disease progression, unacceptable toxicity, or patient preference for discontinuation. Patients were monitored at regular intervals with clinical assessment and laboratory evaluation, including hematologic, hepatic, and renal function parameters.

4. Response Evaluation Criteria

Treatment outcome was evaluated under five headings: (a) symptomatic, (b) biochemical, and (c) imaging response, (d) survival outcomes, and (e) toxicity profiles. Response assessment of (a) symptomatic, (b) biochemical, and (c) imaging was performed at 8 weeks following the last treatment. Patients were classified as responders = complete response (CR) + partial response (PR) + SD and nonresponders = PD based on their assessment.

5. Results

A total of 66 patients with mCRPC (a median age of 67 years and range 43–76 years) who had documented PD on ARPIs and docetaxel were included in the study. Of these, 49 patients were included in cohort 1, and remaining 17 patients in cohort 2. In cohort 1, patients received treatments as follows: (1) 15 patients received [²²⁵Ac]Ac‐PSMA‐617(the range of 4.44–7.4 MBq = 120 uCi to 200 uCi per cycle with a mean dose of 5.79 MBq = 156.6 uCi per cycle) in arm A. (2) 18 patients were treated with rechallenge [¹⁷⁷Lu]Lu‐PSMA‐617 (the range of 5.55–6.29 GBq = 150–170 mCi per cycle and a mean dose of 5.661 GBq = 153 mCi per cycle) in arm B. (3) 8 patients received chemotherapy with cabazitaxel in arm C and (4) 8 patients received OMCT in arm D. In cohort 2; (1) 14 patients were treated with cabazitaxel in arm E and (2) 3 patients received OMCT in arm F.

The demographic and clinical characteristics of the patients were mentioned in Table 1 with matched baseline characteristics (disease burden, [¹⁸F]F‐FDG avidity, and ISUP grade). All patients had high‐burden disease (defined by ≥ 4 skeletal lesions with ≥ 1 lesion beyond the vertebral bodies and pelvis). All patients had received prior treatment with androgen‐receptor targeted therapies (abiraterone and/or enzalutamide) and docetaxel. Other prior treatments undertaken by these patients included definitive surgery, including radical prostatectomy, bilateral orchidectomy, and external beam radiotherapy, as summarized in Table 1.

6. Response Assessment

7. Toxicity and Tolerability

The most frequently reported adverse event in arm A was xerostomia, reported in all patients, which was generally mild in most cases (11 patients with Grade‐1 or 2 and 4 patients needing medical care). Other adverse events included fatigue and transient pain, managed effectively with short‐course opioid analgesics. The most commonly reported adverse events in arm B were fatigue in 6 patients (33%), transient pain flare in 9 patients (50%), and grade 1/2 xerostomia in 12 patients (66%). Among patients who underwent chemotherapy in (arm C and D), fatigue, nausea/vomiting, diarrhoea, stomatitis, and loss of appetite were the predominant adverse events. Patients who received cabazitaxel had more severe adverse effects than with OMCT, with 3/8 (37.5%) patients in arm C reporting grade 3 toxicities, including diarrhoea (requiring intravenous hydration) and dose modification in one patient, and pneumonitis (requiring hospitalization) in one patient. None of the patients in arms D reported any grade 3 or worse events. In arm E, 3/14 patients developed grade 3 acute/subacute toxicities, whilst there was no incidence in arm F.

With respect to hematological parameters, treatment‐emergent grade 3–4 adverse events were observed in 2 (13.3%) patients in arm A, 3 patients (16.6%) in arm B, 5 (62.5%) patients in arm C, and 3 patients (20%) in arm D. 2 patients (14.2%) had grade 3 anemia and leukocytopenia in arm D. No patient in any arm required permanent treatment discontinuation due to toxicity. No grade 5 (fatal) events occurred in any patients. The toxicity profiles were summarized in Table 4.

8. Discussion

Therapeutic options for mCRPC postprogression on ARPIs and docetaxel are limited and not employed uniformly by practitioners. Available strategies include chemotherapy (cabazitaxel or OMCT), PSMA‐PRLT using beta emitters or alpha emitters, immunotherapy, and olaparib (in patients with BRCA1/BRCA2 mutations) [14]. Immunotherapy, though a promising option for many cancers, has limitations such as high cost, limited availability, high rate of severe toxicities, and discouraging results in many studies [15]. Similarly, the use of olaparib is confined to the patients harboring homologous recombination repair mutations, which constitute only a small percentage of the overall mCRPC population.

