Trials in mCRPC: PSMA ADC; model for predicting OS; second-line therapy aflibercept vs placebo with dtx/pred

Expert Opinion published on August 5, 2013 in ASCO 2013 Highlights
Download Transcript Download Audio
Daniel Petrylak, MD
Director, Genitourinary Oncology Program
Co-director, Signal Transduction Research Program
Yale University Smilow Cancer Center
New Haven, Connecticut
Trials in mCRPC: PSMA ADC; model for predicting OS; second-line therapy aflibercept vs placebo with dtx/pred

Hello, my name is Dr. Daniel Petrylak, and I am the director of genitourinary oncology and the co-director of the Signal Transduction Research Program at the Yale University Smilow Cancer Center. I am reporting live from the American Society of Clinical Oncology annual meeting being held in Chicago, Illinois. Today, I would like to speak you about three different abstracts. The first abstract is prostate-specific membrane antigen antibody drug conjugate or PSMA ADC, a phase I trial in metastatic castration-resistant prostate cancer previously treated with a taxane. This is a phase I trial that we ran at multiple institutions looking at different dosages of an antibody conjugate in castration-resistant prostate cancer. PSMA is an antigen that is expressed almost ubiquitously in prostate cancer and strangely it is expressed in the CAPRA endothelium of non-prostate tumors, so it may be a target that we can use for a variety of different malignancies. We formed a conjugate of an antibody that targets an external epitope of PSMA. PSMA is a transmembrane protein that is possibly responsible for folate transport, but it does not have any signal transduction capabilities. But this is a target that is expressed in both benign and normal prostate tissue and it may be up-regulated as one is treated with hormone therapy. This antibody was conjugated to a cytotoxic agent called MME, which is an antitubulin drug, and the theory is that this drug would bind to the external portion of the prostate cancer cell and then the conjugate would be internalized, cleaved, and the MME could then cause its cytotoxic effect. We performed a dose-finding study and we found that our maximal tolerated dose was 2.5 mg/kg. We actually got up to 2.8. We found that dose-limiting toxicity was neutropenia. We also noted that fatigue and neuropathy were other important side effects in this particular trial. We started seeing clinical activity at 1.8 mg/kg and in fact if you start looking at PSA declines and declines in the circulating tumor cells, if you use a 30% PSA decline and the conversion of greater than 5 to less than 5 circulating tumor cells, 40% of our patients responded. If you use the 50% PSA benchmark, it is 30% of patients overall. So, these were patients who had extensive prior therapy including chemotherapy and hormonal treatment, and so to see any degree of activity I think is promising with this particular conjugate. The recommended phase II dose as I mentioned before was 2.5 mg per kg and phase II studies in taxane-refractory metastatic prostate cancer are now ongoing.

I would like to talk about the second abstract which is double-blinded randomized trial of aflibercept versus placebo with docetaxel and prednisone for the treatment of metastatic castration-resistant prostate cancer. We know that angiogenesis is an important target for prostate cancer. We know that if we look at human prostate cancer specimens, we can find that VEGF is expressed in the tumors. We have also seen in the past that circulating levels of VEGF may potent a poorer prognosis in castrate-resistant prostate cancer and the thought was to combine an anti-angiogenesis agent, VEGF trap, along with docetaxel, and compare it to the standard docetaxel regimen. The trial accrued more than 1,200 patients and unfortunately as we saw in the story with bevacizumab, there was no improvement in survival when you compared the combination treatment to the standard docetaxel-prednisone arm. In fact, the survival was almost exactly the same as we saw in the Avastin trial of 22.1 months. What was different in this particular study was we did see more toxicity in the VEGF trap arm. This was particularly manifested as far as hypertension was concerned, also as far as the rates of bleeding or other known effects of the VEGF pathway. Interestingly, in contrast to the study performed with bevacizumab, this trial demonstrated no difference in PSA response rates, no difference in time to progression, and these were secondary endpoints. We did see that in the other study with bevacizumab. So in summary, unfortunately, the angiogenesis approach to castrate-resistant prostate cancer, at least in combination of docetaxel, does not show an improvement in overall survival.

So, our third abstract is a prognostic model for predicting overall survival in metastatic castration-resistant prostate cancer in men who were treated with second-line chemotherapy. We looked at a variety of different prognostic factors in first-line chemotherapy, and these generally have included alkaline phosphatase, the level of LDH, PSA declines, and the question was from this particular study was were the prognostic factors any different for those patients being treated with second-line chemotherapy? This study included second-line agents such as satraplatin and cabazitaxel and the data was pulled and we looked at a variety of different prognostic factors. Aside from the standard prognostic factors that have been identified in the past, such as PSA, ECOG performance status, we also demonstrated that the time from the prior docetaxel treatment to the second-line therapy was also prognostic for survival. Additionally, the duration of hormonal treatment was also prognostic for survival. So, this will help to stratify some of the our other second-line cytotoxic trials and help to even out what may be imbalances in smaller trials that could certainly affect the survival outcome. I thank you for tuning in to listen to our analyses of these three abstracts, and we hope that we elucidated some of the issues that are going on castration-resistant prostate cancer. Thank you for your attention.

 

References:
Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in metastatic castration-resistant prostate cancer (mCRPC) previously treated with a taxane. http://meetinglibrary.asco.org/content/112557-132

A prognostic model for predicting overall survival in metastatic castrate-resistant prostate cancer (mCRPC) men treated with second-line chemotherapy. http://meetinglibrary.asco.org/content/110602-132

Double-blind randomized trial of aflibercept versus placebo with docetaxel and prednisone for treatment of metastatic castration-resistant prostate cancer (mCRPC). http://meetinglibrary.asco.org/content/109616-132

Last modified: August 5, 2013
Related Items by Category
Discussions on mCRPC including the AFFINITY trial, AA plus prednisone and ipilimumab
Tomasz Beer, MD
Expert Opinion published on August 5, 2013 in ASCO 2013 Highlights
Outcomes from ALSYMPCA and analysis of dtx on sipuleucel-T in PROCEED patients
A. Oliver Sartor, MD
Expert Opinion published on August 5, 2013 in ASCO 2013 Highlights
Related Items by Author
What are the most prevalent risk factors in developing prostate cancer?
Daniel Petrylak, MD
Expert Opinion published on June 28, 2013 in Basic facts
My doctor told me prostate cancer spread to my bones. Is there any way for me to stop that from happening?
Daniel Petrylak, MD
Expert Opinion published on June 28, 2013 in Treatment
What is seed implantation and when is it used in the treatment of prostate cancer?
Daniel Petrylak, MD
Expert Opinion published on June 28, 2013