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

Abstract

Background: 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).

Methods: 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.

Results: 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.

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

Trial registration: NCT03454750.

Conflict of interest statement

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.

© 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Figures

Fig. 1. Association of plasma AR status with prostate-specific antigen (PSA) response.

Waterfall plots showing PSA declines by AR copy number status in castration-resistant prostate cancer patients treated with 177Lu-PSMA. Only two patients (one with AR gain) were not evaluable for PSA response due to rapid deterioration and death. Bars clipped at maximum 100%.

Fig. 2. A representative cases of durable activity of 177Lu-PSMA-617.

Seventy-one-year-old mCRPC patient with nodal and lung metastases and circulating AR normal, previously treated with docetaxel, abiraterone, and cabazitaxel. The patient received 4 cycles of 177Lu-PSMA-617 radioligand therapy (activity per cycle: 4.4 GBq every 6–8 weeks). October 2017, baseline PSA = 52.4 ng/mL; May 2018 post-177Lu-PSMA therapy PSA: 2.26 ng/mL. October 2018 disease relapse (nodes, lung, and bone). a Pre-therapy PSMA-PET/CT, b baseline 177Lu PSMA whole-body scan, c post-therapy 177Lu PSMA whole-body scan, d post-therapy PSMA-PET/CT, e PSMA-PET/CT at last follow-up.

Fig. 3. Association between circulating AR status and clinical outcome.

Kaplan–Meier estimate of overall survival (a) and progression-free survival (b) according to circulating AR status.

Fig. 4. Swimmer plot of patient events.

Arrow indicates patients without PSA and radiological progression-free survival (PFS) up to cut-off date.