Eltanexor (KPT-8602), a second-generation selective inhibitor of nuclear export (SINE) compound, in patients with metastatic castration-resistant prostate cancer (mCRPC).

197 Background: Overexpression of exportin 1 (XPO1) in malignant cells increases the nuclear export/inactivation of tumor suppressor proteins (eg. p53), and promotes the translation of eIF4E-bound oncoprotein mRNAs (eg. c-MYC). XPO1 inhibition reduces total androgen receptor levels, including ARv7, and may re-sensitize prostate cancer (PC) cells to androgen deprivation therapy. Selinexor, the first-in-human SINE compound, showed anticancer activity in patients (pts) with mCRPC. Eltanexor (ELTA), a second-generation SINE compound, showed promising anticancer activity in preclinical models of PC, including in abiraterone (ABI) resistant cell lines. Therefore, ELTA ± ABI was evaluated in mCRPC. Methods: This was part of a phase 1/2 study to determine the safety, preliminary efficacy, and recommended phase 2 doseof ELTA in pts with advanced cancers. Pts with mCRPC received oral ELTA once daily for 5 days per week over a 28-day cycle in 4 cohorts: single-agent (20 mg; n=7 or 30 mg; n=6) or in combination with ABI (20 mg; n=13 or 30 mg; n=4). Pts may have prior exposure to chemotherapy. Pts receiving ELTA + ABI had prior response to ABI then progressed. Response was evaluated by PCWG3 / RECIST v1.1. Results: As of 17 Sept 2018, 30 pts were treated with ELTA ± ABI with a median age of 71 and a median of 4 prior regimens; (87% ABI, 60% enzalutamide, and 57% chemotherapy). Twenty-one pts with mCRPC were evaluable for efficacy: 2 partial response (10%), 15 stable disease (71%), and 4 progressive disease (19%). The median treatment duration is 75.5 days; 4 pts still on treatment. Treatment-related adverse events (TRAEs) occurring in ≥30% of the pts: fatigue (67%; 13% Gr≥3), nausea (63.3%; 0% Gr≥3), decreased appetite (57%; 0% Gr≥3), diarrhea (47%; 3% Gr≥3), weight decreased (43%; 3% Gr≥3), vomiting (37%; 7% Gr≥3), anemia (33%; 7% Gr≥3), and dysgeusia (33%; 0% Gr≥3). The 2 Gr4 TRAEs were neutropenia and elevated AST. Conclusions: ELTA± ABI is well-tolerated with AEs mostly limited to Gr 1/2 and demonstrates preliminary anti-tumor activity in patients with mCRPC. With enrollment complete, these results warrant further investigation of ELTA ± ABIin mCPRC. Clinical trial information: NCT02649790.

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Darolutamide as a second-generation Androgen receptor inhibitor in the treatment of prostate cancer

Current Molecular Medicine ◽

10.2174/1566524020666200903120344 ◽

2020 ◽

Vol 20 ◽

Author(s):

Ali Abbasi ◽

Ahmad Movahedpour ◽

Ahmad Amiri ◽

Mohamad Samare Najaf ◽

Zohreh MostafaviPour

Keyword(s):

