A phase II study evaluating the efficacy of enzalutamide and the role of ARv7 in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with visceral disease.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5052-5052
Author(s):  
Pierangela Sepe ◽  
Giuseppe Procopio ◽  
Umberto Basso ◽  
Orazio Caffo ◽  
Vera Cappelletti ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Stable Disease ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Recist 1.1 ◽  
Visceral Metastases ◽  
Visceral Disease ◽  
Hormone Therapies

5052 Background: Enzalutamide is a second-generation androgen receptor inhibitor that showed to prolong survival in different setting of prostate cancer. Visceral metastases, occurring in 10–30% of mCRPC pts, have been associated with poor outcomes. Given the poor prognosis, trial investigating hormone therapies often excluded men with visceral disease, especially in the pre-docetaxel setting. To date, there are no prospective studies designed ad hoc to test hormone therapies in this subgroup of pts. Methods: In this open label phase II multicentre study mCRPC pts with visceral metastases were treated with enzalutamide 160 mg orally once daily as first or second line after docetaxel until progressive disease or unacceptable toxicity. Pts were eligible if they had documented measurable metastatic visceral disease (according to RECIST 1.1 criteria), including lesions in lung or liver or extraregional lymphnodes. Pts must have PSA progression or radiographic progression (according to PCWG2). Primary endpoint was to determine the clinical benefit, as measured by 3-months (mo) disease control rate (DCR) defined as the proportion of pts with best overall response of confirmed complete (CR) or partial responses (PR) or stable disease as per RECIST 1.1 at mo 3. Secondary endpoints were safety, quality of life (assessed by EQ-5D-5L e FACT-P questionnaire), pain assessment (by BPI-SF questionnaire). Exploratory objectives were to assess the association between ARv7 splicing variants (in CTCs samples) and treatment response/resistance. For CTC and ARv7 detection, we used the Adna test Prostate Cancer Panel. Results: From March 2017 through January 2021, 68 pts were enrolled at 6 Italian centres. One pt never started treatment because of withdrawal of consent. Median age was 70 years (IQR 65- 78). All pts presented with visceral disease at baseline: 27, 6, 55 pts presented with lung, liver and lymphnodes lesions, respectively. 26 pts presented with only one metastatic site, 22 pts with two, while the remaining part with multiple sites. 15 pts received a previous treatment with docetaxel in the mCRPC phase. The median follow-up was 10 mo. The median time on treatment was 8 mo. At mo 3, 24 pts presented a stable disease, 1 pt achieved a confirmed CR and 20 pts a PR for a 3 mo-DCR of 67% (45/67). Discontinuations due to adverse-events, disease-related death, or disease progression occurred in 6%, 7%, and 40% of pts, respectively. So far, only 26 patients were evaluated for baseline CTC and ARv7. Interestingly, 75% of patients experiencing a progression at month 3 were classified as ARv7 positive at baseline. Conclusions: The study met its primary endpoint showing enzalutamide is an active treatment option for men with mCRPC and visceral disease in both pre or post-docetaxel setting. CTCs status combined with ARv7 detection could be useful to personalize treatments. Clinical trial information: NCT03103724.

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.

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.

A randomized phase II, open-label study of sipuleucel-T with concurrent or sequential enzalutamide in metastatic castration-resistant prostate cancer (mCRPC).

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. e16071-e16071 ◽  
Author(s):  
David I. Quinn ◽  
Daniel Peter Petrylak ◽  
Christopher Michael Pieczonka ◽  
Andrew Sandler ◽  
Todd DeVries ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Open Label Study ◽  
Label Study ◽  
Castration Resistant ◽  
Randomized Phase Ii

A phase II study of cabozantinib in metastatic castration-resistant prostate cancer (mCRPC) with visceral metastases (VM) with very small nuclear circulating tumor cell (vsnCTC) association studies.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 208-208
Author(s):  
Richard Huynh ◽  
Jie-Fu Chen ◽  
Mourad Tighiouart ◽  
Margarit Sievert ◽  
Amy Oppenheim ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Clinical Benefit ◽  
Kinase Inhibitor ◽  
Association Studies ◽  
Hepatic Metastases ◽  
Predictive Marker ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Visceral Metastases

208 Background: Cabozantinib is a multi-targeted tyrosine kinase inhibitor (TKI) that has recognized clinical activity in mCRPC. While phase 3 studies did not show a significant improvement in overall survival (OS), patients with VM had improved OS compared to those with only osseous metastases in subgroup analysis. Our group has also identified a subgroup of CTCs strongly associated with the presence of VM (Chen, Cancer 2015). We hypothesized that cabozantinib would yield clinical benefit and changes in vsnCTC counts would reflect disease behavior. Methods: This study was designed as an open label study of cabozantinib 60 mg daily, for mCRPC patients with visceral disease. The primary endpoint is clinical benefit rate (radiographic stable disease + partial response (PR) by RECIST 1.1) at 12 weeks (CBR12). Serum PSA concentrations were not used as a primary endpoint. CTCs were enumerated by NanoVelcro CTC Assay and characterized using published methods. Results: Thirteen patients have completed at least 8 weeks of treatment. In this group, 38% had pulmonary metastases; 77% had hepatic metastases; CBR12 was 92% at the time of this report. A quarter of the patients experienced a PR. Mean time to radiographic progression for responders was 38 weeks (19-57). Discordant responses were noted between VM and bone scans. Grade 3 or higher toxicities were compatible with prior studies and observed in 50% of patients. In this advanced mCRPC and relatively heavily pre-treated population, treatment discontinuation due to toxicity was 33%. Eleven of 13 patients were assessable for CTC and imaging. Of the 11 patients, 7 had vsnCTCs detected at baseline. All 7 patients reported subjective improvement that was associated with a decrease in vsnCTCs by 6-8 weeks. In patients who had a PR, no vsnCTCs were detected at 6 weeks while on active treatment. An increase in vsnCTCs was seen prior to visceral progression. Conclusions: Cabozantinib is a TKI with activity in mCRPC with visceral metastases. Toxicity is consistent with previous reports and manageable. The NanoVelcro vsnCTC assay may be a predictive marker of response. Clinical trial information: NCT01834651.

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