Predicting response to platinum chemotherapy in metastatic castration-resistant prostate cancer (mCRPC) using a genomic signature for “BRCAness”: A phase II clinical trial of satraplatin in men with mCRPC who have progressed on docetaxel.

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.

Download Full-text

Phase II Trial of Carboplatin, Everolimus, and Prednisone in Metastatic Castration-resistant Prostate Cancer Pretreated With Docetaxel Chemotherapy: A Prostate Cancer Clinical Trial Consortium Study

Urology ◽

10.1016/j.urology.2015.08.008 ◽

2015 ◽

Vol 86 (6) ◽

pp. 1206-1211 ◽

Cited By ~ 23

Author(s):

Ulka Vaishampayan ◽

Daniel Shevrin ◽

Mark Stein ◽

Lance Heilbrun ◽

Susan Land ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trial ◽

Phase Ii ◽

Phase Ii Trial ◽

Cancer Clinical Trial ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Docetaxel Chemotherapy

Download Full-text

An open-label phase II clinical trial of the RXR agonist IRX4204 in taxane-resistant, castration-resistant metastatic prostate cancer (CRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.15_suppl.5073 ◽

2014 ◽

Vol 32 (15_suppl) ◽

pp. 5073-5073 ◽

Cited By ~ 1

Author(s):

Fairooz F. Kabbinavar ◽

Nazy Zomorodian ◽

Matthew Rettig ◽

Faraz Khan ◽

Daniel Reif Greenwald ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trial ◽

Phase Ii ◽

Metastatic Prostate Cancer ◽

Phase Ii Clinical Trial ◽

Open Label ◽

Castration Resistant ◽

Open Label Phase

Download Full-text

The effect of low-dose GTx-758 on free testerone levels in men with metastatic castration resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.60 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 60-60 ◽

Cited By ~ 1

Author(s):

Evan Y. Yu ◽

Robert H. Getzenberg ◽

Jordan Smith ◽

Michael L. Hancock ◽

Ronald Tutrone ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trial ◽

Side Effects ◽

Adverse Events ◽

Bone Turnover ◽

Phase Ii ◽

Low Dose ◽

Hot Flashes ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

60 Background: Luteinizing hormone-releasing hormone (LHRH) agents used for androgen deprivation therapy (ADT) were designed to lower total testosterone (T) levels to those achieved by orchiectomy for palliative care of advanced prostate cancer. This castration equivalent level was based upon the lower limits of quantitation (50ng/dL) of outdated assays. Contemporary assays reveal that actual total T levels in men after orchiectomy are significantly lower (<20ng/dL), with 30 to 40% of men on LHRH agonists not achieving that level. There is growing literature showing that lower T levels correlate with improved outcomes. Additionally, the biologically active form of T is unbound, free T. GTx-758 (Capesaris) is an oral estrogen receptor α agonist that increases sex hormone binding globulin (SHBG), lowers free T levels, and ameliorates estrogen deficiency side effects associated with ADT. Methods: In a phase II open label study (G200712), 38 men with metastatic castration resistant prostate cancer (mCRPC) were continued on their current form of ADT along with a low dose of GTx-758, 125 mg, for at least 90 days. Exclusion criteria included men at increased risk for venous thrombolic events (VTE). Results: The initial 14 patients in this trial completed 90 days on study and are evaluable for select trial endpoints. All treated men had a greater than or equal to a 150% increase in SHBG levels. Eleven of the 14 men began the study with suboptimal castration (free T >0.7 pg/ml) and 91% (10 out of 11) of these men became optimally castrated by day 90. Four out of 14 patients had a more than 45% decrease in prostate-specific antigen. Stable or improved hot flashes and bone turnover markers were observed in 71% and 73% of treated men, respectively. While some patients experienced adverse events, none were vascular related and there were no serious adverse events or VTEs. Conclusions: The majority of patients on an LHRH agonist enrolled in this phase II study had suboptimal levels of free T that were further lowered by GTx-758 administration. GTx-758 treatment resulted in stabilization and/or improvement in reported hot flashes and bone turnover, two major side effects of ADT. While the phase II clinical trial is ongoing, and full results are forthcoming, these preliminary findings show that 125 mg of GTx-758 has clinical effectiveness and is well tolerated. Exploration of 250 mg a day is planned. Clinical trial information: NCT01615120.

Download Full-text