Prostate Cancer ◽

Clinical Trials ◽

Androgen Receptor ◽

Chemical Structure ◽

Second Generation ◽

Phase 1 ◽

Serum Testosterone ◽

Castration Resistant ◽

Anti Tumor Activity

: Prostate cancer (PC) is known as the most frequent cancer among men in the world. Androgen Deprivation Therapy (ADT) is one of the initial treatment approaches in the PC therapy and various drugs can be used in routine Hormonal therapy for PC therapy. Nevertheless, PC cells can survive and continue their growth via different mechanisms which lead to their resistance to common treatments i.e., Enzalutamide. Darolutamide (ODM-201) is a second-generation androgen receptor (AR) inhibitor with a new chemical structure and has a high affinity to the AR. Darolutamide doesn’t cross the bloodbrain barrier, for this reason, reduces the possibility of seizures. Darolutamide also can inhibit the transcriptional activity of several AR mutant variants (F877L, F877L/T878A, and H875Y/T878A) which are Enzalutamide resistant. In this review we reviewed the results of different studies: in vitro, animal model and phase 1, 2 and 3 clinical trials (ARADES, ARAFOR and ARAMIS). We shall discuss worldwide phase 2 and 3 clinical trials (ARASENS and ODENZA) that are in progress, in order to demonstrate the advantages of Darolutamide consumption in different groups of patients. Darolutamide has shown high potential in inhibiting the growth of MR49F (Enzalutamide resistant PC cells) and VCaP (Castration-resistant PC cells) cell lines and transcriptional activities of AR. Fewer doses of Darolutamide is needed compared to Enzalutamide. The drug had significant anti-tumor activity and had no effect on serum testosterone levels in animal models. Darolutamide demonstrates its safety and efficacy in different studies and was well tolerated nearly in all of the patients.

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Preliminary activity of veliparib (V) in BRCA2-mutated metastatic castration-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.7_suppl.170 ◽

2015 ◽

Vol 33 (7_suppl) ◽

pp. 170-170 ◽

Cited By ~ 10

Author(s):

Shalu Pahuja ◽

Leonard Joseph Appleman ◽

Chandra Prakash Belani ◽

Alice Chen ◽

Edward Chu ◽

...

Keyword(s):

Prostate Cancer ◽

Brca Mutation ◽

Phase 1 ◽

Single Agent ◽

Maximum Tolerated Dose ◽

Castration Resistant Prostate Cancer ◽

Brca Mutations ◽

Therapeutic Implications ◽

Castration Resistant ◽

Increased Risk

170 Background: Male BRCA mutation carriers have a 2-8-fold increased risk of prostate cancer when compared to the general population, and up to 3% of patients (pts) with prostate cancer carry an inherited mutation in BRCA1 or 2. The therapeutic implications of germline BRCA mutations in prostate cancer are largely unknown. BRCA mutation enhances sensitivity to inhibition of the PARP1 and PARP2 enzymes, due to a synthetic lethal effect on DNA repair. We therefore conducted a phase 1 study of the PARP 1, 2 inhibitor, veliparib (V), in 2 cohorts of pts- BRCA germline mutated (BRCA+) and BRCA-wild type (BRCA-wt; consisting of serous ovarian cancer and triple-negative breast cancer). Methods: A 3+3 dose escalation phase I trial was performed to determine a maximum tolerated dose (MTD) and recommended phase II dose (RP2D). V was administered orally continuously on a 28-day cycle. Results: A total of98 (70 BRCA+ and 28 BRCA-wt) pts were enrolled. The maximum administered dose (MAD) was 500 mg BID and the MTD/RP2D was 400 mg BID. In BRCA+ cohort at doses ≥ 400 mg BID, overall response rate (ORR) defined as complete response (CR)+ partial response (PR) was 37%, and clinical benefit rate (CBR) defined as CR+PR+stable disease (SD) > 6 cycles was 40%. Three pts with BRCA2+ metastatic castration-resistant prostate cancer (mCRPC) were enrolled on the RP2D and were evaluable for response. In these pts, the ORR was 2/3 (66%) and CBR 3/3 (100%) (summarized in table). One pt with rapidly progressive mCRPC involving liver and bone achieved PR and undetectable serum PSA, and remains on therapy at 19+ cycles. The most common adverse effects in these pts were grade 1/2 nausea/vomiting, fatigue, and leukopenia consistent with the overall study population. Conclusions: Single-agent V demonstrates evidence of activity in BRCA2+ mCRPC. These data support the role of genotype-directed therapy in prostate cancer. Clinical trial information: NCT00892736. [Table: see text]

