Metastatic Castration-Resistant Prostate Cancer: Insights on Current Therapy and Promising Experimental Drugs

Abstract

The therapeutic landscape of metastatic hormone sensitive and metastatic castration-resistant prostate cancer (mCRPC) is rapidly changing. We reviewed the current treatment options for mCRPC, with insights on new available therapeutic strategies. Chemotherapy with docetaxel or cabazitaxel (for patients progressing on docetaxel), as well as treatment with androgen receptor axis targeted therapies, and Radium-223 are well-established treatment options for patients with mCRPC. The advent of theragnostic in prostate cancer established Lutetium-177 (177Lu)-PSMA-617 as a new standard of care for PSMA-positive mCRPC previously treated with ARAT and taxane-based chemotherapy. Olaparib, a poly-ADP-ribose polymerase (PARP) inhibitor, is approved for selected patients with mCRPC progressed on ARATs and in combination with abiraterone acetate as first-line treatment for mCRPC. Immunotherapy showed limited efficacy in unselected patients with mCRPC and novel immunotherapy strategies need to be explored. The search for biomarkers is a growing field of interest in mCRPC, and predictive biomarkers are needed to support the choice of treatment and the development of tailored strategies.

Keywords: PARP inhibitors; androgen-receptors axis targeted therapies; chemotherapy; metastatic castration resistant prostate cancer; predictive biomarkers; theragnostic.

Figure 1

Lutetium-177-PSMA-617 mechanism of action. Prostate-Specific Membrane Antigen (PSMA) is a type II transmembrane glycoprotein. It is mainly expressed in prostate tissue but can also be expressed in the peripheral and central nervous system, small intestine, and salivary gland tissues. In aggressive forms of prostate cancer PSMA is significantly overexpressed, making it an important target for both imaging and treatment of prostate cancer. Compared to whole antibodies, small molecule inhibitors like PSMA-617 can bind to PSMA more rapidly and with higher affinity, making them ideal for radionuclide therapy. Lutetium-177 (177Lu) is a β-emitter complex with a PSMA-binding small molecule inhibitor (PSMA- 617) (1). 177Lu-PSMA-617 binds rapidly to PSMA (2) and is endocytosed into the cell (3), where it remains over the 6.7-day half-life of 177Lu. The β-decay of 177Lu (4) induces different types of DNA damage (6), including both single-strand breaks (SSBs) and double-strand breaks (DSBs). Furthermore, 177Lu has a maximal tissue penetration of about 2 mm, so it can reach even adjacent cells (5) that may express lower levels of PSMA. 177Lu also emits low energy γ-rays on decay, enabling image acquisition and dosimetric calculation using SPECT (7) or planar scintigraphy. This theranostic approach allows for direct visualization of tumour and normal tissues, while also providing the ability to estimate the delivered dose of radiotherapy.

Figure 2

PARP inhibitors mechanism of action. DNA damage and PARPsThe most common type of DNA damage is DNA Single-Strand Break or SSB (1), which is repaired mostly by PARP-dependent Base Excision Repair (BER) pathway (2).The PARP (Poly ADP-Ribose Polymerase) enzyme family can catalyze the transfer of ADP-ribose to target proteins. Some isoforms of PARP family have the function of detecting and initiating an immediate response to DNA SSBs. Once a SSB is detected, one of these PARPs binds to the DNA (3) and undergoes a conformational change, allowing β-NAD+ (the PARP co-factor) to bind to the active site of the enzyme (4). At this point, the enzyme uses the hydrolysis of β-NAD+ to catalyze the transfer of ADP-Ribose moieties onto target proteins, leading to the synthesis (PARylation) of a Polymeric ADP-Ribose (PAR) chain (5). This step allows the recruitment (via their PAR-binding domains) of DNA repair effectors(6), which are required for efficient DNA repair (7). The process ends with the degradation of PAR chains via Poly (ADP-ribose) Glycohydrolase (PARG) and the release of PARP and repair enzymes. PARP inhibitorsPARP inhibitors or PARPi (8) induce catalytic inhibition of PARP-dependent repair (preventing PARylation) and binding of PARP on damaged DNA (9). Failure to repair SSBs leads to DSBs (Double-Strand Breaks) during DNA replication, thus PARP inhibition induces further DNA damage (10). Nevertheless, DNA damage can also be repaired through Homologous Recombination (HR) mechanisms, so HR-proficient cells can repair DSBs originated from SSBs and survive (11), while HRdeficient cells that cannot repair DSBs die (12). Usually, cancer cells are mutated in one of their DNA repair pathways. For example, BRCA1 and BRCA2 encode key components of the HRR mechanism, so mutations of these two genes lead to the inability to repair DSBs. Accordingly, PARP inhibitors exploit a principle called synthetic lethality, in which two conditions that independently of each other allow the cell to survive together cause cell death.

Figure 3

Ipatasertib mechanism of action. PI3K /AKT signaling pathway. Several types of cancers are characterized by dysregulation of the PI3K (phosphatidylinositol 3-kinase)/AKT (or PKB, protein kinase B) signaling pathway, which is involved in the regulation of multiple cellular processes, including metabolism, cell-cycle control, survival, proliferation, motility and differentiation. The PI3K/AKT pathway starts from stimulation of Receptor Tyrosine Kinase (RTK). When signaling molecules bind to the RTK extracellular ligand binding domain (1), two RTK monomers get close and form a cross-linked dimer (2). Cross-linking activates the intracellular tyrosine kinase domains (TKDs) and each RTK monomer phosphorylates multiple tyrosines on the other RTK monomer (3). These phosphotyrosine residues serve as recruitment sites for several downstream signaling proteins, which lead to PI3K phosphorylation and activation (4). PI3K mediates the conversion of PIP2 into PIP3 (5), which, together with activating kinases, leads to the phosphorylation and activation (6) of AKT. AKT is the central node of the pathway and its downstream signaling controls many key cellular activities (7). The PI3K/AKT pathway is tightly regulated by the tumor suppressor PTEN (8), through its ability to dephosphorylate and inhibit PIP3. In many cancers are present alterations in the genes that encode key proteins of the pathway (including PTEN, PI3K and AKT), leading to hyperactivation of AKT signaling. This hyperactivation promotes uncontrolled cell growth. Ipatasertib can inhibit AKT by binding to the ATP-binding pocket (9), leading to inhibition of downstream signaling. Thus, ipatasertib reduces cell growth and proliferation.