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Clinical Studies

Circulating androgen receptor gene amplification and resistance to 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer: results of a Phase 2 trial



In a Phase 2 clinical trial, we aimed to determine the lutetium-177 [177Lu]-PSMA-617 activity and the clinical utility of levels of plasma androgen receptor (AR) gene in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC).


We determined AR copy number in pretreatment plasma samples. We used logistic regression to estimate the odds ratio (OR) and 95% confidence intervals (95% CIs) in order to evaluate the independent relevance of AR status and to evaluate patients with early progressive disease (PD) defined as treatment interruption occurring within 4 months after the start of 177Lu-PSMA-617.


Twelve of the 15 (80%) with AR gene gain and 5 of the 25 (20%) patients with no gain of AR had early PD (p = 0.0002). The OR for patients without PSA response having AR gain was 3.69 (95% CI 0.83–16.36, p = 0.085). The OR for patients with early PD having AR gain was 16.00, (95% CI 3.23–79.27, p = 0.0007). Overall, median PFS and OS were 7.5 and 12.4 months, respectively. AR-gained had a significant shorter OS compared to AR-normal patients (7.4 vs 19.1 months, p = 0.020). No treatment interruptions due to adverse effects were reported.


Plasma AR status helped to indicate mCRPC with early resistance to 177Lu-PSMA-617.

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Fig. 1: Association of plasma AR status with prostate-specific antigen (PSA) response.
Fig. 2: A representative cases of durable activity of 177Lu-PSMA-617.
Fig. 3: Association between circulating AR status and clinical outcome.
Fig. 4: Swimmer plot of patient events.

Data availability

All data generated or analysed during this study are included in this published article and its Supplementary information data.


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This work was partially supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) and Ricerca Finalizzata Italian Ministry of Health (no grant number applicable).

Author information




Conception and design: UDG, GP. Development of methodology: UDG, MS, SS, MM, FF, DC, GP. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): UDG, MS, SS, SN, MM, GG, FF, CC, VC, MC, VDI, DC, FM, FEvE, GA, GP. Analysis and interpretation of data (e.g. statistical analysis, biostatistics, computational analysis): SN, MM, GG, FF, CC, VDI. Writing, review, and/or revision of the manuscript: UDG, MS, SS, SN, MM, GG, FF, CC, VC, MC, VDI, DC, FM, FEvE, GA, GP. Administrative, technical, or material support (i.e. reporting or organising data, constructing databases): MM, FF. Study supervision: UDG, MS, SS, GP.

Corresponding author

Correspondence to Ugo De Giorgi.

Ethics declarations

Ethics approval and consent to participate

Written informed consent was obtained from each patient prior to entry into the study. The study was conducted in compliance with the principles of the Declaration of Helsinki and local ethical and legal requirements. The protocol and informed consent were approved by the Institutional Review Board of Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy (NCT03454750).

Competing interests

UDG reports honoraria, consulting fees, or travel support from Merck, Bristol Myers Squibb, Janssen, Pfizer, Novartis, Astellas, Bayer, Sanofi, and Novartis and grant support from Merck and Amgen. VC reports honoraria, consulting fees, or travel support Bayer, Astellas, Janssen-Cilag, and Sanofi-Aventis. GA certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (e.g. employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: GA reports receiving commercial research grants from Janssen, Arno Therapeutics, and Innocrin Pharma; has received honoraria and/or travel support from the speakers’ bureaus of Janssen, Astellas, Sanofi-Aventis, and Roche/Ventana; has received travel support from Pfizer, Abbott Laboratories, Bayer Healthcare, and Essa Pharmaceuticals; has ownership interest (including patents) in The Institute of Cancer Research Rewards to Inventors; and is a consultant for/advisory board member of Janssen-Cilag, Veridex, Bayer Healthcare, Roche/Ventana, Astellas, Medivation, Pfizer, Novartis, Millennium Pharma, Abbott Laboratories, and Essa Pharma.

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De Giorgi, U., Sansovini, M., Severi, S. et al. Circulating androgen receptor gene amplification and resistance to 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer: results of a Phase 2 trial. Br J Cancer (2021).

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