Outcomes in men with metastatic castrate-resistant prostate cancer treated with early platinum-based chemotherapy following an unsatisfactory response to androgen receptor (AR) inhibition as part of the phase II dynamic allocation modular sequential (DynAMo) trial.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 83-83
Author(s):  
Paul Vincent Viscuse ◽  
Miao Zhang ◽  
Jingjing Liu ◽  
Rebecca Tidwell ◽  
Sumit Kumar Subudhi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Phase Ii ◽  
Molecular Data ◽  
Abiraterone Acetate ◽  
Rapid Progression ◽  
Castration Resistant Prostate Cancer ◽  
Dynamic Allocation ◽  
Durable Response ◽  
Platinum Based Chemotherapy

83 Background: Most prostate cancers are driven by the androgen receptor (AR) and have significant responses to AR inhibition. However, approximately 20-30% respond poorly to AR signaling inhibitors and have an atypical and virulent clinical course. Previous studies have shown that early declines in PSA and CTC on treatment are linked with “AR-responsiveness” in metastatic castration resistant prostate cancer (mCRPC). Few non-androgen directed therapies are approved for AR-unresponsive patients though combination cabazitaxel and carboplatin showed efficacy in this patient population in a phase I/II trial (Corn et al. Lancet Oncol, 2019). We hypothesized that early addition of chemotherapy in AR-unresponsive patients would improve outcomes. Methods: In a modular phase II trial (NCT02703623), men with mCRPC treated with abiraterone acetate plus prednisone and apalutamide were classified at week 8 as having a ‘satisfactory’ decline in PSA (≥ 50% from baseline) and CTC (≤5/7.5mL) or ‘unsatisfactory’. Patients with ‘unsatisfactory’ declines had carboplatin and cabazitaxel added to the AR inhibitors. Primary objectives included the estimation of the overall survival (OS) of patients in this cohort. Results: 198 men were registered. 59 (31.5%) of 187 evaluable had ‘unsatisfactory’ marker declines. Patients were primarily white/non-Hispanic men (81%) over the age of 60 (78%) with ECOG score of 0 (75%). Median baseline PSA and CTC were 11.3 ng/mL and 9.0 cells/mL respectively. Median follow-up was 31.7 months with median OS 19.2 months (95% CI 14.8-27.8). Median TTF was 9.0 months (6.9-11.0). Related adverse events included decreased WBC (39%; 15% G3+), anemia (56%; 7% G3+), and lymphopenia (59%; 8% G3+). There was one grade 5 sepsis of unknown attribution. Conclusions: Although early platinum-based chemotherapy offers a durable response in a subset of AR unresponsive patients, there were patients that continued to have rapid progression. We will present additional clinical and molecular data (IHC, RNA-seq, WES) in an attempt to further differentiate AR responders from AR non-responders. Clinical trial information: NCT02703623.

scholarly journals Morphologic, Molecular and Clinical Features of Aggressive Variant Prostate Cancer

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1073 ◽  
Author(s):  
Rodolfo Montironi ◽  
Alessia Cimadamore ◽  
Antonio Lopez-Beltran ◽  
Marina Scarpelli ◽  
Gaetano Aurilio ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Large Cell Carcinoma ◽  
Large Cell ◽  
Final Diagnosis ◽  
Undifferentiated Carcinoma ◽  
Castration Resistant Prostate Cancer ◽  
Platinum Based Chemotherapy ◽  
Intermediate Part ◽  
Aggressive Variant

The term aggressive variant prostate cancer (AVPCa) refers to androgen receptor (AR)-independent anaplastic forms of prostate cancer (PCa), clinically characterized by a rapidly progressive disease course. This involves hormone refractoriness and metastasis in visceral sites. Morphologically, AVPCa is made up of solid sheets of cells devoid of pleomorphism, with round and enlarged nuclei with prominent nucleoli and slightly basophilic cytoplasm. The cells do not show the typical architectural features of prostatic adenocarcinoma and mimic the undifferentiated carcinoma of other organs and locations. The final diagnosis is based on the immunohistochemical expression of markers usually seen in the prostate, such as prostate-specific membrane antigen (PSMA). A subset of AVPCa can also express neuroendocrine (NE) markers such as chromogranin A, synaptophysin and CD56. This letter subset represents an intermediate part of the spectrum of NE tumors which ranges from small cell to large cell carcinoma. All such tumors can develop following potent androgen receptor pathway inhibition. This means that castration-resistant prostate cancer (CRPCa) transdifferentiates and becomes a treatment-related NE PCa in a clonally divergent manner. The tumors that do not show NE differentiation might harbor somatic and/or germline alterations in the DNA repair pathway. The identification of these subtypes has direct clinical relevance with regard to the potential benefit of platinum-based chemotherapy, poly (ADP-ribose) polymerase inhibitors and likely further therapies.

