Advanced Prostate Cancer Newsletter

Over the last several years’ prostate cancer treatment options for men with advanced prostate cancer has gone from rags to riches.  We now have multiple options for treatment and there is every indication that the number of options will continue to grow.

However, we do see that not all men will respond to all treatments.  Given that all of these treatments are very costly and all come with the promise of significant side effects it would be beneficial to be able to know in advanced without having to administer a treatment if a particular treatment will actual benefit a man.

“Enzalutamide (Xtandi) has been hailed as a miracle drug for many patients with advanced prostate cancer, but a significant proportion of men do not receive any clinical benefit from this agent,” said Emmanuel Antonarakis, M.D., an assistant professor of oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore. “Our data show that AR-V7 seems to predict resistance to enzalutamide in virtually all cases. These findings are clinically relevant and could save patients time and money because oncologists could identify those men that are unlikely to respond to enzalutamide before they receive it and direct them to alternative therapies.”

According to research conducted by Dr. Antonarakis, men with metastatic, castration-resistant prostate cancer who started treatment with enzalutamide and had a molecule called AR-V7 present in their circulating tumor cells (CTCs) prior to starting treatment had a worse response to The enzalutamide compared with those who had no detectable AR-V7.  These results were presented at the AACR Annual Meeting 2014 where I was in attendance, thus I have not had the opportunity to post over the last week.

According to Antonarakis and many others our hormones (androgens), such as testosterone, are the main drivers of prostate cancer. These androgens work by binding to a protein called the androgen receptor (AR), which then attaches to certain regions of the DNA of the prostate cancer cell, fueling its growth and division. This AR-V7 protein in question is a shortened form of the AR protein. It is missing the part of AR that testosterone binds, which is the same part that enzalutamide binds, but it can still attach to DNA and fuel cell growth and division, even when testosterone is not bound to it.

This was a small study enrolling only 31 men with metastatic, castration-resistant prostate cancer who were about to begin enzalutamide treatment. Blood samples were obtained from each man prior to starting treatment with enzalutamide, at the time of the man’s maximum response to treatment, and at the time of disease progression. CTCs were isolated from blood samples and analyzed for the presence of AR-V7 mRNA, an intermediate between the AR gene and the AR-V7 protein.

The researchers found that 12 of the 31 men had AR-V7 mRNA detectable in CTCs obtained prior to the start of enzalutamide treatment. These AR-V7-positive men had worse responses to enzalutamide compared with men who had no AR-V7 mRNA detected in CTCs.

Levels of prostate-specific antigen (PSA), a measure of prostate cancer disease activity, failed to drop in the blood of all 12 AR-V7-positive men, whereas PSA levels dropped by 50 percent or more in 10 of the 19 AR-V7-negative men.

They also found that AR-V7 positive men also had their disease progress sooner (as assessed by bone scan or computed tomography) compared with those who were AR-V7-negative: Time to radiographic progression was 2.1 months compared with 6.1 months.

Antonarakis also said “Before we can conduct the large-scale prospective trials needed to verify our results, we need to have the test that we used to detect AR-V7 mRNA in CTCs certified in a Clinical Laboratory Improvement Amendments (CLIA) setting to ensure the necessary quality control. We are currently in the process of doing this and we hope that things will run smoothly so we can continue to move forward.”

He also added that, “We are also conducting a small study to see whether AR-V7 might predict resistance to another AR-targeted therapy, abiraterone [Zytiga] ….We hope to be able to present the results from that study later this year.”

Joel T Nowak, M.A., M.S.W.

Today, Malecare posted our latest teleconference with Dr. Neil Shore, M.D.   The conference, which was recorded last week, is about Bone Health and Prostate Cancer.  It discusses the importance of maintaining healthy bones and methods to accomplish this task when facing advanced prostate cancer.  This teleconference was made possible by the generous support of Bayer.

This teleconference joins the following, all of which are available to listen to and to read the transcript:

1-    New Prostate Cancer Tests with Drs. Daniel Lieber and Steve Hershman.  The teleconference explored the current state of affairs of genetic testing and prostate cancer.

2-    All About New Options for Men with Advanced Prostate Cancer with Dr. James Gulley from the National Cancer Institute (NCI).  Dr. Gulley talked about advanced prostate cancer treatments, immunotherapy and clinical trials.

3-    All About Provenge was discussed by Dr. Neil Shore. Provenge, the only approved immunotherapy to treat advanced prostate cancer.

4-    Dr. James McKiernan provided us with a general conversation abour advanced prostate cancer.

All of these teleconferences are available for you to listen and to read their transcript at:  www.malecare.org/teleconferences

Joel T. Nowak, M.A., M.S.W.

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Would you be willing to trade off some survival time to lower your risk of developing bone metastases (BM)?  Well, men in the UK and Sweden are willing.

 Men from the UK and Sweden with castrate resistant prostate cancer (CRPC) and at high risk for developing BM because they have been on androgen-deprivation (ADT) or hormone therapy for more than 3 years were asked to complete an online survey with 10 questions. They were asked if they would prefer to receive a hypothetical prophylactic medication (HPM), which provided an increased risk of developing osteonecrosis of the jaw (ONJ) as well as a possible increase of survival to decrease their risk of developing BM or to decline HPM thus not receiving any treatment benefit or risk. The researchers defined the HPMs by providing a delay in BM (0-23 months) and with a risk of ONJ (0-9%).

The proportion of men who chose HPM with different combinations of BM delay and ONJ risk was calculated. To further evaluate the impact of BM to patients, time tradeoff was used to assess men’s’ willingness to trade off between life years with and without bone complications (i.e., skeletal-related events, including spinal cord compression, surgery or radiation to bone, and pathologic fracture).

