The role of PSMA-based radioligand therapy in hormone-sensitive prostate cancer

Abstract

Purpose: Conventional systemic therapies are valuable options in prostate cancer (PCa); however, such treatments can determine adverse events and toxicity. The observed improvement in overall survival, coupled with PSA reduction and a favorable safety profile in the post-taxane castration-resistant PCa (CRPC) setting has prompted the consideration of PSMA-based radioligand therapy (RLT) earlier in the treatment sequence. In this review, we will describe the literature and ongoing clinical trials regarding the use of PSMA-based RLT in hormone-sensitive PCa (HSPC) including the neoadjuvant, de-novo/synchronous metastatic, adjuvant, and early BCR settings.

Methods: We performed a systematic literature search on the PubMed/MEDLINE/EMBASE and clinicaltrials.gov databases for studies and protocols assessing the role of PSMA-based RLT in HSPC.

Results: The literature search yielded 140 results. After screening titles and abstracts and applying inclusion and exclusion criteria, we selected 25 papers showing the potentialities of earlier RLT in HSPC, with several ongoing trials.

Conclusion: Early use of PSMA-based RLT holds significant potential in HSPC patients from the neoadjuvant to the BCR setting. In these stages, the lower tumor burden, more frequent exclusive nodal involvement, and higher organ reserve may improve treatment efficacy and allow for treatment combinations while maintaining a less toxic profile.

Keywords: HSPC; PCa; Prostate-specific membrane antigen; RLT; Theranostics.

Fig. 1

Schematic representation of the theranostics concept through a case example. The term “theranostics” is derived from the combination of “therapy” and “diagnosis”, summarizing the concept of using a specific molecule (i.e., PSMA) to first identify areas of high target expression with a diagnostic agent (e.g., [⁶⁸Ga]Ga or [¹⁸F]), and subsequently treat them with a therapeutical agent (e.g., [¹⁷⁷Lu]Lu or [²²⁵Ac]Ac) for effective treatment. We present the case of an 80-year-old patient diagnosed with metastatic prostate adenocarcinoma (ISUP 4, Gleason Score 4 + 4) in 1995 initially treated with RT followed by hormone therapy. By 2016, the patient had become castration-resistant and underwent therapy with abiraterone, followed by enzalutamide. Due to disease progression and refused chemotherapy, he underwent RLT with [¹⁷⁷Lu]Lu-PSMA-617 in early 2017. Enrollment [⁶⁸Ga]Ga-PSMA-11 PET/CT (1a, maximum intensity projection - MIP; 1b, fused axial images) showed high PSMA expression in the prostatic bed and lymph node metastases. The patient underwent four cycles of [¹⁷⁷Lu]Lu-PSMA-617 RLT, with a cumulative administered activity of 24.9 GBq. Post-treatment planar whole-body images (1c, anterior acquisition) acquired 24 h post-injection after the first RLT confirmed a high radiopharmaceutical concentration in the lesions previously identified by [⁶⁸Ga]Ga-PSMA-11 PSMA PET/CT as further magnified by [¹⁷⁷Lu]Lu-PSMA-617 SPECT/CT (1d, fused axial images). The patient showed a progressive decline in PSA values (from 76.9 ng/ml to 0.8 ng/ml) and exhibited a partial response to 4 RLT cycles at post-treatment [⁶⁸Ga]Ga-PSMA-11 PET/CT (1e, MIP; 1f, fused axial images)

Fig. 2

Overview of the studies selection process

Fig. 3

Main ongoing trials regarding PSMA-based RLT in HSPC