- 30-40% of diagnosed prostate cancer patients will develop biochemical recurrence after treatment and a considerable proportion of these will develop mCRPC
- ADCs are a new, potentially favorable approach for treating mCRPC
- In prostate cancer, antigens such as PSMA, STEAP1, TROP2, CD46 and B7-H3 are now being studied as targets for ADCs in currently recruiting and/or active clinical trials
Metastatic Castration-Resistant Prostate Cancer
According to the National Cancer Institute, prostate cancer is the most common cancer, and the second leading cause of cancer death, among men in the United States.1 When diagnosed, many patients have localized disease. 5% of patients, however, are diagnosed with metastatic disease. In addition, 30-40% of patients will develop biochemical recurrence after treatment. A considerable proportion of these patients will develop metastatic castration-resistant prostate cancer (mCRPC). The prognosis for patients with mCRPC is poor over the long-term, with a somewhat short overall survival (OS), although survival differs greatly depending on individual disease characteristics.2
What are Antibody-Drug Conjugates in mCRPC?
ADCs are seen as a new, potentially favorable approach in treating mCRPC, in part due to practice-changing results in other types of cancer. ADCs are made up of monoclonal antibodies (mAbs) directed at certain antigens overly expressed on cancer cells versus normal cells. A stable linker attaches a cytotoxic payload to the mAb. These new compounds recognize antigens expressed over cancer cells’ surface helping to ensure minimal exposure of healthy tissue to cytotoxic agents, thus expanding the therapeutic window of ADCs.3 In prostate cancer, antigens such as PSMA, STEAP1, TROP2, CD46 and B7-H3 are now being studied as targets for ADCs.4
Recent Early Phase ADC Trials for mCRPC
As of July 2022, the FDA has approved 12 ADCs for cancer therapy, and more than 80 ADCs are currently under development worldwide. In the area of urologic oncology, enfortumab vedotin has been approved for the treatment of cisplatin-ineligible urothelial carcinoma, a disease with few treatment options.5 Given this level of activity in clinical trials, ADCs clearly are viewed as potentially important cancer treatments, including in mCRPC. The following sections provide brief descriptions of a selection of early-stage clinical trials of ADCs for mCRPC.
FOR46 (enfotumab vedotin), a CD46 Targeted Antibody-Drug Conjugate
According to data from an active phase 1a/1b trial (NCT03575819) of Astella’s FOR46 (enfotumab vedotin), the CD46 targeted ADC showed encouraging evidence of antitumor activity in patients with mCRPC with a safety profile like other ADCs with a monomethyl auristatin E (MMAE) cytotoxic payload. As presented during the 2022 ASCO Annual Meeting, results showed that 45% of evaluable patients (n =43) experienced a prostate-specific antigen (PSA) decline of at least 50% (PSA50), with a median duration of PSA response of at least 16 weeks (range, 6-48+).6
Based on encouraging early readouts, additional studies with FOR46 are recruiting participants, including a phase 1/2 combination trial (NCT05011188) with enzalutamide and a Phase II monotherapy umbrella trial (NCT04754191).
ARX517, a PSMA Targeted Antibody-Drug Conjugate
A Phase I study of the PSMA targeting ADC ARX517 is currently recruiting patients with mCRPC and other solid tumors with PSMA expression such as pancreatic, lung, and ovarian cancers (NCT04662580). Patients with prostate cancer must have metastatic disease by CT, have previously received an FDA-approved drug for the treatment of mCRPC, and be on ongoing hormone therapy. In preclinical models of prostate cancer, ARX517 demonstrated adequate pharmacokinetic (PK) and toxicity profiles in both enzalutamide (Xtandi)-sensitive and -resistant tumors. The ADC is Ambrx, Inc.’s lead internal asset and their second ADC to enter the clinic.7
AMG 509, a STEAP1 Targeted Antibody Drug Conjugate
AMG 509, a new treatment targeting the six-transmembrane epithelial antigen of prostate 1 (STEAP1) antigen is currently being evaluated in a Phase I study of safety, tolerability, PK and efficacy (NCT04221542). STEAP1 is overexpressed on the surface of prostate cancer cells with low to no expression on normal cells. AMG 509 is a bispecific XmAb 2+1 T-cell engager that concurrently binds to STEAP1 on tumor cells and the CD3 complex on T cells causing T-cell mediated lysis of STEAP1-expressing cells. AMG 509 demonstrated significant antitumor activity in preclinical prostate cancer models.8 AMG 509 is one of several molecules in Amgen’s prostate cancer pipeline.
