Deep and ongoing response of castrate-resistant prostate cancer on very low-dose enzalutamide in an elderly chemotherapy–naïve patient: a case report

Abstract Background Enzalutamide is an orally administered drug that blocks signaling in the androgen receptor with clinical activity in both chemotherapy–naive and post-chemotherapy patients with castrate-resistant prostate cancer (CRPC). Enzalutamide is generally well-tolerated, but dose reductions are nonetheless needed in case of side effects. Case An 82-year-old patient with chemotherapy–naive metastatic castration-resistant prostate cancer was treated with a very low dose of 40 mg enzalutamide once daily. The trough levels of enzalutamide and the active metabolite N-desmethylenzalutamide were 4.5 mg/L and 3.0 mg/L, respectively. This exposure provided a long-term response without any significant side effects. Conclusion Low doses of enzalutamide may be efficacious, while also reducing the risk of side effects. Furthermore, employing a lower dose would reduce healthcare costs and increase access to enzalutamide. Studies exploring the efficacy of lower enzalutamide doses are warranted.

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Studies of a novel modified E2F-targeted peptide with activity against castration-resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.205 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 205-205

Author(s):

Joseph R. Bertino ◽

Zoltan Szekely ◽

Kathleen W Scotto

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Cell Cycle Progression ◽

Target Genes ◽

Replication Proteins ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant ◽

The Stability

205 Background: The E2F family of genes encodes transcription factors that are key to the regulation of a number of target genes, including those encoding cyclins , CDKs , checkpoints regulators, and DNA repair and replication proteins. One of the primary functions of the E2Fs is to control the cell cycle, playing a major role in regulating the G1/S transition. One of the primary regulators of E2F expression is the retinoblastoma gene, RB, a chromatin associated protein that, in its unphosphorylated state, binds to and negatively regulates E2F; hyperphosphorylation of RB releases E2F, allowing cell cycle progression. Many tumor cells have mutant or dysfunctional RB, allowing the aberrant overexpression of the E2Fs and tumor cell proliferation; this aberrant overexpression is better tolerated when p53 is mutated, suppressing subsequent apoptosis. Overexpression of E2F, particularly E2F1, has thus been an attractive target for therapeutic intervention. However, this approach has not yet been successful, most likely due to the redundancy of the E2Fs and the lack of biomarkers for sensitivity. Methods: Using phage display, we have previously identified a novel peptide that, when coupled with penetratin (PEP) to enhance uptake), targets the E2F consensus site in E2F1,2 and 3a, leading to the downregulation of the activating E2Fs and their downstream targets. We have recently enhanced the stability and potency of this peptide by substituting L-Arg within the peptide with D-Arg. Results: Castrate resistant prostate cancer (CRPC) cells, DU-145, lack functional RB, have mutant p53, and are more sensitive to the D-Arg PEP than LnCap or PC-3 cells, with functional RB. Xenograft studies in mice show that the PEP, when encapsulated in PEGylated liposomes (PL-D-Arg PEP) , regresses DU-145 tumors without toxicity. Current studies are examining the combination of the (PL-D-Arg PEP) with taxotere, cisplatin and irradiation in prostate cancer xenografts and organoids from patients. Conclusions: A peptide that inhibits transcription of the activating E2Fs has promise to treat CRPC.

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Metastatic Castration-Resistant Prostate Cancer: Critical Review of Enzalutamide

Clinical Medicine Insights Oncology ◽

10.4137/cmo.s11670 ◽

2013 ◽

Vol 7 ◽

pp. CMO.S11670 ◽

Cited By ~ 3

Author(s):

Joelle El-Amm ◽

Nihar Patel ◽

Ashley Freeman ◽

Jeanny B. Aragon-Ching

Keyword(s):

Prostate Cancer ◽

Clinical Trials ◽

Survival Benefit ◽

First Generation ◽

Phase Iii ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant ◽

Overall Survival Benefit

Enzalutamide, previously known as MDV300, is an oral, second-generation androgen receptor (AR) signaling inhibitor or antagonist that was approved by the Food and Drug Administration in 2012 for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) postdocetaxel. Preclinical studies have demonstrated impressive affinity to the AR compared to the first-generation AR inhibitors. The landmark Phase III AFFIRM trial demonstrated improved overall survival benefit compared to placebo in addition to improvement in all tested parameters. Enzalutamide is currently being studied in several trials prechemotherapy and in earlier settings of prostate cancer. This review will discuss the mechanism of action of enzalutamide, its pharmacokinetics, the preclinical and clinical trials that led to its approval, the ongoing clinical trials, its safety and efficacy, as well as patterns of resistance, and discusses its place in therapy within the context of several recently approved agents for mCRPC.

