1664: Androgen Metabolism Genotypes as Predictors of PSA Progression and First line Hormonal Deprivation Failure

242 Background: In the present guidelines for the management of metastatic castration-resistant prostate cancer (CRPC), it is unclear who benefits from androgen receptor axis-targeted agents (ARATs) or docetaxel as a first-line treatment. Methods: We conducted a single-institutional retrospective study to explore treatment-specific biomarkers for treatment response of metastatic CRPC. A cohort of 211 patients with metastatic CRPC treated with either ARAT (abiraterone acetate or enzalutamide) or docetaxel as a first-line treatment was evaluated. In addition to well-established biomarkers such as hemoglobin, neutrophil-to-lymphocyte ratio, alkaline phosphatase, and lactate dehydrogenase, we also assessed red cell distribution width, platelet count, and mean platelet volume (MPV). Laboratory measures were assessed within 1 month before starting treatment. Prostate-specific antigen progression-free survival (PSA-PFS) and radiographic progression-free survival (RPFS) were evaluated. Multivariable Cox regression models were used to assess the association between biomarkers and the risk of events. We also studied the statistical interaction between biomarkers and clinical outcomes. Results: Of all blood-based biomarkers, multivariable Cox regression models identified pre-treatment MPV (≤9.0 fL) as an independent prognostic factor of both PSA progression (hazard ratio [HR]: 2.62, 95% confidence interval [CI]: 1.25-5.48, P = 0.011) and radiographic progression (HR: 4.46, 95% CI: 1.79-11.1, P = 0.001). In addition, these models showed a lower risk of PSA progression (HR: 0.38, 95% CI: 0.15-0.96, P = 0.041) and radiographic progression (HR: 0.16, 95% CI: 0.05-0.50, P = 0.002) with docetaxel compared with ARAT when pre-treatment MPV was small. Conclusions: The present study identified MPV as a significant treatment-specific prognostic factor of PSA progression and radiographic progression in patients with metastatic CRPC treated with a first-line treatment. Furthermore, our results suggested that small MPV was associated with superior survival benefit on docetaxel over ARAT.

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The effect of AKR1C3 on the switch from prednisone to dexamethasone in metastatic castration-resistant prostate cancer patients receiving abiraterone.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.133 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 133-133

Author(s):

Yuchao Ni ◽

Jinge Zhao ◽

Junru Chen ◽

Guangxi Sun ◽

Sha Zhu ◽

...

Keyword(s):

Prostate Cancer ◽

Progression Free Survival ◽

Castration Resistant Prostate Cancer ◽

First Line ◽

Free Survival ◽

Castration Resistant ◽

Kaplan Meier ◽

Psa Progression ◽

Biochemical Progression ◽

First Line Treatment

133 Background: Abiraterone is the first-line treatment for men with metastatic castration-resistant prostate cancer (mCRPC) and is recommended to be used with prednisone. Previous studies had demonstrated that the switch from prednisone to dexamethasone in some mCRPC patients can reverse abiraterone-resistance. However, it remains uncertain which group of patients will benefit from such switching. AKR1C3 is a critical enzyme contributing to the drug-resistance of abiraterone. Here, we aim to explore the significance of AKR1C3 in predicting the therapeutic efficacy of the corticosteroid switching in mCRPC patients receiving abiraterone. Methods: In total, 43 PCa patients treated with abiraterone after mCRPC between 2016 and 2018 in our institution were included. After biochemical progression in abiraterone plus prednisone, all cases received a corticosteroid switch to abiraterone plus dexamethasone. The expression of AKR1C3 was detected by immunohistochemical staining from re-biopsy (re‐Bx) of primary prostate lesions at the time of mCRPC. Kaplan‐Meier curves were used to analyze the association between AKR1C3 and treatment outcomes. Results: Totally, AKR1C3 was positive in 19 of 43 (44.19%) cases. In the corticosteroid switch treatment, 30% PSA decline was confirmed in 18/43 (41.86%) patients, while the median PSA progression‐free survival (PSA-PFS) and overall survival (OS) was 4.93 Mo and 31.57 Mo, respectively in the whole cohort. AKR1C3 expression was associated with statistically shorter median PSA-PFS (4.50 Mo vs 7.73 Mo; p =0.010) and numerically lower median OS (25.43 Mo vs 39.37 Mo, p =0.274). While the 30% PSA decline rate was numerically comparable between those with and without AKR1C3 expression (31.6% vs 50.0%, p =0.224). Conclusions: This study showed AKR1C3 detection in tissues from prostate re‐Bx at mCRPC was associated with poor PSA-PFS in the corticosteroid switch from abiraterone plus prednisone to abiraterone plus dexamethasone. These results would be helpful in making optimal personalized treatment decisions for patients with mCRPC, facilitating physicians predicting the effectiveness of corticosteroid switch treatment.

