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.

P1, N=352, Recruiting, Ambrx, Inc. | N=262 --> 352 | Trial completion date: Mar 2027 --> Dec 2028 | Trial primary completion date: Dec 2025 --> May 2026

P1, N=262, Recruiting, Ambrx, Inc. | Phase classification: P1/2 --> P1

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

P1/2, N=222, Recruiting, Ambrx, Inc.

P1/2, N=222, Recruiting, Ambrx, Inc. | N=150 --> 222

In summary, our study opens the door for further evaluation of ADCs in several indications not explored before.

[In]In-ePSMA-DM1 and [Lu]Lu-ePSMA-DM1 were both obtained in high radiochemical yields and purities (>95%), with >90% stability in PBS and >80% stability in mouse serum for up to 24 h post incubation at 37 °C. SPECT/CT imaging studies allowed for a faint tumor visualization of [In]In-ePSMA-DM1 at 1 h p.i., and the ex vivo biodistribution showed tumor uptake (2.39 ± 0.29% ID/g) at 1 h p.i., with the compound retained in the tumor for up to 24 h. Therefore, ePSMA-DM1 is a promising T-SMDC candidate for prostate cancer, and the data obtained so far warrant further investigations, such as therapeutic experiments, after further optimization.

Multiple SD and PSA decrease were observed at DLs of 0.08-0.14 mg/kg, conferred a promising preliminary antitumor activity in pts with mCRPC despite of COVID-19's impacts. MTD was not reached and dose-escalation to establish the RP2D is continuing.

First, we used functionalized liposomes to determine that imidazoquinoline TLR agonists Imiquimod (IMQ), Resiquimod (RSQ), and Gardiquimod (GDQ) are substrates for P-gp and determined their KD values...We expect that the SMDCs are taken up by prostate cancer cells and following conversion, efflux the imidazoquinoline, with enhanced efflux observed in MDR cancer cell lines. We anticipate on presenting our synthesis of the SMDCs as well as their applications and findings following in vitro studies.

But while PSMA has thus far been the 'front runner' target for these novel immunotherapeutic techniques, it may not be the ideal target for immunotherapy and there are other potential targetable TAAs that will require further exploration. This review will focus on these various PSMA-directed therapies, as well as other potential targets for immunotherapy beyond PSMA.

P1/2, N=150, Recruiting, Ambrx, Inc. | Phase classification: P1 --> P1/2 | N=76 --> 150 | Trial completion date: Aug 2024 --> Mar 2027 | Trial primary completion date: Feb 2024 --> Dec 2025

The serum stability of ARX517 should effectively deliver more payload to target tumor cells, and in multiple CDX and PDX prostate cancer models, ARX517 showed dose-dependent anti-tumor activity in both enzalutamide-sensitive and enzalutamide-resistant models. The strong preclinical data and recent clinical validation of PSMA as a mCRPC target provide rationale for evaluation of ARX517 as a potential prostate cancer treatment. ARX517 is currently in a Phase 1 dose escalation trial (ARX517-2011 [NCT04662580]) in the United States.

ADCT-212 was tolerated as a single 20 mg/kg dose in male rats, with exposure data being indicative of a linear PK profile with a half-life of approximately 12 days. In conclusion, ADCT-212 demonstrated potent and specific in vitro and in vivo anti-tumor activity while it was stable and well tolerated in the rat, warranting further development of ADCT-212 into the clinic.

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.

P1, N=50, Recruiting, Telix International Pty Ltd | Not yet recruiting --> Recruiting | Trial primary completion date: Dec 2022 --> Mar 2023

P2, N=50, Recruiting, Telix International Pty Ltd | Not yet recruiting --> Recruiting

To avoid undesired PSMA internalization in patients treated with PSMAxCD3 bsAbs, we are conducting functional screens evaluating various clathrin-dependent endocytosis inhibitors, eg, statins and chloroquine, which are clinically approved for the treatment of other diseases and thus would readily be available for combinatorial approaches . Latest results will be presented at the meeting. Altogether, our results con firm the involvement of clathrin in PSMA internalization and pave the way for combinatorial approaches that bolster the sensitivity / efficacy of approaches relying on the binding of tumor expressed target antigens.

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.

Antibody-targeted amanitin conjugates (ATACs) induced immunogenic cell death in vitro and resulted in an increased anti-tumor effect in combination with an immune checkpoint inhibitor in a subcutaneous CDX model if human PBMCs were present.Consequently, the data presented provide a rationale to the use of ATACs in combination therapy with immune checkpoint inhibitors.

Kaplan-Meier analyses of statin use and HER2+gastric cancer disease outcome in patients treated with trastuzumab suggested that patients without statin treatment have worse survival than patients treated with a statin. Additionally, statins synergize with therapeutic antibodies to decrease oncogenic signaling pathways.Our data suggest that acute statin treatment with appropriate pharmacokinetics/pharmacodynamics are potential adjuvants for specific antibody-targeted therapies.