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Application of a novel method weighing drug costs against survival in castrate-resistant prostate cancer cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.31_suppl.271 ◽

2013 ◽

Vol 31 (31_suppl) ◽

pp. 271-271

Author(s):

Helmy M. Guirgis

Keyword(s):

Prostate Cancer ◽

Drug Costs ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Castrate Resistant Prostate Cancer ◽

Previously Treated ◽

Novel Method ◽

Different Populations ◽

Initial Survey ◽

Castrate Resistant

271 Background: In the last few years, 5 new anticancer drugs have been introduced for the treatment of castration-resistant prostate cancer (CRPC). The objective was to apply a simplified methodology of weighing drug costs against overall survival (OS) in CRPC. Methods: Estimated cost in United Sates (US) dollars of an entire treatment course of an evaluated drug was divided by previously reported median OS gain over control. An initial survey of 45 drugs demonstrated that the maximal cost/OS/day gain was $757. Accordingly, a scale of crude scores was constructed with a 0% assigned to a cost/OS gain greater than $1,000 and 100% to a cost/OS gain of $1. Value scores were calculated after adjusting for quality of life (QoL), adverse events (AEs), and specialized administration and preparation (AP). Results: The lowest cost/OS gain and highest value score were demonstrated by generic docetaxel. Enzalutamide in previously-treated and abiraterone in chemo-naïve and treated patients x 6 months showed cost/OS gain lower than that of docetaxel but significantly higher than cabazitaxel. Pricing of sipuleucel-T based on cost of the entire course partly accounted for its highest cost/OS and lowest scores. Extending abiraterone and enzalutamide treatment to 12 months increased cost/OS gain and decreased scores. Conclusions: Methodology was proposed to weigh drug cost against OS/day gain with and without adjustment for QoL, AEs, and AP. Results in CRPC tend to support use of docetaxel, abiraterone, and enzalutamide rather than cabazitaxel and sipuleucel-T. Varying drug indications and different populations within the CRPC spectrum preclude direct drug comparison.

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Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

Cancers ◽

10.3390/cancers13040779 ◽

2021 ◽

Vol 13 (4) ◽

pp. 779 ◽

Cited By ~ 1

Author(s):

Asta Juzeniene ◽

Vilde Yuli Stenberg ◽

Øyvind Sverre Bruland ◽

Roy Hartvig Larsen

Keyword(s):

Prostate Cancer ◽

Clinical Status ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Visceral Metastases ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant ◽

Specific Membrane ◽

Clinical Advances ◽

Made In

Bone, lymph node, and visceral metastases are frequent in castrate-resistant prostate cancer patients. Since such patients have only a few months’ survival benefit from standard therapies, there is an urgent need for new personalized therapies. The prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer and is a molecular target for imaging diagnostics and targeted radionuclide therapy (theragnostics). PSMA-targeted α therapies (PSMA-TAT) may deliver potent and local radiation more selectively to cancer cells than PSMA-targeted β− therapies. In this review, we summarize both the recent preclinical and clinical advances made in the development of PSMA-TAT, as well as the availability of therapeutic α-emitting radionuclides, the development of small molecules and antibodies targeting PSMA. Lastly, we discuss the potentials, limitations, and future perspectives of PSMA-TAT.

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USE OF 177Lu-PSMA FOR RADIONUCLIDE THERAPY IN PATIENTS WITH CASTRATE-RESISTANT PROSTATE CANCER

Siberian Journal of Oncology ◽

10.21294/1814-4861-2021-20-3-115-123 ◽

2021 ◽

Vol 20 (3) ◽

pp. 115-123

Author(s):

A. A. Medvedeva ◽

V. I. Chernov ◽

E. A. Usynin ◽

R. V. Zelchan ◽

O. D. Bragina ◽

...

