PSMA is an ideal target for precision diagnosis and treatment of prostate cancer. P17-088 is a novel albumin-binding PSMA-targeted radioligand. This study aims to explore the safety and efficacy of 177Lu-labeled P17-088 for treating patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).

Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) has demonstrated promising potential for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Conjugation of albumin-binding moieties to PSMA-targeted radioligands can prolong their circulating half-life in the blood, thereby markedly enhancing tumor uptake and therapeutic efficacy. P17-088 incorporates a pegylated p-iodophenylbutanoyl group as an albumin binder with moderate binding affinity yet superior overall performance, which achieves a refined balance between augmented tumor accumulation and favorable safety profiles.

In our preliminary first-in-human study, 177Lu-P17-088 was observed to exhibit elevated distribution in organs including the red bone marrow and kidneys, with a considerably higher accumulation magnitude in tumor lesions. Satisfactory therapeutic outcomes were achieved even at a low activity dose of 1.11 GBq, validating its potential for further clinical translational research.

This single-arm study is designed to further evaluate the safety and efficacy of low-dose 177Lu-P17-088 in mCRPC patients. 177Lu-P17-088 will be administered at a fixed activity of 3.7 GBq (±10%) once every 6 to 8 weeks, with a total of four planned treatment cycles.

Post-treatment follow-up (safety and efficacy): Upon discontinuation of treatment, all enrolled participants will undergo systematic safety surveillance, including a 30-day short-term safety follow-up (FUP) assessment and extended long-term safety monitoring for approximately 12 months.

Survival follow-up: Following the termination of study treatment or completion of the post-treatment follow-up period, participants' vital status will be collected via telephone contact every 90 days as part of survival surveillance. Strict adherence to the survival follow-up schedule shall be ensured to facilitate complete survival data acquisition. Survival follow-up and the overall study will be concluded once the required number of overall survival (OS) events for the final survival analysis is reached.

Inclusion Criteria:

1. Metastatic Castration-Resistant Prostate Cancer (mCRPC) mCRPC refers to prostate cancer that progresses despite serum testosterone at castrate levels (< 50 ng/dL or 1.7 nmol/L), meeting at least one of the following criteria:

   • PSA >1 ng/mL with two consecutive rises at least 1 week apart, each increase ≥ 50% above the nadir.
   • Radiographic progression: Either two or more new bone lesions on bone scan, or soft tissue lesion progression as per RECIST 1.1 criteria. Progression based on symptoms alone is insufficient for mCRPC diagnosis and requires further evaluation.

2. Failure of, Refusal of, Absence of, or Refractoriness to Standard Therapy, or Disease Progression, or No Available Standard Therapy per Current Guidelines:

   • Patients who have not received, refused, or progressed after receiving at least 1 but no more than 2 prior taxane-based therapies. The taxane regimen must have included exposure for at least 2 cycles. Patients who received only one taxane may be included if the investigator deems them unsuitable for a second taxane (e.g., due to frailty assessed by geriatric/comorbidity evaluation or intolerance).
   • Patients who have progressed after receiving at least one novel androgen axis drug [NAAD] (e.g., abiraterone, enzalutamide).

3. Ability to understand and voluntarily sign a written informed consent form (ICF), and willingness and ability to comply with trial procedures including examinations and follow-up.

4. Age 18-90 years (inclusive).

5. Expected survival > 6 months.

6. ECOG performance status ≤ 2.

7. Presence of high-uptake lesions confirmed by 68Ga-PSMA-11 PET/CT imaging (positive defined as lesion uptake >1.5 times the liver background).

8. At least one measurable lesion per RECIST 1.1 criteria OR at least one bone metastasis per PCWG3 criteria.

9. Adequate organ function (No blood products, growth factors, or albumin administered within 14 days prior to baseline lab tests):

   • Bone Marrow Function: Neutrophil count ≥ 1.5 × 10#/L, White blood cell count ≥ 3.0 × 10^9/L, Platelet count ≥ 100 × 10^9/L, Hemoglobin ≥ 10 g/dL (≥ 100 g/L).
   • Liver Function: Albumin ≥ 30 g/L, Total bilirubin ≤ 1.5 × ULN, ALT or AST ≤ 3.0 × ULN (without liver metastases) or ≤ 5.0 × ULN (with liver metastases).
   • Renal Function: Serum creatinine ≤ 1.5 × ULN.

10. Agreement to comply with prescribed radiation protection measures during the trial period.

Exclusion Criteria:

1. Inability to tolerate imaging procedures;

2. Patients who have received systemic anticancer therapy (e.g., chemotherapy, radiotherapy, immunotherapy; excluding endocrine therapy), investigational drugs, or device therapy within 4 weeks prior to dosing;

3. Patients who received radionuclide therapy (Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, Lutetium-177) within 6 months, or any External Beam Radiation Therapy (EBRT) within 2 months prior to the first dose;

4. Patients with unresolved Grade 4 myelosuppression from prior anticancer therapy within 2 weeks, or Grade 3 myelosuppression requiring >6 weeks for recovery;

5. Planned use of cytotoxic chemotherapy, antitumor immunotherapy, radioligand therapy, or similar agents during the study;

6. Use of blood products or albumin within 14 days before dosing to meet enrollment criteria;

7. Brain metastasis at screening, except:

   • Asymptomatic cases confined to supratentorial/cerebellar regions (no midbrain/pons/medulla/spinal cord involvement) without corticosteroid therapy and with lesions ≤1.5 cm;
   • Symptomatic cases with treated and radiologically stable lesions (>4 weeks);

8. Other malignancies within 5 years (excluding cured localized cancers like basal/squamous cell skin carcinoma);

9. Superscan on bone scintigraphy;

10. Symptomatic or impending spinal cord compression;

11. Prior EBRT involving extensive bone marrow (>25%);

12. Significant cardiac disease at screening, including:

    • QTcF >470 ms or long QT syndrome history;
    • Myocardial infarction, angina, or CABG within 6 months deemed ineligible by investigators;

13. Any condition that, per investigator judgment, may compromise safety, data interpretation, or indicate high risk;

14. Uncontrolled bladder outlet obstruction, urinary incontinence, claustrophobia, or radiophobia at screening;

15. Positive for HCV-Ab, HIV, or syphilis antibodies at screening;

16. HBsAg-positive patients with active HBV replication (confirmed by HBVDNA per investigator assessment);

17. Known allergy to proteins/peptides, excipients, or structurally related compounds;

18. History of drug/alcohol abuse within 1 year or chronic substance abuse;

19. Failure to use effective contraception during the trial and for 6 months post-last dose;

20. Severe active infection prior to the first administration.