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Correlation between time to PSA progression (TTPP), radiographic progression-free survival (rPFS) and overall survival (OS) in first-line abiraterone/enzalutamide (Abi/Enza) and docetaxel (Doc) treated patients in a prospective cohort study.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.267 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 267-267 ◽

Cited By ~ 1

Author(s):

David Lorente ◽

Elena Castro ◽

Rebeca Lozano ◽

Javier Puente ◽

Nuria Romero-Laorden ◽

...

Keyword(s):

Cohort Study ◽

Cox Regression ◽

Predictive Accuracy ◽

Treatment Options ◽

Progression Free Survival ◽

First Line ◽

Free Survival ◽

Observational Cohort ◽

Psa Progression

267 Background: Abiraterone, enzalutamide and docetaxel represent first-line (1L) treatment options in mCRPC. A significant correlation between rPFS and OS has been reported for patients treated with 1L abi and enza in mCRPC. It is however unclear whether TTPP or rPFS present a similar magnitude of correlation with OS in Doc-treated pts. Methods: We evaluated the association of TTPP and rPFS with OS in pts treated with 1L Abi/Enza or Doc in a prospective multicenter observational cohort study. TTPP and rPFS were defined as per PCWG2. Correlation between TTPP and rPFS with OS was evaluated with Spearman rho coefficients (r), and by calculating the concordance index (c-index) in Cox-regression models. Results: 406 out of 419 pts received 1L Abi/Enza or Doc. After a median follow-up of 40 months (m), 253 mCRPC-related deaths were observed, with a median OS of 31.3 m (95% CI: 27.6-35). Median rPFS and TTPP were 10.8 m (95% CI:9.7-11.9) and 7.2 m (95% CI:6.7-7.7), respectively. Significant correlations between rPFS/TTPP and OS were observed in all pts treated at 1L, as well as in Abi/Enza and Doc treated pts (Table). R and c-index were consistently higher in Abi/Enza treated pts than in Doc treated pts, with a higher difference in predictive accuracy of the Cox regression model observed when comparing the association between TTPP and OS (c-index 0.788 in Abi/Enza treated pts vs 0.627 in Doc treated pts). Conclusions: Differences in r and c-index were observed when evaluating the association between TTPP/rPFS and OS in Abi/Enza and Doc treated pts, suggesting rPFS and TTPP may better predict OS in Abi/Enza than in Doc-treated pts. Indirect comparisons of TTPP in Abi/Enza vs Doc pts may therefore not reflect their true impact on OS. Further insight on the exact significance of TTPP is needed. Clinical trial information: NCT03075735. [Table: see text]

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440: Clinical Course and Response to First-Line Androgen Deprivation Therapy in Patients with PSA-Progression After Radical Prostatectomy

The Journal of Urology ◽

10.1016/s0022-5347(18)37702-4 ◽

2004 ◽

Vol 171 (4S) ◽

pp. 116-116 ◽

Cited By ~ 1

Author(s):

Fernando J. Bianco ◽

Zohar A. Dotan ◽

Michael W. Kattan ◽

Paul A. Fearn ◽

James A. Eastham ◽

...

Keyword(s):

Radical Prostatectomy ◽

Androgen Deprivation Therapy ◽

Clinical Course ◽

Androgen Deprivation ◽

First Line ◽

Psa Progression

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WNT activating pathway mutations confer resistance to first-line antiandrogen therapy in castration-resistant prostate cancer (CRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.5068 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 5068-5068

Author(s):

Pedro Isaacsson Velho ◽

Nooshin Mirkheshti ◽

Fahad Qazi ◽

Farah Shaukat ◽

Wei Fu ◽

...

