Enzalutamide treatment in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy and abiraterone acetate

Thomsen, Frederik Birkebæk; Røder, Martin Andreas; Rathenborg, Per; Brasso, Klaus; Borre, Michael; Iversen, Peter

doi:10.3109/21681805.2013.860189

Cited by 58 publications

(47 citation statements)

References 12 publications

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“…Expression of AR splice variants in CTCs was also recently associated with primary resistance to abiraterone or enzalutamide (27) although AR amplification was not evaluated in this study, which may be significant since fulllength AR is typically coexpressed with AR-V7 (28) and may be required for tumor growth mediated by AR splice variants (29). Nevertheless, it is likely that divergent aberrations of the AR underpin cross-resistance between different novel agents targeting the androgen-AR axis (30)(31)(32)(33)(34)(35)(36)(37), as exemplified by our observation that AR exon 8 mutations were mutually exclusive with AR copy number gain in 73% of cases. With this in mind, real-time serial analysis of circulating biomarkers, including cfDNA, could aid optimal therapy sequencing for individual patients.…”

Section: Discussionmentioning

confidence: 89%

Androgen Receptor Gene Aberrations in Circulating Cell-Free DNA: Biomarkers of Therapeutic Resistance in Castration-Resistant Prostate Cancer

Azad

Volik²,

Wyatt³

et al. 2015

Clinical Cancer Research

431

384

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Purpose: Although novel agents targeting the androgen–androgen receptor (AR) axis have altered the treatment paradigm of metastatic castration-resistant prostate cancer (mCRPC), development of therapeutic resistance is inevitable. In this study, we examined whether AR gene aberrations detectable in circulating cell-free DNA (cfDNA) are associated with resistance to abiraterone acetate and enzalutamide in mCRPC patients. Experimental Design: Plasma was collected from 62 mCRPC patients ceasing abiraterone acetate (n = 29), enzalutamide (n = 19), or other agents (n = 14) due to disease progression. DNA was extracted and subjected to array comparative genomic hybridization (aCGH) for chromosome copy number analysis, and Roche 454 targeted next-generation sequencing of exon 8 in the AR. Results: On aCGH, AR amplification was significantly more common in patients progressing on enzalutamide than on abiraterone or other agents (53% vs. 17% vs. 21%, P = 0.02, χ2). Missense AR exon 8 mutations were detected in 11 of 62 patients (18%), including the first reported case of an F876L mutation in an enzalutamide-resistant patient and H874Y and T877A mutations in 7 abiraterone-resistant patients. In patients switched onto enzalutamide after cfDNA collection (n = 39), an AR gene aberration (copy number increase and/or an exon 8 mutation) in pretreatment cfDNA was associated with adverse outcomes, including lower rates of PSA decline ≥ 30% (P = 0.013, χ2) and shorter time to radiographic/clinical progression (P = 0.010, Cox proportional hazards regression). Conclusions: AR gene aberrations in cfDNA are associated with resistance to enzalutamide and abiraterone in mCRPC. Our data illustrate that genomic analysis of cfDNA is a minimally invasive method for interrogating mechanisms of therapeutic resistance in mCRPC. Clin Cancer Res; 21(10); 2315–24. ©2015 AACR.

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Section: Discussionmentioning

confidence: 89%

Androgen Receptor Gene Aberrations in Circulating Cell-Free DNA: Biomarkers of Therapeutic Resistance in Castration-Resistant Prostate Cancer

Azad

Volik²,

Wyatt³

et al. 2015

Clinical Cancer Research

431

384

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“…[31][32][33][34][35][36][37][38] Data seem to show a blunted effect of each after the use of the other, suggesting cross-resistance. It remains unclear which patients benefit from one agent as the first agent compared with the other.…”

Section: Sequential Therapy Using Asismentioning

confidence: 99%

Current treatment strategies for advanced prostate cancer

et al. 2017

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During the past decade, treatment strategies for patients with advanced prostate cancer involving stage IV (T4N0M0, N1M0 or M1) hormone-sensitive prostate cancer and recurrent prostate cancer after treatment with curative intent, as well as castration-resistant prostate cancer, have extensively evolved with the introduction and approval of several new agents including sipuleucel-T, radium-223, abiraterone, enzalutamide and cabazitaxel, all of which have shown significant improvement on overall survival. The appropriate use of these agents and the proper sequencing of these agents are still not optimized. The results of several recently reported randomized controlled trials and retrospective studies could assist in developing a treatment strategy for advanced prostate cancer. In addition, prospective studies and molecular characterization of tumors to address these issues are ongoing.