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ODM-204, a novel dual inhibitor of CYP17A1 and androgen receptor for the treatment of castration-resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.230 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 230-230

Author(s):

Pekka Kallio ◽

Riikka Oksala ◽

Anu Moilanen ◽

Reetta Riikonen ◽

Petteri Rummakko ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Antitumor Activity ◽

Phase 1 ◽

Single Agent ◽

Xenograft Model ◽

Castration Resistant Prostate Cancer ◽

Intact Male ◽

Dual Inhibitor ◽

Castration Resistant

230 Background: Castration-resistant prostate cancer (CRPC) is characterized by high androgen receptor (AR) expression and persistent activation of AR signaling axis by residual tissue androgens. Inhibiting AR and androgen biosynthesis together may be more effective than inhibiting either alone to treat CRPC. ODM-204 is a potent, orally administered investigational non-steroidal dual inhibitor of CYP17A1 and AR. In vivo, ODM-204 shows favourable pharmacokinetic/ pharmacodynamics (PK/PD) properties in intact mature male monkeys and strong antitumor activity in VCaP xenograft. Methods: The inhibition of CYP17A1 by ODM-204 was studied by using human testicular microsomes and adrenal cortex cell line. Potency to human AR was demonstrated in cells stably transfected with the full-length AR and androgen-responsive reporter gene constructs. PK/PD relationships were evaluated in intact male mature monkeys after single and multiple doses of ODM-204 (10-30 mg/kg/day) by measuring plasma PK after several time points and serum testosterone (T), dehydroepiandrosterone (DHEA), luteinizing hormone (LH), aldosterone, and cortisol 5 hours after the daily dose. Efficacy was further studied in VCaP xenograft in intact male nude mice treated with ODM-204, enzalutamide (enza), abiraterone (abi), or enza+abi-combination for 28 days. Results: ODM-204 binds to AR with a high affinity (Ki47 nM) and selectivity, and has a high potency towards CYP17A1 (IC5022 nM). In intact monkeys, ODM-204 was well tolerated and showed good oral bioavailability with linear and dose proportional pharmacokinetics. Already after a single oral dose of ODM-204, serum T and DHEA were markedly suppressed. After multiple days of dosing, LH was increased, however, changes in cortisol and aldosterone were only minimal. In VCaP xenograft model, ODM-204 showed significant antitumor activity, better than single agent enza or abi, or their combination. Conclusions: ODM-204 is a novel, dual CYP17A1 and AR inhibitor for the treatment of CRPC. A clinical phase 1/2 dose-escalation trial (NCT02344017) is ongoing in patients with mCRPC to determine PK, PD, safety and anti-tumor activity of ODM-204.

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A phase 1 study to assess the safety, pharmacokinetics, and anti-tumor activity of the androgen receptor n-terminal domain inhibitor epi-506 in patients with metastatic castration-resistant prostate cancer

Investigational New Drugs ◽

10.1007/s10637-021-01202-6 ◽

2021 ◽

Author(s):

Corinne Maurice-Dror ◽

Ronan Le Moigne ◽

Ulka Vaishampayan ◽

Robert B. Montgomery ◽

Michael S. Gordon ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Phase 1 ◽

Castration Resistant Prostate Cancer ◽

Phase 1 Study ◽

Terminal Domain ◽

Castration Resistant ◽

Anti Tumor Activity

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Piperlongumine inhibits migration and proliferation of castration-resistant prostate cancer cells via triggering persistent DNA damage

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03369-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ding-fang Zhang ◽

Zhi-chun Yang ◽

Jian-qiang Chen ◽

Xiang-xiang Jin ◽

Yin-da Qiu ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Dna Damage ◽

Cell Adhesion ◽

Anticancer Activity ◽

Cancer Cells ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Dna Damage And Repair ◽