Keyword(s):

Wnt Signaling ◽

Clinical Outcomes ◽

Wnt Pathway ◽

Cox Regression ◽

Wnt Signaling Pathway ◽

Johns Hopkins Hospital ◽

Castration Resistant Prostate Cancer ◽

First Line ◽

Psa Progression ◽

Antiandrogen Therapy

5068 Background: Wnt signaling is a cellular pathway responsible for embryogenesis and neoplasm. When activated, in about 10-20% of mCRPC, the WNT signaling pathway may cause androgen-independent growth and consequently antiandrogen resistance. To further characterize the clinical features and biology of this subtype of mCRPC, we studied mutations in genes of this pathway, including APC, CTNNB1, RNF43, ZNRF3 and RSPO2, in patients who received treatment at Johns Hopkins Hospital (JHH). Methods: Patients with CRPC who received first-line antiandrogen (abiraterone or enzalutamide) therapy for CRPC at JHH were retrospectively studied. Pathological staging, extension of primary disease, tumor somatic genomic data by Next Generation Sequencing (NGS) were correlated with clinical outcomes such as time to PSA progression, PSA response and overall survival (OS). Cox regression was used to test associations between variables and clinical outcomes and Kaplan-Meier method was used for time-to-event data. Results: Of 137 pts who received first-line antiandrogen therapy for CRPC, 10.9% (15 pts) had NGS with at least one activating WNT pathway alteration, including mutations in APC (6 pts), CTNNB1 (8 pts) and RNF43 (3 pts). Patients with WNT mutations had fewer T3/T4 tumors (30.8% vs. 51.4%, p = 0.24), but were balanced in other aspects. The median time to PSA progression in WNT activated patients was 6.5 months vs. 9.6 months in WNT negative patients (HR 2.3, 95% CI 1.3 - 4.1, p = 0.003). The presence of WNT mutations (HR 2.3, 95% CI 1.2 - 4.3, p = 0.007) and previous chemotherapy (HR 1.8, 95% CI 1.2 – 2.7, p = 0.003) were independently associated with shorter time to PSA progression. PSA50 response was numerically worse in WNT activated patients (53% vs 75%, p = 0.12). The OS in patients with WNT mutations was 23.6 months vs 27.7 months in patients without WNT mutations (HR 2.2, 95% CI 1.1 - 4.5, p = 0.01). Conclusions: Patients with WNT pathway mutations may have worse outcomes to first-line abi/enza compared to patients without these aberrations. Time to PSA progression and OS were inferior in WNT activated population. Our data reinforce the necessity to develop effective WNT pathway inhibitors to test in clinical trials for WNT activated patients.

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Association of body composition with survival and efficacy of first-line treatment in patients with castration-resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.115 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 115-115

Author(s):

Jae Young Joung ◽

Sahyun Pak

Keyword(s):

Skeletal Muscle ◽

Skeletal Muscle Mass ◽

Progression Free Survival ◽

Castration Resistant Prostate Cancer ◽

First Line ◽

Free Survival ◽

Castration Resistant ◽

Psa Progression ◽

First Line Treatment ◽

Radiologic Progression

115 Background: We aimed to investigate the association of body composition with survival and efficacy of first-line treatments in patients with castration-resistant prostate cancer (CRPC). Methods: Records of CRPC patients who were treated with first-line docetaxel or androgen receptor signaling inhibitors (ARSi) between 2005 and 2018 were reviewed. Skeletal muscle index (SMI), visceral fat index, and subcutaneous fat index were evaluated using pretreatment computed tomography images. Results: Of the 230 eligible patients, 144 patients received docetaxel and 86 received ARSi as the first-line treatment for CRPC. SMIhi (based on median value) group had higher prostate-specific antigen (PSA) progression-free survival (median 13.5 vs. 8.3 months, p=0.030), radiologic progression-free survival (14.9 vs. 9.1 months; p<0.001), and overall survival (24.1 vs. 16.9 months, p=0.015) compared than SMIlo group. In multivariable analysis, SMI was independently associated with risk of PSA progression (HR=0.68; 95% CI, 0.50-0.93; p=0.017), radiologic progression (HR=0.54; 95% CI, 0.39-0.75; p=0.001), and overall survival (HR=0.72; 95% CI, 0.52-0.98; p=0.037), regardless of BMI. In docetaxel-treated patients, PSA progression-free survival (13.5 vs. 5.9 months, p=0.016) and radiologic progression-free survival (14.6 vs. 6.7 months, p<0.001) were higher in SMIhi than SMIlo group. However, PSA progression-free survival and radiologic progression-free survival were similar between two groups in ARSi-treated patients. Based on treatment-specific hazards of radiologic progression, patients with SMIlo are more likely to benefit from ARSi compared than docetaxel. Conclusions: High skeletal muscle mass may be associated with reduced risks of disease progression and mortality in patients with CRPC. However, the significance of these relationships is limited in patients treated with docetaxel. These results suggest that skeletal muscle mass may be helpful in treatment selection and predicting treatment response in CRPC. Further prospective studies are warranted.