In the surveya total of 201 UK men and 200 Swedish men completed the survey. When asked about the tradeoff between life years with and without bone complications, 52% of UK patients and 26% of Swedish patients were willing to trade off 5 months of survival to avoid bone complications; nearly three-quarters of the men were willing to trade off 3 months of survival to avoid bone complications.

A majority of the surveyed men in both the UK and Sweden were willing to take the fabricated drugs, HPMs to delay the development of BM even with the treatment-related risk of developing ONJ and the trade off of giving up 3 to 5 months of survival.

What about you, would you trade increasing your risk of developing ONJ and decreasing your life expectancy to avoid the problems of bone metastases?

J Clin Oncol 32, 2014 (suppl 4; abstr 117): Yi Qian, A. Brett Hauber, Juan Marcos Gonzalez, Joshua Posner, Ateesha F Mohamed, Bertrand Tombal, Jean-Jacques Body, Francesca Gatta, Jorge Arellano

Joel T. Nowak, M.A., M.S.W.

 

The explosion of new therapies for men with metastatic castration resistant prostate cancer (mCRPC) raises serious questions about the optimal sequencing of these new treatments as well as whether cross-resistance occurs between these drugs.

It was recently reported that chemotherapy with docetaxel (D) is not effective in in men who did not have a ? 50% PSA decline on prior Zytiga treatment (Ann Oncol 2012; 23(11):2943-7). To evaluate this, Azad etal. looked at the activity of D in men with mCRPC who had previously taken Zytiga.

They drew their subject pool from two Canadian cancer registries.

Outcomes from D treatment were compared between Zytiga responders (? 50% PSA decrease with prior Zytiga) and Zytiga non-responders (< 50% PSA decrease with prior Zytiga). Progression-free survival (PFS) (Prostate Cancer Working Group 2 criteria) and overall survival (OS) were estimated using the Kaplan-Meier method.

In the anaylisis they had 40 eligible men, 14 (35%) were classified as Zytiga responders and 26 (65%) as Zytiga non-responders (including 16 men who had no PSA decline on Zytiga). The median number of cycles of D administered to Zytiga responders and non-responders was 6 (range: 1-10) and 4 (range: 1-13) respectively. Thirty (75%) men had also received D prior to Zytiga. Notably, among 39 men evaluable for PSA response, no difference was seen in the proportion of Zytiga responders and non-responders who had PSA falls ? 50% (p=0.72; Fisher’s exact test) or ? 30% (p=0.75; Fisher’s exact test) on D.

Analysis of the overall survival which went from the date of initiation of D also revealed similar median PFS (p=0.54; log-rank) and median OS (p=0.93; log-rank) in both groups.

They concluded thatPSA response rates to D did not differ between Zytiga responders and non-responders. These data suggest that the anti-tumor activity of D in mCRPC may be independent of prior response to Zytiga and that chemotherapy is still a therapeutic option in men who do not respond to Zytiga.

Given the contradiction of the data additional studies in cross resistance of Zytiga and D as well as additional studies evaluating the optimal sequencing of Zytiga and D in mCRPC are warranted.

J Clin Oncol 32, 2014 (suppl 4; abstr 97); Arun Azad, Renee Lester, Daniel Yick Chin Heng, Bernhard J. Eigl, Kim N. Chi.

Joel T. Nowak, M.A., M.S.W.

 

Many of us believe that the risk developing bone fractures is more common in men who have stage 4 prostate cancer that has developed distant metastasis than those men with stage 4 prostate cancer that do not have distant metastasis.  This increased risk, or actually the increase of fractures has significant clinical consequences, such as increased pain and a decreased quality of life.

A study was performed to confirm this assumption by estimating the prevalence of fractures among men diagnosed with stage 4 non-distant metastatic (M0) prostate cancer as opposed to men with stage 4 prostate cancer with distant metastasis (M1).  It also evaluated the risk factors associated with developing fractures.

The researchers estimated the prevalence of fractures among men age 66 or older diagnosed with M0 or M1 prostate cancer using data from the U.S. SEER-Medicare datasets between the years of 2000 to 2007. The men were followed through December 2009 or until they were lost to follow up.

Among the 9,826 men with prostate cancer (M1 = 7301; M0 = 2525) who were followed, 12.9% of them experienced a post-diagnosis fracture. The prevalence of fractures was nearly twice as high in men with M1 versus M0 prostate cancer (M1 = 14.7%; M0 = 7.5%).

The median time from diagnosis of M1 prostate cancer to their first fracture was five months and for men with M0 prostate cancer it was 34 months.

Compared to men with no fractures, men who experienced fractures were more likely to be older (20.3% vs. 17.8%), of white/non-Hispanic race (81.1% vs. 75.3%), have well (cancer grade 1) or moderately (cancer grade 2) differentiated tumors (48.7% vs. 41.7%), have a claim of osteoporosis (2.4% vs. 0.6%) or osteoarthritis (9.3% vs. 6.5%) in the year prior to the prostate cancer diagnosis, and to have taken a bone mineral density (BMD) test (13.5% vs. 8.1)

The real surprise was that 92% of men did not receive bone mineral density (BMD) testing at any time post diagnosis despite the fact that 67% of the men ad been on a hormone treatment (ADT).

For men with M1 prostate cancer the prevalence of fractures is higher and the time to having a fracture is substantially shorter than in men with M0 prostate cancer.

Additionally, most men with prostate cancer do not receive BMD testing. A significant need remains to monitor bone health and treat fractures, particularly among men with M1 prostate cancer.

J Clin Oncol 32, 2014 (suppl 4); Abdulla M. Abdulhalim, Ebere Onukwugha, Corinne Woods, Yi Qian, Jorge Arellano, Arun Balakumaran, C. Daniel Mullins, Arif Hussain

Joel T. Nowak, M.A., M.S.W.