Cabazitaxel remains an important salvage therapeutic option after progression on ARPIs and docetaxel, with multiple prior studies demonstrating significant survival benefit in this clinical setting [16, 17]. While the TheraP trial reported better PSA response rates with [¹⁷⁷Lu]Lu‐PSMA‐617 over cabazitaxel in mCRPC without OS benefit of PRLT [18], Cabazitaxel continues to be widely used in many centers due to limited availability of PRLT and lack of dedicated nuclear medicine infrastructure. However, data regarding the efficacy of cabazitaxel following progression on [¹⁷⁷Lu]Lu‐based PRLT remain limited [19]. The OMCT has also been explored as a treatment option in progressive mCRPC, with several studies demonstrating symptomatic as well as survival benefits with acceptable toxicity profiles. However, OMCT is generally reserved for patients with poor baseline hematologic parameters or those unable to tolerate aggressive systemic therapies [20, 21, 22]. PRLT (alpha‐ or beta‐emitters) is evolving as an excellent treatment option over the recent years. Nevertheless, resistance develops in approximately 30% of patients following [¹⁷⁷Lu]Lu‐PSMA‐617, necessitating additional salvage treatment strategies. The efficacy and feasibility of rechallenge [¹⁷⁷Lu]Lu‐PSMA‐617 in such cases has been evaluated in a few studies, with variable biochemical response rates of 26% to 80% reported after the first or second rechallenge cycles in the available literature [23, 24].

Alpha‐based PRLT has been investigated as a strategy to overcome resistance to beta‐based PRLT. Multiple studies have reported favorable outcomes for [²²⁵Ac]Ac‐PSMA‐617 in mCRPC [25, 26]. Recent prospective evidence from the phase I AcTION study presented at ASCO 2026 demonstrated encouraging antitumor activity with [²²⁵Ac]Ac‐PSMA‐617, with an acceptable safety profile in patients with mCRPC, regardless of prior [¹⁷⁷Lu]Lu‐PSMA RLT, representing the first prospective clinical data of alpha‐based PRLT [27].

In the present study, we found that patients treated with alpha‐based PRLT demonstrated encouraging clinical and biochemical outcomes. A significant proportion (66%) of patients (Figures 3 and 4) reported clear‐cut reduction in symptoms following Alpha based‐PRLT, with a noticeable reduction in the mean VAS scores, from 7.8 pretherapy to 4 posttherapy, comparable to the findings as reported in literature [28]. PSA₅₀ response (≥ 50% PSA decline) was achieved in 60% of patients treated with Alpha based‐PRLT, with a DCR of 80% on anatomical imaging. On literature survey, PSA₅₀ response rates achieved with Alpha based‐PRLT were relatively lower than those reported by Sathkege et al., who observed a 91% PSA response in chemotherapy‐ or [¹⁷⁷Lu]Lu‐based PRLT‐ naïve patients. Such findings align with existing evidence suggesting that prior resistance to these treatments may negatively influence treatment outcomes with Alpha‐based PRLT [28, 29]. Nevertheless, our findings were in concordance with the observations in the studies by Feurecker et al. (65%), Sen et al. (66%), the WARMTH act (57%) and the AcTION trial (58.8%–85%), where the population characteristics were similar to our cohort [25, 27, 30, 31]. We found modest but clinically relevant response rates following rechallenge [¹⁷⁷Lu]Lu‐PSMA‐617 RLT, similar to a recent literature review [32]. Biochemical response was observed in approximately 25% of patients receiving cabazitaxel or OMCT following prior [¹⁷⁷Lu]Lu‐PSMA‐617, with imaging DCR achieved in 62.5% and 37.5% respectively. Among PRLT naïve patients, (cohort 2), cabazitaxel was associated with a DCR of 57.1%, hence, remaining an important treatment option for mCRPC following progression on multiple lines of therapy, particularly in settings where radioligand therapies are unavailable or unsuitable. In our cohort, clinical benefit was observed in a subset of patients receiving chemotherapy, although treatment‐related toxicities were more frequent than those observed with PRLT. The overall cohort demonstrated a median PFS of 5 months and median OS of 12 months, reflecting the advanced stage of disease and limited therapeutic options available in this setting. Toxicity assessment across the treatment arms highlighted a favorable safety profile of Alpha based‐PRLT, with minimal myelotoxicity and negligible renal or hepatic toxicity, making it a feasible option in heavily pretreated mCRPC patients. Xerostomia as an adverse effect was universal among patients in the Alpha based‐PRLT arm as similarly reported in literature [29, 30, 31, 33], with varying degrees of severity, which was partially mitigated through the use of sialagogues, application of ice packs post therapy, and local artificial salivary drops, albeit with limited symptomatic relief in most patients. Patients treated with rechallenge [¹⁷⁷Lu]Lu‐PSMA‐617 exhibited a low toxicity profile, with no reports of grade ≥ 3 adverse events. In contrast, a significant proportion of patients (67%) in the cabazitaxel arm experienced both clinical and hematological severe adverse effects, with 33% patients requiring additional supportive care. Patients treated with metronomic chemotherapy demonstrated fewer adverse effects, albeit with modest therapeutic responses, supporting its role in patients with poor baseline clinical or hematological status.

