Treating Patients with Metastatic Castration Resistant Prostate Cancer: A Comprehensive Review of Available Therapies

Abstract

New therapies for metastatic castration resistant prostate cancer have brought new challenges with regard to treatment selection and sequencing. While hormonal agents provide good therapeutic responses, resistance may be intrinsic without prior drug exposure. Identifying predictors of response and relevant biomarkers will allow therapies to be more precisely tailored to individual patient profiles.

PSMA-Targeted Radionuclide Therapy of Metastatic Castration-Resistant Prostate Cancer with 177Lu-Labeled PSMA-617

“…Nevertheless, the findings are noteworthy in view of the high number of prior treatments seen by our patients before receiving 177 Lu-PSMA-617. The novel mCRPC agents have been approved with hormone therapy (Cougar-302, PREVAIL) or hormone and docetaxel (Cougar-301, AFFIRM, TROPIC) being the only pretreatments (27). In contrast, if the novel drugs are applied consecutively, the more than 50% PSA response rate is commonly less than 40% (28).…”

The context of prostate cancer genomics in personalized medicine

“…Individual patients have a distinct pattern of genetic alterations; therefore, treatment should be guided by the profile of diagnostic biomarkers (14,22,32). The AR signaling axis is a major target for numerous hormone therapies, throughout the stages of cancer (59)(60)(61). Once castration resistance develops, cancer cells harboring aberrant AR markedly evolve.…”

“…Once castration resistance develops, cancer cells harboring aberrant AR markedly evolve. Potent drugs, including AR antagonists and CYP17 inhibitors, may be used to inhibit the adapted AR and microenvironment due to androgen depletion (59,60). For ETS fusion-positive cancer, agents inhibiting fusion cofactors, such as DNA damage repair genes [poly(ADP-ribose) polymerase (PARP) 1, DNA-protein kinase (PK) and histone deacetylase 1], demonstrated a preferential effect in this subtype during clinical phase studies (61).…”

“…High expression levels of nuclear AR with the combined presence of cytoplasmic CYP17 demonstrated an improved response to AR targeted therapy, including abiraterone and enzalutamide, for cancer cases with bone metastasis (59,(61)(62)(63). AR-V7 splice variant is able to constitutively activate AR target genes without the requirement of androgen binding.…”

“…AR-V7 splice variant is able to constitutively activate AR target genes without the requirement of androgen binding. Its expression has been hypothesized as a primary underlying mechanism of resistance to abiraterone and enzalutamide (59,61). Cancer with high expression levels of the drug efflux transporter genes, including multidrug resistance protein 1 (MDR1) and certain β-tubulin isotypes (βIII-tubulin), demonstrate increased resistance to chemotherapies, such as docetaxel (64).…”