In the present review, the developmental course, composition and mechanism of action of ADCs are explored, with a specific focus on recently published studies and ongoing trials aimed at investigating the efficacy and safety of ADCs in treating PCa. Lastly, ongoing challenges in ADC development and corresponding strategies to combat them are discussed.

ADCs have advanced from hematologic to solid tumours, notably in breast cancer, and are now pivotal in metastatic urological cancers as both monotherapies and in combination regimens, underscored by the FDA's approval of enfortumab vedotin and sacituzumab govitecan for metastatic urothelial cancer. There is a continual search for agents in the metastatic, relapsed testicular cancer landscape. ADCs have emerged as a pivotal innovation in oncology, blending targeted antibody therapy with potent cytotoxic drugs, significantly advancing treatment options for urological malignancies.

P1, N=120, Recruiting, AbbVie

In this review, we summarize the oncogenic functions of STEAP1 by cancer type. This review also provides new insights into the development of new anticancer strategies targeting STEAP1.

Chemotherapy involves the use of anti-tubulins (docetaxel, cabazitaxel), platinum salts, and topoisomerase inhibitors (TOPO1, TOPO2A)...Biomarkers of resistance include ERCC1 (Platinum), TUBB3 (taxanes), ALDH1A1 (cyclophosphamide), while response biomarkers include TOPO1 (irinotecan, topotecan), TOPO2A (doxorubicin, epirubicin), and hENT1 (Gemcitabine)...ERCC1, a marker for resistance to platinum-based agents, was not detected in 26% of cases, potentially enabling a cisplatin/carboplatin-based regimen in 1/4th of prostate cancer patients...These include doxorubicin biomarker TOPO2A in 34% of cases with 10x range, gemcitabine biomarker hENT1 in 36% of cases (4x range), temozolomide biomarker MGMT (ND in 12% of cases)...Trop2 was quantitated in 93% of the cases and had wide range of 37x (437 -16267 amol/ µg). The capacity to multiplex 72 protein biomarkers from 2-3 FFPE sections yields a wealth of actionable information for clinical treatment or patient stratification in clinical trials.

ADCs seem to provide efficacy benefits, even with potential toxicity. The results of most prospective ongoing studies are still awaited, and a longer follow-up time is warranted to evaluate the real impact of ADCs in PCa.

In prostate cancer, PSMA, STEAP1, TROP2, CD46 and B7-H3 are antigens currently being studied as targets for ADCs. In this paper, we discuss the composition of ADCs and focus on their application and challenges as treatment options in prostate cancer.

Novel treatment strategies using new antigen-directed therapies, drugs targeting the immunosuppressive tumor microenvironment, and combination immunotherapy therapies show great potential and are currently in clinical development. In addition, a deeper understanding of predictors of response and resistance to immunotherapy in prostate cancer is allowing for a more personalized approach to therapy.

Therefore, we focus on recently published and ongoing trials designed to investigate the clinical activity of ADCs against prostate malignancy, characterizing these agents. Lastly, we briefly discuss some ADCs-related issues with corresponding strategies to overwhelm them, along with future perspectives for these promising novel compounds.

P1/2, N=27, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2021 --> Jan 2022 | Trial primary completion date: Jan 2021 --> Jan 2022

P1/2, N=27, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2020 --> Jan 2021 | Trial primary completion date: Jan 2020 --> Jan 2021

P1/2, N=27, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2019 --> Jan 2020 | Trial primary completion date: Jan 2019 --> Jan 2020