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Future directions in castrate-resistant prostate cancer therapy.

ABSTRACT: Although several new therapies have recently become available for the treatment of castrate-resistant prostate cancer (CRPC), the disease remains universally incurable and demands novel therapeutic approaches. To this end, great strides have been made in our understanding of the biologic and molecular mechanisms driving prostate cancer growth and progression in the past few years, resulting in widespread clinical investigation of numerous new targeted therapies. This review will highlight some of the key therapeutic agents that (in the opinion of the authors) may have the largest effect on the future management of CRPC, with a focus on both molecular targets and clinical trial design. These agents include angiogenesis inhibitors, mTOR pathway inhibitors, apoptosis-inducing drugs, IGF pathway inhibitors, Src family inhibitors, Hedgehog pathway antagonists, epigenetic therapies, PARP inhibitors, and prodrug approaches. The future of CRPC therapy appears brighter than ever before.

SUBMITTER: Antonarakis ES

PROVIDER: S-EPMC4029111 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Future directions in castrate-resistant prostate cancer therapy.

Antonarakis Emmanuel S ES Antonarakis Emmanuel S ES Carducci Michael A MA

Clinical genitourinary cancer 20101201 1

Although several new therapies have recently become available for the treatment of castrate-resistant prostate cancer (CRPC), the disease remains universally incurable and demands novel therapeutic approaches. To this end, great strides have been made in our understanding of the biologic and molecular mechanisms driving prostate cancer growth and progression in the past few years, resulting in widespread clinical investigation of numerous new targeted therapies. This review will highlight some o ...[more]

PMID: 21208854

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Project description:Abstract Background Radioligand therapy (RLT) with 177lutetium (Lu)-labelled prostate-specific membrane antigen (PSMA) ligands has been increasingly used in recent years for therapy of metastatic castrate-resistant prostate cancer (mCRPC). Studies have revealed that 177Lu-PSMA ligand therapy is well tolerated and appears to cause fewer adverse effects than current standard of care third-line treatments. Notably, since 177Lu-PSMA agents are predominantly excreted by kidneys, there are concerns relating to their potential nephrotoxicity and renal outcomes. Although many recent studies have focused on mostly nephrotoxic adverse reactions at up to 3-month follow-up, assessment of renal outcomes after 177Lu-PSMA RLT in longer term follow-up is lacking. The aim of this study was to assess the influence of 177Lu-PSMA RLT on renal function in patients treated for mCRPC at >3?months post-therapy. Methods In this retrospective cohort study, we assessed 195 men with progressive mCRPC who had received therapy with 177Lu-PSMA as second- or third-line after standard therapeutic interventions. Patients underwent investigations with 68Ga-PSMA-ligand positron emission tomography/computed tomography scan to confirm PSMA-expressing mCRPC. Eligible patients were required to have estimated glomerular filtration rate (eGFR) >30?mL/min/1.73 m2, an Eastern Cooperative Oncology Group performance status score <3, no severe liver injury (as characterized by liver function tests) and no significant bone marrow dysfunction. Enrolled patients received two to five cycles of intravenous 177Lu-PSMA I&T or 177Lu-PSMA-617, at 6- to 10-week intervals. Renal outcomes were assessed according to Kidney Disease: Improving Global Outcomes guidelines as incidence of acute kidney injury (AKI), acute kidney disease (AKD) or chronic kidney disease (CKD). All assessments and tests were undertaken between therapy cycles and at follow-up of at least 3?months. Results Of 195 assessed men with mCRPC, 110 patients aged [mean ± SD (range)] 70?±?8 (53–92) years were recruited into this study with median follow-up of 8 (interquartile range 5–12, minimum 3, maximum 29) months and mean baseline eGFR 81?±?13?mL/min/1.73 m2. Pre-existing CKD was identified in 12% of patients. None of the patients experienced an AKI during RLT. Two AKD and three CKD G3a cases were identified. Analysis of possible impact of prior CKD and major risk factors (hypertension, diabetes, history of AKI) on incidence of AKD or CKD demonstrated relative risk 4.2 [95% confidence interval (CI) 1.23–14.29] and 1.91 (95% CI 1.14–3.12), respectively. However, Fisher’s exact test did not reveal statistical significance of the impact of both conditions. Conclusions Current Lu-PSMA RLT protocols appear to carry a mild nephrotoxic risk with the rate of about 4.5%. Prior CKD is potentially the most significant risk factor of post-RLT renal dysfunction.

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Future directions in castrate-resistant prostate cancer therapy.

Publications

Future directions in castrate-resistant prostate cancer therapy.

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