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A Multicentric, Retrospective Efficacy and Safety Study of Nanosomal Docetaxel Lipid Suspension in Metastatic Castration-Resistant Prostate Cancer

Prostate Cancer ◽

10.1155/2020/4242989 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7

Author(s):

Aseem Samar ◽

Srikant Tiwari ◽

Sundaram Subramanian ◽

Nisarg Joshi ◽

Jaykumar Sejpal ◽

...

Keyword(s):

Prostate Cancer ◽

Specific Antigen ◽

Efficacy And Safety ◽

Castration Resistant Prostate Cancer ◽

First Line ◽

Castration Resistant ◽

Psa Response ◽

Psa Progression ◽

Weekly Group

Purpose. To evaluate the efficacy and safety of nanosomal docetaxel lipid suspension (NDLS, DoceAqualip) in patients with metastatic castration-resistant prostate cancer (mCRPC). Materials and Methods. In this multicenter, retrospective study, we analyzed the medical charts of mCRPC patients, who were treated with NDLS administered as 2-weekly (50 mg/m2) or 3-weekly regimens (75 mg/m2). The study endpoints were prostate-specific antigen (PSA) response (>50% PSA decline from baseline), PSA progression (PSA increase from baseline beyond 12 weeks: ≥25% and ≥2 ng/mL), median PSA decline, and time-to-treatment failure (TTF). Overall survival (OS) and safety were also evaluated. Results. Data of 24 patients with mCRPC were analyzed in this study. NDLS was administered as a 2-weekly regimen in 37.5% (9/24; all first-line) patients and as a 3-weekly regimen in 62.5% patients (15/24; first-line: 20% (3/15), second-line: 80% (12/15)). Overall, PSA response was reported in 66.7% (16/24) patients. The PSA response was 77.8% (7/9 patients) in the 2-weekly group and 60% (9/15 patients) in the 3-weekly group. The median decline in PSA was 96.31% in the 2-weekly group and 83.29% in the 3-weekly group; the median TTF was 6.7 and 6.5 months in the 2 weekly group and 3-weekly group, respectively. The median OS was 14.6 months (follow-up: 5.5–25.8 months) in the 2-weekly group whereas it was not reached in the 3-weekly group (follow-up: 7.9–15.6 months). The most common hematological AEs were anemia, lymphopenia, thrombocytopenia, and neutropenia whereas nausea, weakness, constipation, vomiting, and diarrhea were the most common (≥10%) nonhematological AEs. Overall, NDLS treatment was well tolerated without any new safety concerns. Conclusions. Nanosomal docetaxel lipid suspension (2-weekly or 3-weekly) was effective and well tolerated in patients with metastatic castration-resistant prostate cancer.

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The prognostic role of IDC-P in mCRPC and its predictive value in those treated with docetaxel or abiraterone as first-line therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.e603 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. e603-e603

Author(s):

Jinge Zhao ◽

Hao Zeng ◽

Pengfei Shen ◽

Guangxi Sun ◽

Jiandong Liu ◽

...

Keyword(s):