IMMU-132, a Trop2 Targeted Antibody-Drug Conjugate
IMMU-132 (Sacituzumab Govitecan or SG) is a novel ADC based on a humanized anti-Trop-2 antibody (hRS7) conjugated to an SN-38 payload. SG has been approved by the FDA (Treldovy) for treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease. As mentioned above, the FDA also granted an accelerated approval to SG for patients with locally advanced or metastatic urothelial cancer who previously had a platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor.
A currently recruiting clinical trial (NCT03725761) of SG is evaluating the safety and efficacy of the treatment in patients with mCRPC who have progressed while on therapy with combination enzalutamide/abiraterone or ARN-509/abiraterone in.
MCG018, an Anti B7-H3 Targeted Antibody-Drug Conjugate
B7-H3 (CD276), a member of the B7 family of immunomodulatory molecules, is overexpressed in primary and metastatic prostate cancer, and correlates with disease severity and poor clinical outcome. MGC018, a duocarmycin-based B7-H3 antibody-drug conjugate, is currently being evaluated in clinical studies.9
A Phase 1/2 clinical trial of MGC018 (Anti-B7-H3 ADC) alone and in combination with MGA012 (Anti-PD-1 Antibody) is currently actively studying patients with advanced solid tumors, including those with mCRPC (NCT03729596). MGC018 is also being evaluated in a currently recruiting randomized, open-label Phase 2/3 study in comparison to androgen receptor axis targeted therapy (Abiraterone or Enzalutamide) in patients with mCRPC (NCT05551117).
With as many as 30-40% of diagnosed prostate cancer patients developing biochemical recurrence after treatment and a considerable proportion of those developing metastatic disease, there is considerable unmet need in mCRPC. ADCs present a new and promising treatment approach and are being studied in a number of early phase clinical trials.
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2Henríquez, I.; Roach, M., III; Morgan, T.M.; Bossi, A.; Gómez, J.A.; Abuchaibe, O.; Couñago, F. Current and Emerging Therapies for Metastatic Castration-Resistant Prostate Cancer (mCRPC). Biomedicines 2021, 9, 1247. https://doi.org/10.3390/biomedicines9091247
3Rosellini, M.; Santoni, M.; Mollica, V.; Rizzo, A.; Cimadamore, A.; Scarpelli, M.; Storti, N.; Battelli, N.; Montironi, R.; Massari, F. Treating Prostate Cancer by Antibody-Drug Conjugates. Int. J. Mol. Sci. 2021, 22, 1551. https://doi.org/10.3390/ijms22041551
4Georges Mjaess et al, Antibody-Drug Conjugates in Prostate Cancer: Where Are we? Clinical Genitourinary Cancer, https://doi.org/10.1016/j.clgc.2022.07.009
6Ryan C. FOR46 Shows Early Antitumor Activity in Metastatic Castration-Resistant Prostate Cancer. OncLive web site, 12July2022, accessed 10Jan2023. https://www.onclive.com/view/for46-shows-early-antitumor-activity-in-metastatic-castration-resistant-prostate-cancer
7Tucker N. Antibody-drug conjugate ARX517 joins rapidly expanding PSMA pipeline. Urology Times web site, https://www.urologytimes.com/view/antibody-drug-conjugate-arx517-joins-rapidly-expanding-psma-pipeline 09Aug2019, accessed 12Jan2023.
8Danila DC, Waterhouse DM, Appleman LJ, et al. A phase 1 study of AMG 509 in patients with metastatic castration-resistant prostate cancer. DOI: 10.1200/JCO.2022.40.16_suppl.TPS5101 Journal of Clinical Oncology 40, no. 16_suppl (June 01, 2022) TPS5101-TPS5101.
9Scribner JA, Chen FZ, De Costa A et al. Targeting B7-H3 in prostate cancer: Preclinical proof of concept with MGC018, an investigational anti-B7-H3 antibody-drug conjugate. Cancer Res (2022) 82 (12_Supplement): 330.