(UroToday.com) The 2023 GU ASCO annual meeting included a session on advanced prostate cancer, specifically new targets, new drugs, and new victories, featuring a presentation by Dr. Johann De Bono discussing new targets and new concepts for metastatic castration-resistant prostate cancer (mCRPC). Dr. De Bono notes that prostate cancer is not one disease, with inter-patient heterogeneity and different genotypes including dMMR, BRCA2/PALB2 loss, ATM loss, and PTEN loss leading to subtypes having differing prognosis and therapy vulnerability. The androgen receptor is often activated despite resistance to available androgen receptor signaling inhibitors, with androgen receptor splice variants being detectable, and androgen mutations being less common. Additionally, intra-patient heterogeneity and genomic instability are driven by androgen receptor blockade, with tumor cells switching from luminal to a basal/EMT/senescent phenotype to survive. Dr. De Bono notes that this (including RB1/TP53 loss) is implicated in drug resistance.
Dr. De Bono notes that there are practical implications of this biology background:
- Molecular classification can optimize outcomes, for example, PD-1/PD-L1 targeting, MMR defective cases, and PARP inhibitors or carboplatin for BRCA altered prostate cancer
- Disease progression without PSA increase or PSMA PET progression, which is a particular feature with emerging visceral disease (ie. multiple liver metastases)
- Response and surrogate biomarkers monitoring disease outcome, whereby surrogacy for a drug class does not equate to all drugs (including rPFS and PSA-progression free survival)
- Monitoring disease sub-clones serially over time is needed, likely requiring serial ctDNA/circulating tumor cell genomic analyses
With regard to new therapeutic strategies, Dr. De Bono notes that this is a rapidly burgeoning research space. Selective tumor cell killing remains the ‘holy grail’. This may be accomplished by several mechanisms:
- Targeting androgen receptor gene splicing/androgen receptor splice variant generation/signaling
- Cell signaling inhibition (ie. AKT, JAK/STAT, FGFR/RAF/MEK, WNT, Notch, CDK4/6)
- Targeting inhibitors of apoptosis (ie. MCL-1/BCL-xL/BCL-2, BIRC5)
- Novel synthetic lethal strategies (ie. with RB1 loss, ATM loss, genomic instability)
- Targeting tumor cell metabolic dependencies (ie. glutamine metabolism)
- Reverse epigenetic remodeling of the prostate cancer transcriptome (ie. EZH2i, LSD1i)
- Blocking microbiota generation of androgenic (and other) metabolites
Dr. De Bono emphasized that so much research is going on, however rational therapeutic combinations are likely to be critically important to changing care.
With regards to targeting tumor cell surface antigens, Dr. De Bono notes that the antigen needs to be primarily expressed on tumor cells (ie. B7-H3, TROP2, HER3, DLL3, CD46, HER3, PSCA, and others). This allows targeting with radionuclides, immunoconjugates, and radioimmunoconjugates:
Novel immunotherapy strategies include (i) multi-specific antibody constructs such as BiTEs, (ii) CAR-T cells, which are preferably multi-antigen targeting, (iii) immune checkpoint inhibition (and novel checkpoint combinations), and (iv) reversing T-cell exhaustion (ie. adenosine axis/TGFbeta signaling):
Targeting tumor-stroma paracrine interactions includes myeloid cells, B-cells/plasma cells, and fibroblasts. This is important given that secreted proteins can fuel tumor growth (ie. IL-23, IL-6, and NRG1).
Dr. De Bono then provided several examples of areas of research/treatment that he is particularly excited about. First, targeting B7-H3, which when analyzing RNAseq data Dr. De Bono and colleagues found (based on work funded by the Prostate Cancer Foundation) CD276 or B7-H3 (PD-L1 is B7-H1) was highly negatively associated with MMRd prostate cancer:
Dr. De Bono notes that B7-H3 protein expression in mCRPC may be clinically important to B7-H3 targeted therapies. Furthermore, a B7-H3 anti-body drug conjugate (DS-7300) has antitumor activity in B7-H3 positive prostate cancer patient-derived xenograft models in vivo:
In a phase I/II trial (n = 54), DS-7300 showed clinical antitumor activity in mCRPC with response rates of 33% and confirmed partial response in 28% of patients.
Second, Dr. De Bono is interested in blocking CXCR2 and myeloid cell chemotaxis. Myeloid inflammation is implicated in advanced prostate cancer progression and therapy resistance. Additionally, prostate cancer clinical outcomes have not been improved by advances in cancer immunotherapy. Peripheral blood and intratumoral myeloid inflammation is associated with shorter survival and treatment resistance to taxanes and anti-androgens. Dr. De Bono notes that myeloid inflammatory cells are recruited to the prostate tumor bed down chemokine gradients via CXCR2. Furthermore, CXCR2 is expressed by myeloid inflammatory cells to facilitate myeloid cell recruitment into the tumor microenvironment. Together with Dr. Andrea Alimonti, Dr. De Bono noted the following hypothesis: Targeting myeloid chemotaxis via the CXCR2 receptor axis can inhibit myeloid inflammatory cell recruitment into the prostate tumor bed and block the paracrine effects of myeloid inflammation in driving prostate tumor growth and therapeutic resistance:
As such, they led an investigator initiated trial with the following trial design:
They found that CXCR2 inhibition reduced intratumor myeloid cells (15/21 patients):
Dr. De Bono concluded his presentation discussing new targets and new concepts for mCRPC with the following take-home messages:
- Inter-patient disease molecular heterogeneity results in different therapeutic vulnerabilities for individual sub-types and necessitates stratification strategies
- Intra-patient sub-clone heterogeneity and evolution can be dissected by serial analysis of circulating genomic biomarkers that can guide treatment selection
- Multiple new precision medicine therapeutic strategies are in development and it is envisioned that the next decade will result in further advances in care (ie. immunoconjugates, immunotherapy antibody constructs, and CAR-T cells)
- Holistic consideration of the patient and their disease need to be taken into account, including studies of microbiota and druggable tumor-stromal interactions. The microbiota may fuel tumor growth through generated metabolites, and myeloid and other stromal cells may secrete paracrine, druggable factors that fuel growth and induce T-cell exhaustion
Presented by: Johann S. De Bono, MD, PhD, The Institute of Cancer Research and The Royal Marsden, London, UK
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023.