Androgen Receptor Rediscovered: The New Biology and Targeting the Androgen Receptor Therapeutically

2011 ◽  
Vol 29 (27) ◽  
pp. 3651-3658 ◽  
Author(s):  
Charles J. Ryan ◽  
Donald J. Tindall
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Clinical Success ◽  
Abiraterone Acetate ◽  
Clinical Findings ◽  
Phase Iii ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Synthesis ◽  
Castration Resistant

Discoveries over the past decade suggest that castration-resistant prostate cancer (CRPC) is sensitive, but not resistant to, further manipulation of the androgen–androgen receptor (AR) axis. Several new therapies that target this axis have demonstrated clinical activity. In this article, preclinical and clinical findings occurring in the field of AR-targeted therapies are reviewed. Reviews of scientific and clinical development are divided into those occurring prereceptor (androgen production and conversion) and at the level of the receptor (AR aberrations and therapies targeting AR directly). Intracrine androgen production and AR amplification, among others, are among the principal aberrancies driving CRPC growth. Phase III data with abiraterone acetate and phase II data with MDV-3100, along with other similar therapies, confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease. Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way. The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling, even in the castrate state.

Spironolactone: A selective androgen receptor modulator in castration-resistant prostate cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 212-212 ◽  
Author(s):  
Philippe Barthelemy ◽  
Eva Erdmann ◽  
Brigitte Duclos ◽  
Jean Pierre Bergerat ◽  
Jean-Emmanuel Kurtz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Abiraterone Acetate ◽  
Functional Assay ◽  
Castration Resistant Prostate Cancer ◽  
Lncap Cells ◽  
Selective Androgen Receptor Modulator ◽  
Receptor Modulator ◽  
Castration Resistant ◽  
High Concentrations

212 Background: Spironolactone is an effective drug to treat arterial hypertension as well as fluid retention and hypokalemia. Recently, some data suggested that spironolactone might induce progression in castration-resistant prostate cancer (CRPC) patients treated by abiraterone acetate, a recently approved selective CYP17 inhibitor. Nevertheless, no biological data are available to explain these clinical observations. The purpose of this study was to identify the potential underlying molecular mechanism. Methods: Effect of spironolactone with or without Abiraterone acetate (AA) on androgen receptor (AR) was assessed on LNCaP cells in this study. We performed a yeast-based functional assay with different levels of spironolactone with and without AA. The nuclear localization and activation of androgen receptor (AR) were detected by immunofluorescence and luciferase assays. Results: Results from the yeast-based functional assay show that the wild type androgen receptor is activated by high concentrations of spironolactone in an androgen-depleted environment. Moreover, spironolactone-induced AR transcriptional activity is downregulated by different AR antagonists as well as high concentrations of AA. These results suggest that spironolactone is possibly a potential AR modulator. Luciferase reporter assays showed that AR transcriptional activity in LNCaP cells was upregulated by spironolactone as well. Finally, AR immunoreactivity was almost nuclear in spironolactone-exposed cells. Taken together, these results suggest that spironolactone is a selective androgen receptor modulator. Conclusions: Spironolactone is a selective androgen receptor modulator and should be used with caution in routine practice in patient with metastatic prostate cancer treated by hormonotherapy especially AA.

Enzalutamide monotherapy: Phase II study results in patients with hormone-naive prostate cancer.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 18-18 ◽  
Author(s):  
Bertrand Tombal ◽  
Michael Borre ◽  
Per Rathenborg ◽  
Patrick Werbrouck ◽  
Axel Heidenreich ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Phase Ii ◽  
Nuclear Translocation ◽  
Phase Ii Study ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Hot Flush ◽  
Study Results ◽  
Psa Response