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“…For treatment sequences involving enzalutamide or abiraterone as a second-line agent following the opposite agent, several other studies have reported that 17-28% of patients achieved a PSA response. [26][27][28][29][30][31][32][33][34] A report from Schnadig et al showed that more patients reached a third-line treatment if they received docetaxel followed immediately by cabazitaxel, compared to docetaxel followed by abiraterone. 35 This retrospective analysis in 667 post-docetaxel mCRPC patients showed that 31% of patients who received cabazitaxel second-line received abiraterone in third-line, compared to only 12% of patients who received cabazitaxel third-line if they received abiraterone second-line.…”

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confidence: 99%

Efficacy, quality of life, and safety of cabazitaxel in Canadian metastatic castration-resistant prostate cancer patients treated or not with prior abiraterone

Saad¹,

Winquist²,

Hubay³

et al. 2016

CUAJ

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Introduction: In the TROPIC study, cabazitaxel improved overall survival in abiraterone-naïve metastatic castration-resistant prostate cancer (mCRPC) patients post-docetaxel. To evaluate cabazitaxel in routine clinical practice, an international, single-arm trial was conducted. Efficacy, safety, and quality of life (QoL) data were collected from Canadian patients enrolled. Overall survival and progression-free survival were not collected as part of this study. Importantly, prior abiraterone use was obtained and its impact on clinical parameters was examined. Methods: Sixty-one patients from nine Canadian centres were enrolled, with prior abiraterone use known for 60 patients. Prostatespecific antigen (PSA) response rate, safety, and impact on QoL life were analyzed as a function of prior abiraterone use. Results: Overall, 92% of patients were ECOG 0/1, 88% had bone metastases, and 25% visceral metastases. Patients treated without prior abiraterone (NoPriorAbi) (n=35, 58%) and with prior abiraterone (PriorAbi) (n=25, 42%) had similar baseline characteristics, except for age and prior cumulative docetaxel dose. Median number of cabazitaxel cycles received was similar between groups (NoPriorAbi=6, PriorAbi=7), as was PSA response rate (NoPriorAbi=36.4%, PriorAbi=45.0%, p=0.54). Almost one-third (31%) of patients received prophylactic granulocyte colony-stimulating factors. Most frequent Grade 3/4 toxicities were neutropenia (14.8%); anemia, febrile neutropenia, fatigue (each at 9.8%); and diarrhea (8.2%). No treatment-related adverse event leading to death was observed. QoL and pain were improved with no difference seen between groups. Treatment discontinuation was mainly due to disease progression (45.9%) and adverse events (32.8%). Conclusions:In routine clinical practice, cabazitaxel's risk-benefit ratio in mCRPC patients previously treated with docetaxel seems to be maintained independent of prior abiraterone use.

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Enzalutamide treatment in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy and abiraterone acetate

Abstract: Previous abiraterone therapy is associated with a less marked fall in PSA following enzalutamide therapy in post-chemotherapy mCRPC patients compared with reported results in randomized trials. Larger prospective studies of sequencing are warranted.

Cited by 58 publications

References 12 publications

Androgen Receptor Gene Aberrations in Circulating Cell-Free DNA: Biomarkers of Therapeutic Resistance in Castration-Resistant Prostate Cancer

Androgen Receptor Gene Aberrations in Circulating Cell-Free DNA: Biomarkers of Therapeutic Resistance in Castration-Resistant Prostate Cancer

Current treatment strategies for advanced prostate cancer

Efficacy, quality of life, and safety of cabazitaxel in Canadian metastatic castration-resistant prostate cancer patients treated or not with prior abiraterone

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