Clinical Outcomes ◽

Large Scale ◽

Cox Regression ◽

Treated Group ◽

Rank Test ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Psa Response ◽

Psa Progression

e603 Background: Intraductal carcinoma of prostate (IDC-P) is recognized as a newly pathological entity in 2016. Its role in metastatic castration-resistant prostate cancer (mCRPC) remains unknown. The aim of this study is to explore the association of IDC-P with clinical outcomes and to further identify its potential predictive role in making first-line treatment decision for mCRPC patients. Methods: We retrospectively analyzed data of 131 men with mCRPC. IDC-P was diagnosed by re-biopsy at the time of mCRPC. After mCRPC, 45 and 41 patients received abiraterone (Abi) or docetaxel (Doc) as first-line therapy, respectively. PSA response, PSA progression-free survival (PSA-PFS) and overall survival (OS) from mCRPC to death were analyzed. Kaplan-Meier curves, log-rank test, Cox regression models and Harrell’s C-index were conducted to analyze disease progression, treatment efficacy and outcomes. Results: The incidence of IDC-P in mCRPC reached to 47.3%. IDC-P was not only related to rapid PSA progression, but also associated with 20-month decrease of OS. Among IDC-P(-) patients, PSA response, PSA-PFS and OS were comparable in Abi-treated and Doc-treated groups. In contrast, among IDC-P(+) patients, PSA response rate is higher in Abi-treated vs. Doc-treated group (52.4% vs. 21.7%; p = 0.035), also, PSA-PFS and OS were much longer in Abi-treated group (PSA-PFS:13.5 vs.6.0 months, p = 0.012; OS:23.6 vs.14.7 months, p = 0.128). Cox regression indicated that, for IDC-P(+) patients, Abi was associated with prolonged time of PSA-PFS (HR = 0.33, 95%CI: 0.14-0.79, p = 0.013), and could significantly increase the predictive accuracy of standard model, with an obvious increase of the C-index from 0.719 to 0.778 (p = 0.009). Conclusions: The presence of IDC-P in mCRPC from re-biopsy was not only an independent prognosticator for clinical outcomes, but also strongly associated with poor response to Doc-based chemotherapy. We also found that IDC-P status could be considered as a novel predictive marker in helping physicians precluding Doc as first-line therapy in IDC-P(+) patients. Also, these findings require large-scale prospective validation.

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Enzalutamide plus androgen deprivation therapy (ADT) versus flutamide plus ADT in men with castration-resistant prostate cancer (CRPC): AFTERCAB.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.81 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 81-81

Author(s):

Hiroji Uemura ◽

Kazuki Kobayashi ◽

Akira Yokomizo ◽

Shiro Hinotsu ◽

Shigeo Horie ◽

...

Keyword(s):

Group Performance ◽

Eastern Cooperative Oncology Group ◽

Specific Antigen ◽

Disease Stage ◽

Second Line ◽

First Line ◽

Second Line Therapy ◽

First Line Therapy ◽

Line Therapy ◽

Psa Progression

81 Background: Enzalutamide has been approved for the treatment of CRPC in Japan since 2014. This study compared the efficacy and safety of enzalutamide + ADT and flutamide + ADT in the treatment of men with CRPC who progressed despite combined androgen blockade with bicalutamide + ADT. The sequential order of treatment was also investigated. Methods: The open-label, Phase 4 AFTERCAB study (NCT02918968) was conducted from November 2016–March 2020 in Japanese men aged ≥20 years with asymptomatic or mildly symptomatic CRPC (metastatic or nonmetastatic) and an Eastern Cooperative Oncology Group performance status of 0 or 1 who progressed despite bicalutamide + ADT. Patients were initially randomized to enzalutamide (160 mg/day) + ADT (enzalutamide first) or flutamide (375 mg/day [125 mg 3 × daily]) + ADT (flutamide first) as first-line therapy. Following prostate-specific antigen (PSA) progression, other disease progression, or discontinuation of first-line therapy due to an adverse event (AE), patients switched to the other treatment as second-line therapy. The primary endpoint was time to PSA progression with first-line therapy (TTPP1). Secondary endpoints included TTPP2 (TTPP1 + time to PSA progression with second-line therapy). AEs were monitored to assess safety. Results: 206 men were randomized, stratified by study site and disease stage. Baseline demographics and disease characteristics were similar between treatment arms. Median treatment exposure was 14.3 months (range 0.8–35.9) with enzalutamide first and 5.6 months (range 0.3–37.7) with flutamide first. 133 patients transitioned to second-line therapy (n=48 for enzalutamide first and n=85 for flutamide first). TTPP1 was significantly improved with enzalutamide first versus flutamide first; numerically longer TTPP2 was observed with enzalutamide first versus flutamide first (Table). With first-line therapy, 92.2% (n=94) of patients reported treatment-emergent AEs (TEAEs) and 28.4% (n=29) reported serious TEAEs for enzalutamide first. Corresponding numbers for flutamide first were 76.0% (n=79) for TEAEs and 14.4% (n=15) for serious TEAEs. Conclusions: Treatment with enzalutamide + ADT provided a significant improvement in time to PSA progression versus flutamide + ADT as first-line therapy. Both treatments were generally well tolerated, with AEs consistent with the known safety profiles. Clinical trial information: NCT02918968. [Table: see text]

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