18 Background: Enzalutamide (ENZA) is an oral androgen receptor inhibitor that has been approved in the US and shown to increase overall survival by 4.8 months over a placebo (HR, 0.63) in patients with metastatic castration resistant prostate cancer (CRPC) previously treated with docetaxel (Scher et al, N Engl J Med 2012;367:1187). Compared with bicalutamide in nonclinical studies, enzalutamide had higher androgen receptor–binding affinity, prevented nuclear translocation, showed no DNA binding, and induced apoptosis (Tran et al, Science 2009;324:787). In contrast to previous phase II and III studies that exclusively enrolled patients with CRPC receiving androgen deprivation therapy (ie, testosterone (T) levels ≤50 ng/dL), this phase II study assessed the efficacy and safety of ENZA monotherapy in patients who had never received hormone therapy; presenting with non-castrate T levels (≥230 ng/dL). Methods: This was a 25-wk, open-label, single-arm study of patients with hormone-naïve, histologically confirmed prostate cancer (all stages) requiring hormonal treatment, an ECOG PS score of 0, and a life expectancy >1 y. All patients received ENZA 160 mg/d without concomitment castration. Primary endpoint was PSA response (>80% decrease at wk 25). Secondary endpoints included changes in endocrine levels and safety/tolerability. Results: Among 67 men enrolled, the median (range) age was 73 (48, 86) y; 39% had metastases; 36% and 24% had undergone prostatectomy or radiotherapy before study entry. The PSA response rate (>80% PSA decline at wk 25) was 93%, with a median (range) decrease of −99% (−100, −57) at wk 25. Serum T and estrogen levels increased by a median (range) of 113% (−32, 300) and 58% (−49, 321) at wk 25, respectively, compared with baseline. 82% of men reported drug-related AEs (mostly Grade 1 or 2). Most frequent treatment-emergent AEs included gynaecomastia (36%), fatigue (34%), and hot flush (18%). 7% of men experienced SAEs; none were drug-related. Conclusions: ENZA monotherapy (160 mg) was associated with significant PSA response in nearly all men with hormone-naïve prostate cancer. Endocrine level changes and most common AEs (gynecomastica, fatigue and hot flush) were consistent with potent AR inhibition. Clinical trial information: NCT01302041.

A phase II open-label trial of GTx-758 in men with castration-resistant prostate cancer: Final analysis of the primary endpoint.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 185-185
Author(s):  
Evan Y. Yu ◽  
Michael L. Hancock ◽  
Tamas Babicz ◽  
Ronald F. Tutrone ◽  
Christopher Ng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Androgen Receptor ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Castration Resistant ◽  
Open Label Trial ◽  
Lhrh Therapy

185 Background: Recently approved agents that target the androgen receptor pathway emphasize the importance of the persistent activity of the androgen receptor pathway in castration-resistant prostate cancer (CRPC). This raises the possibility that agents with distinct mechanisms of action may add value. GTx-758 is a selective ERα agonist that can increase SHBG and therefore reduce biologically active testosterone (T) levels. Reported here are the results, including the final primary endpoint analysis, from the 250 mg daily GTx-758 cohort of a phase II clinical trial in men on LHRH agonists that developed CRPC. Methods: This phase II open label trial (G200712, NCT01615120) treated men with high risk nmCRPC or mCRPC with T levels < 50 ng/dL who continued to receive their current form of ADT along with either 125 mg or 250 mg of GTx-758 daily, for at least 90 days. The primary endpoint was the proportion of men with a PSA decline ≥ 50% by day 90, while secondary endpoints included serum total and free T, sex hormone binding globulin (SHBG), bone turnover markers and hot flashes. Results: The 250 mg cohort (n = 39) has completed the time period for assessment of the primary endpoint. Ten of the 39 (26%) subjects exhibited a ≥ 50% decrease in PSA by Day 90, with 11/39 (28%) by Day 120, while 18/39 (46%) had PSA declines of ≥ 30%. Median SHBG levels increased 301% of baseline, confirming the principal mechanism of drug action. While on study, median free T decreases of 44% were observed across all subjects and 20/26 (77%) of the subjects with baseline serum free T levels > 0.7 pg/ml fell below this level. Therefore, 250 mg GTx-758 decreased free testosterone levels in an additive fashion to their existing LHRH therapy. The bone turnover biomarker, C-telopeptide, decreased in 79% of the subjects. 250 mg of GTx-758 has been generally well tolerated with two reported possibly drug related SAEs (VTE and MI). Conclusions: In this phase II trial, 250 mg daily GTx-758 has activity, likely mediated by lowering free T levels in patients with CRPC on LHRH therapy, and may provide amelioration of estrogen deficiency side effects associated with ADT. Clinical trial information: NCT01615120.

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