Keyword(s):

Prostate Cancer ◽

Radionuclide Therapy ◽

Malignant Tumors ◽

Tumor Grade ◽

Current Data ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Psma Pet ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant

Purpose of the study: to present current data regarding challenges in treatment of castration-resistant prostate cancer (CRPC) and the relationship between CRPC and the expression of prostate-specific membrane antigen (psma).Material and Methods. The search for relevant sources was carried out in the Pubmed, elibrary, Medline databases. The review included 43 publications, most of which were published over the past 5 years.Results. Currently, prostate cancer (PC) is one of the most common cancers in men. Moreover, over time, most patients develop resistance to therapy, which significantly worsens the prognosis of the disease. Psma is one of the molecular markers of prostate cancer; a number of studies have demonstrated a direct correlation between the level of psma expression and the tumor grade, stage and aggressiveness. Numerous studies indicate that psma represents an excellent target for radionuclide therapy of prostate cancer. 68Ga or 18F-psma Pet/Ct is the most common method for diagnosing PC. It should be noted that modern trends in the development of nuclear medicine are closely related to theranostics; therefore, the creation of highly specific theranostic pairs for diagnosis and subsequent therapy of malignant tumors is of great significance. The data obtained indicate that 177lu demonstrates the most optimal radiation and physical characteristics for therapeutic radionuclides, while psma-617 is one of the most studied ligands for radionuclide therapy.Conclusion. Currently, there are several studies covering radionuclide therapy with various psmacompounds labeled with 177lu. Radionuclide therapy with 177lu-psma has been shown to be recommended for patients with metastatic CRPC, who have no benefits from alternative therapies or have contraindications to them.

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The effect of low-dose GTx-758 on free testerone levels in men with metastatic castration resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.60 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 60-60 ◽

Cited By ~ 1

Author(s):

Evan Y. Yu ◽

Robert H. Getzenberg ◽

Jordan Smith ◽

Michael L. Hancock ◽

Ronald Tutrone ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trial ◽

Side Effects ◽

Adverse Events ◽

Bone Turnover ◽

Phase Ii ◽

Low Dose ◽

Hot Flashes ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

60 Background: Luteinizing hormone-releasing hormone (LHRH) agents used for androgen deprivation therapy (ADT) were designed to lower total testosterone (T) levels to those achieved by orchiectomy for palliative care of advanced prostate cancer. This castration equivalent level was based upon the lower limits of quantitation (50ng/dL) of outdated assays. Contemporary assays reveal that actual total T levels in men after orchiectomy are significantly lower (<20ng/dL), with 30 to 40% of men on LHRH agonists not achieving that level. There is growing literature showing that lower T levels correlate with improved outcomes. Additionally, the biologically active form of T is unbound, free T. GTx-758 (Capesaris) is an oral estrogen receptor α agonist that increases sex hormone binding globulin (SHBG), lowers free T levels, and ameliorates estrogen deficiency side effects associated with ADT. Methods: In a phase II open label study (G200712), 38 men with metastatic castration resistant prostate cancer (mCRPC) were continued on their current form of ADT along with a low dose of GTx-758, 125 mg, for at least 90 days. Exclusion criteria included men at increased risk for venous thrombolic events (VTE). Results: The initial 14 patients in this trial completed 90 days on study and are evaluable for select trial endpoints. All treated men had a greater than or equal to a 150% increase in SHBG levels. Eleven of the 14 men began the study with suboptimal castration (free T >0.7 pg/ml) and 91% (10 out of 11) of these men became optimally castrated by day 90. Four out of 14 patients had a more than 45% decrease in prostate-specific antigen. Stable or improved hot flashes and bone turnover markers were observed in 71% and 73% of treated men, respectively. While some patients experienced adverse events, none were vascular related and there were no serious adverse events or VTEs. Conclusions: The majority of patients on an LHRH agonist enrolled in this phase II study had suboptimal levels of free T that were further lowered by GTx-758 administration. GTx-758 treatment resulted in stabilization and/or improvement in reported hot flashes and bone turnover, two major side effects of ADT. While the phase II clinical trial is ongoing, and full results are forthcoming, these preliminary findings show that 125 mg of GTx-758 has clinical effectiveness and is well tolerated. Exploration of 250 mg a day is planned. Clinical trial information: NCT01615120.

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