Castration Resistant

Abstract Background Metastatic castration-resistant prostate cancer (CRPC) is the leading cause of death among men diagnosed with prostate cancer. Piperlongumine (PL) is a novel potential anticancer agent that has been demonstrated to exhibit anticancer efficacy against prostate cancer cells. However, the effects of PL on DNA damage and repair against CRPC have remained unclear. The aim of this study was to further explore the anticancer activity and mechanisms of action of PL against CRPC in terms of DNA damage and repair processes. Methods The effect of PL on CRPC was evaluated by MTT assay, long-term cell proliferation, reactive oxygen species assay, western blot assay, flow cytometry assay (annexin V/PI staining), β-gal staining assay and DAPI staining assay. The capacity of PL to inhibit the invasion and migration of CRPC cells was assessed by scratch-wound assay, cell adhesion assay, transwell assay and immunofluorescence (IF) assay. The effect of PL on DNA damage and repair was determined via IF assay and comet assay. Results The results showed that PL exhibited stronger anticancer activity against CRPC compared to that of taxol, cisplatin (DDP), doxorubicin (Dox), or 5-Fluorouracil (5-FU), with fewer side effects in normal cells. Importantly, PL treatment significantly decreased cell adhesion to the extracellular matrix and inhibited the migration of CRPC cells through affecting the expression and distribution of focal adhesion kinase (FAK), leading to concentration-dependent inhibition of CRPC cell proliferation and concomitantly increased cell death. Moreover, PL treatment triggered persistent DNA damage and provoked strong DNA damage responses in CRPC cells. Conclusion Collectively, our findings demonstrate that PL potently inhibited proliferation, migration, and invasion of CRPC cells and that these potent anticancer effects were potentially achieved via triggering persistent DNA damage in CRPC cells.

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Treatment of nonmetastatic castration-resistant prostate cancer: focus on second-generation androgen receptor inhibitors

Prostate Cancer and Prostatic Diseases ◽

10.1038/s41391-020-00310-3 ◽

2021 ◽

Author(s):

Fred Saad ◽

Martin Bögemann ◽

Kazuhiro Suzuki ◽

Neal Shore

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Second Generation ◽

Imaging Techniques ◽

Specific Antigen ◽

Conventional Imaging ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Therapeutic Decisions ◽

Consensus Statements

Abstract Background Nonmetastatic castration-resistant prostate cancer (nmCRPC) is defined as a rising prostate-specific antigen concentration, despite castrate levels of testosterone with ongoing androgen-deprivation therapy or orchiectomy, and no detectable metastases by conventional imaging. Patients with nmCRPC progress to metastatic disease and are at risk of developing cancer-related symptoms and morbidity, eventually dying of their disease. While patients with nmCRPC are generally asymptomatic from their disease, they are often older and have chronic comorbidities that require long-term concomitant medication. Therefore, careful consideration of the benefit–risk profile of potential treatments is required. Methods In this review, we will discuss the rationale for early treatment of patients with nmCRPC to delay metastatic progression and prolong survival, as well as the factors influencing this treatment decision. We will focus on oral pharmacotherapy with the second-generation androgen receptor inhibitors, apalutamide, enzalutamide, and darolutamide, and the importance of balancing the clinical benefit they offer with potential adverse events and the consequential impact on quality of life, physical capacity, and cognitive function. Results and conclusions While the definition of nmCRPC is well established, the advent of next-generation imaging techniques capable of detecting hitherto undetectable oligometastatic disease in patients with nmCRPC has fostered debate on the criteria that inform the management of these patients. However, despite these developments, published consensus statements have maintained that the absence of metastases on conventional imaging suffices to guide such therapeutic decisions. In addition, the prolonged metastasis-free survival and recently reported positive overall survival outcomes of the three second-generation androgen receptor inhibitors have provided further evidence for the early use of these agents in patients with nmCRPC in order to delay metastases and prolong survival. Here, we discuss the benefit–risk profiles of apalutamide, enzalutamide, and darolutamide based on the data available from their pivotal clinical trials in patients with nmCRPC.

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