All doctors are agree that Provenge should be given first. What dr. Petrylak is talking : somebody has spread metastasis all over, maybe in other organs, severe pain that need to be control with narcotic, so aggressive cancer in late stage that doctors need move with very aggressive treatment , in this case maybe Provenge is not the first step .
Remember, the only cancer drug that has the highest recomandation in PRECHEMO for castration-resistant prostate cancer (CRPC) is PROVENGE. Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate and Provenge has Category 1. ZYTIGA has CATEGORY 2B recommendation PRE-CHEMO ( lower-level evidence).
Some men are not candidates for docetaxel chemotherapy, in these men, ZYTIGA with prednisone may be an appropriate therapy. However, the panel agreed that its routine use in the pre-chemo setting should be discouraged.www.jnccn.org/content/10/9/1081.longNow many doctors talk about sequences and combination treatments. some of them ( Dr. Meyers, Dr.Petrylak) are talking about future cure for p.c., maybe combining treatment and give example that most of the cancers that are now "curable" like some lymphomas, are cured as a result of using cancer drugs in combination.www.healingwell.com/community/default.aspx?f=35&m=2540933www.healingwell.com/community/default.aspx?f=35&m=2571322
There is trial Provenge +Zytiga. Result for this trial is expected next summer. Company also will start trial Provenge+ Xtandi next year
. When you look at the trial Provenge+Zytiga you can see 2 arms: Abiraterone acetate plus prednisone treatment will start the next day after the first infusion of sipuleucel-T and continue for 26 weeks or until disease progression, unacceptable toxicity, or death, whichever occurs first;
Abiraterone acetate plus prednisone will start 6 weeks after the last infusion of sipuleucel-T and continue for 26 weeks or until disease progression, unacceptable toxicity, or death, whichever occurs first.www.clinicaltrials.gov/ct2/show/NCT01487863?term=provenge+trials&rank=13
They want determine when better start use Zytiga after Provenge.
I know some doctors continue hormone treatment during Provenge treatment or try again HT after Provenge, others wait 1-6 months or even longer after Provenge before they move to Chemo or Zytiga. It is big challenge for doctors how use these drugs in combination and they will focus next years on it.
There is article in Onclive by Dr. Petrylak 'Robust Sipuleucel-T Immune Activity Is Detailed in Pooled Data Analysis": "The study’s results “tell us that the immune system and APCs are activated when targeted by Provenge, and that the subsequent cytokines that are induced are upregulated—and that correlates with survival,” Petrylak said... added that researchers should focus on how to sequence Provenge and four other therapies available to CRPC patients."www.onclive.com/publications/Oncology-live/2012/October-2012/Robust-Sipuleucel-T-Immune-Activity-Is-Detailed-in-Pooled-Data-Analysis
You can also read :www.onclive.com/publications/obtn/2012/July-2012/Sipuleucel-T-Studies-Support-Earlier-Use-Reveal-Potential-Biomarkerwww.onclive.com/web-exclusives/Researchers-Determine-Immune-Parameters-that-Lead-to-Better-Survival-in-Patients-who-Receive-Sipuleucel-T
"Lawrence Fong, MD, associate professor, Department of Medicine (Hematology/Oncology), University of California, San Francisco, explains that not understanding the mechanism of action for the various immunotherapies is one of the greatest challenges facing the field.
In order to gauge the immune response, a trial was conducted that administered the immunotherapy sipuleucel-T (Provenge) prior to prostatectomy. Once the prostate was removed, the trial examined the immune response in the tissue in order to assess the degree of activity. An increase in T cells was observed within the prostate and specifically around the edges of the tumor, Fong notes. Additionally, an immune response was linked directly to the target antigens used by sipuleucel-T.
Fong believes this trial provides further insight into the mechanism of action of immunotherapies. The next step for these trials is to investigate how the T cells affect the tumors and the degree of clinical activity."
Very interesting trial Provenge+ chemo is starting in Georgia Health Sciences University:
"Researchers must disrupt more than one tumor defense mechanism, which allows for an immune-boosting response for the immune cells rallied against the tumor, Khleif said.
He said that provides “a better environment with less obstacles (for the vaccine) to work and it also provides them a better environment to come to the tumor itself.”www.healingwell.com/community/default.aspx?f=35&m=2576188
There is interesting research paper "Toward Maximizing Immunotherapy in Metastatic Castration-Resistant Prostate Cancer – Rationale for Combinatorial Approaches Using Chemotherapy" by Dr.Slovin.
In this paper, an exploratory analysis of phase III trial (PROVENGE) participants found a substantial survival benefit to receiving docetaxel some months after sipuleucel-T:
"An exploratory post hoc analysis of docetaxel with or without early sipuleucel-T found that there was a benefit to receiving docetaxel some months after sipuleucel-T. Median survival was 34.5 months for patients who received sipuleucel-T followed later by docetaxel (N = 51); 25.7 months for crossover placebo recipients who also received docetaxel (N = 21); and 20.2 months for placebo patients who received docetaxel without ever receiving a vaccine product (N = 10). The adjusted survival hazard ratio (HR) for the first of these groups compared with the others was 2.53 (P = 0.006; Petrylak et al., 2007; Petrylak, 2011)."
So we see:PROVENGE + CHEMO = 34,5;
FROZEN PROVENGE ( crossover placebo patient ) + CHEMO = 25,7;
PLACEBO + CHEMO = 20.2;www.ncbi.nlm.nih.gov/pmc/articles/PMC3362835/?tool=pubmed
I would like to see exploratory post analysis of Zytiga+ Docetaxel even with crossover. For example resent study in UK demonstrated that the activity of Docetaxel in patients with mCRPC who first received treatment with Zytigae was lower than expected:
Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance?Conclusion: The activity of docetaxel post-abiraterone appears lower than anticipated and no responses to docetaxel were observed in abiraterone-refractory patients."annonc.oxfordjournals.org/content/23/11/2943.full
And last you can listen Dr.Oh interview on "Sequencing New Treatments for Prostate Cancer":
"...the challenge facing many physicians is how to optimally sequence these therapies.The guiding principles for sequencing any therapeutic is to begin with the treatment that is the most effective with the least toxicities. Following this approach, treatments can be further sequenced using the mechanism of action (MOA) as a guide. Oh notes, that each of the newly approved therapies for CRPC seem to represent a unique MOA, including cytotoxic agents, immunotherapies, androgen therapies, radiopharmaceuticals, and others.As an example, Oh notes that, since these therapies have multiple MOAs, if a patient does not do well on hormonal therapy another option is available that uses a different approach, such as a cytotoxic. Additionally, he adds that immunotherapies should likely be administered in the frontline, when the immune system is at its strongest.www.onclive.com/onclive-tv/Dr-Oh-on-Sequencing-New-Treatments-for-Prostate-Cancer