A single-arm phase II study of ADT with PD-1 blockade and docetaxel in men with metastatic hormone-sensitive prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS271-TPS271
Author(s):  
Jessica Hawley ◽  
Timothy Geoffrey Bowler ◽  
Xinzheng Victor Guo ◽  
Matthew Dallos ◽  
Emerson A. Lim ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
De Novo ◽  
Phase Ii Study ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Tumor Cell Death ◽  
Serum Samples ◽  
Open Label ◽  
Hormone Sensitive

TPS271 Background: Overall survival of men with de novo metastatic, hormone-sensitive prostate cancer (mHSPC) is improved by treatment intensification with docetaxel and hormone therapy compared to androgen deprivation therapy (ADT) alone. However, castration-resistant prostate cancer (CRPC) invariably develops. Reprogramming the immune system in the mHSPC setting is a novel approach to delay progression to CRPC. In the hormone-sensitive setting, ADT induces a robust and functional immune infiltrate into the tumor microenvironment (TME), with upregulation of immune checkpoint molecules (PD-1 and PD-L1). These effects diminish as castration resistance emerges. Docetaxel causes immunogenic tumor cell death and stimulates antigen presentation. We hypothesize that leveraging the immunogenic effects of ADT with PD-1 blockade and docetaxel will promote antitumor immune killing and improve clinical outcomes. Methods: This is an open-label, single-arm, phase II study of ADT, cemiplimab, and docetaxel in patients with de novo mHSPC (N=20). Subjects will receive continuous ADT, followed by a two-cycle lead-in of cemiplimab prior to the standard six cycles of docetaxel. Cemiplimab will be continued q3weeks for one year or until disease progression or intolerable side effect. The primary endpoint is undetectable PSA at 6 months. Secondary endpoints include time to development of CRPC and radiographic response. Subjects will be monitored for toxicity using a Bayesian adaptive study design with an early stopping rule for toxicity. Correlative studies will determine the effects of ADT and PD-1 blockade on the TME by comparing baseline and on-treatment biopsies using transcriptional data from single-cell RNA-sequencing and standard immunohistochemistry (IHC). Serum samples will also be collected to quantify the effects of therapy on circulating levels of immunosuppressive cytokines. The study is open with 3 patients currently enrolled at the time of submission. Clinical trial information: NCT03951831.

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.

Ketoconazole plus Lenalidomide in patients with Castration-Resistant Prostate Cancer (CRPC): results of an open-label phase II study

2018 ◽  
Vol 36 (6) ◽  
pp. 1085-1092 ◽  
Author(s):  
Pedro C. Barata ◽  
Matthew Cooney ◽  
Prateek Mendiratta ◽  
Allison Tyler ◽  
Robert Dreicer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Castration Resistant ◽  
Open Label Phase

Phase II study of the efficacy of abirateron acetate with dutasteride for castration-resistant prostate cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 112-112
Author(s):  
Hideyasu Matsuyama ◽  
Masaki Shiota ◽  
Kojiro Tashiro ◽  
Hiromi Kanji ◽  
Shizuyo Horiyama ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Combination Therapy ◽  
Phase Ii ◽  
Reductase Inhibitor ◽  
Phase Ii Study ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Secondary Endpoints ◽  
Prospective Phase ◽  
Hormone Sensitive

112 Background: Abiraterone (Abi) has been becoming a pivotal drug not only for metastatic castration resistant prostate cancer (mCRPC), but also for metastatic hormone sensitive prostate cancer (mHSPC). Abi is metabolized to delta-4 Abi (D4A), the strongest antitumor metabolite, by 3βHSD, and D4A is metabolized to 3-keto-5-α Abi, which acts as agonist to AR, by 5 α reductase. Reduction of 3-keto-5-α Abi by 5 α reductase inhibitor may increase the antitumor activity of Abi. Purpose of this study is to evaluate the efficacy and safety of the combination therapy of Abi and dutasteride (Duta), a 5 α reductase inhibitor, for the patients with CRPC. Methods: This is a non-randomized single-arm prospective phase II study. Patients with CRPC without any prior AR-targeting agent or docetaxel were recruited in this study with estimated enrollment of 20. Patients were treated with Abi (1,000 mg daily) and prednisone (5 mg daily) for 4 weeks, followed by the add-on of Duta (0.5 mg daily) for 12weeks. If PSA decline continued, combination treatment was allowed until progression. Abi and its metabolites including D4A and 3-keto-5-α Abi were measured by ESI-TOF-MS at baseline, 4, 6, 8, 12, 16, and 20 weeks, and the sample was collected at 2-4 hours after Abi administration. Primary endpoint was PSA decline >50%, and secondary endpoints were Time-to-treatment failure (TTF), and safety. Results: Totally 17 cases with CRPC (mean age: 78.4, initial PSA:92.6ng/ml, median Gleason score: 9) were recruited, and 14 were eligible for starting the combination therapy. Efficacy could be evaluated in 11 cases except 3 on-protocol treatment. Mean PSA decline of Abi/Duta combination therapy was significantly higher than that of monotherapy (p = 0.0143, 73 vs. 35 %). PSA decline>50% was noted in 36.4% for monotherapy, and 72.7% for combination therapy, respectively. Surprisingly, PSA decline>50% was significantly associated with lower Abi, D4A, and 3-keto 5 α Abi at 2 and 4 weeks after combination. Median TTF and progression (radiographic and/or PSA) was noted in 10.4 months (0.9-32), and 5 (45,4%), respectively with a median follow-up of 13.8 months. Progression was significantly associated with lower D4A, and 3-keto 5 a Abi at 4 and 8 weeks after combination therapy. Concerning safety, Grade 2 vertigo occurred in a case during Abi monotherapy period, while no adverse effect was found in combination therapy. Conclusions: Abi/Duta combination therapy seems to be theoretical to decrease AR-agonistic metabolite (3-keto 5 α Abi), and feasible for patients with first-line treatment of CRPC with lesser toxicity. Clinical trial information: UMIN000027795.

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