Our study has several limitations, including its retrospective design, patient heterogeneity, nonrandomized treatment allocation, and small sample in subgroup analysis leading to limited statistical power and nonsignificant p‐values for comparison. Although patient selection was carefully performed with the baseline clinical and disease characteristics matched across arms, treatment decision was influenced by clinical status, physician preference, treatment availability, and financial considerations, leading to selection bias. Consequently, the findings should be interpreted as descriptive and hypothesis‐generating at its best. Nevertheless, this study reflects a real‐world clinical scenario, comprising heavily pretreated mCRPC patients with limited therapeutic options and deranged blood parameters. The encouraging activity and favorable tolerability observed with Alpha‐based PRLT support further prospective evaluation. Rechallenge [¹⁷⁷Lu]Lu‐PSMA‐617 emerges as a well‐tolerated salvage option, with modest disease control and minimal toxicity.

9. Summary

This study demonstrates encouraging clinical, biochemical, and imaging responses with [²²⁵Ac]Ac‐PSMA‐617 in patients with advanced progressive mCRPC showing PD on various lines of treatment like ARPIs, docetaxel, and initial course of [¹⁷⁷Lu]Lu‐PSMA‐617, with approximately 2/3rd of the patients exhibiting clinical and biochemical response, and a remarkable 80% DCR on imaging. Patients treated with [²²⁵Ac]Ac‐PSMA‐617 had minimal toxicities, further underscoring its clinical utility in patients unfit for cytotoxic chemotherapy. Rechallenge [¹⁷⁷Lu]Lu‐PSMA‐617 also showed clinically meaningful responses, with biochemical PR in roughly 1/3rd of the patients, DCR of 50%, and manageable adverse effects, suggesting its potential as a salvage approach for patients with PD after initial response with [¹⁷⁷Lu]Lu‐PSMA‐617, where nonavailability and high‐cost constraints of alpha‐based PRLT exist. Similarly, cabazitaxel and OMCT provided clinical benefit in selected patients and remain relevant therapeutic options in treatment‐refractory settings where other therapeutic options may not be feasible. Given the retrospective nature of the study and potential selection biases, these findings should be considered descriptive and hypothesis‐generating. Further prospective studies are warranted to better define the role of these treatment approaches in the management of advanced mCRPC.

10. Conclusion

In conclusion, this observational analysis suggests that [²²⁵Ac]Ac‐PSMA‐617 may represent a novel efficacious therapeutic option with minimal adverse effects in heavily pretreated mCRPC patients, while rechallenge [¹⁷⁷Lu]Lu‐PSMA‐617 and chemotherapy remain feasible and important salvage treatment strategies in resource limited settings. Although limited by its retrospective design and potential selection biases, these findings provide a rationale for future prospective, large‐scale, multicentre trials evaluating and comparing the efficacy, toxicity, and survival outcomes for the management of such patients with limited therapeutic alternatives.

Funding

The authors have nothing to report.

Ethics Statement

The work was approved by the Institutional Medical Ethics Committee with the IMEC number‐ P2/Jan/2023. Consent was obtained from all patients at the time of prospective treatment and who were alive during analysis, and waiver was taken for those who had died.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Available on reasonable request.