I have not used 2d line AR drugs yet. CRPC just started six months ago. My PSA is below 1. One small, suspected area on last month's PSMA PET scan. That is the same area that looked suspicious on PSMA PET in 2016 and on Axumin in early 2021. I did IADT 2016-2020, with continuous ADT since Jan 2021.
I'm working on getting provenge treatments scheduled for Jan-Feb 2023. I have Nubeqa approved but have not started taking it yet.
My question is- Is it more effective to start on the Nubeqa before doing Provenge, or should I do Provenge first and then start Nubeqa a few months later? I'm trying to determine whether the Provenge immunotherapy might have a greater positive effect by letting it adapt and build up immunity for a few months first, before suppressing the cancer with the Nubeqa?
I don't think there are any studies on this but maybe there are some theories that point to one recommend order/sequence.
I just found this article. The patient/author feels confident that doing provenge very early in castration resistance, is the better option. I don't think there are any tests showing this evidence though: cancerabcs.org/advanced-pro...
Here is a clip from the Zero Prostate Cancer website discussion section, from 2012, but the comments are still logical:
tony19
Nov 14, 2012 • 11:16 AM
Gillg2,
I would tell a decline in PSA levels, for example, is not a reliable method of determining responses to PROVENGE.
NCCN Guidelines said " Notably, no effect on the time to disease progression was observed, and PSA responses were rare, which poses challenges in predicting and monitoring response... Clinicians and patients should be aware that the common markers of benefit, such as a decline in PSA or improvement in bone or CT scans, are not seen usually, and therefore benefit to an individual patient cannot be ascertained using currently available testing." NCCN gave PROVENGE CATEGORY 1 in PRE-CHEMO setting.
Gillg2, You should remember Provenge didn't reduce PSA . Benefit of this drug is EXTEND OS ( overall survival ). It is a GOLD STANDARD for cancer medicine. On 10/9/2012 NCCN featured updates to the NCCN Guidelines where was confirmed that , PROVENGE has an existing CATEGORY 1 recommendation in the pre-chemo setting.
NCCN also gave CATEGORY 2A after-chemo ( it is still very good but mean that PROVENGE better to be received in pre-chemo setting).
For example ZYTIGA rceived only category 2B recommendations for patients who are asymptomatic or are symptomatic BEFORE CHEMO ( no OS) and CATEGORY 1 AFTER CHEMO ( OS) . XTANDI doesn't have recommendation yet from NCCN and I think it will be like for ZYTIGA.
jnccn.org/content/10/9/1081...
What probably happens with PROVENGE is that there is a slow, long-term response that the body generates to fight the cancer. With immunotherapy, you probably get a brake put on the cancer and you’re certainly slowing down the progression.
I think one of the best benefits is the extremely long half life. Other therapies have a benefit that disappears when the therapy stops but that Provenge will remain in your body for an extremely long time, maybe the rest of your life.
PROVENGE demonstrate OS in THREE DIFFERENT PHASE 3. And in all these trials PROVENGE compete against Frozen version of itself- FROVENGE( for PLACEBO group).
From ABSTRACT 683:" Estimating the overall survival benefit of sipuleucel-T in the IMPACT trial accounting for crossover treatment in control subjects with autologous immunotherapy generated from cyropreserved cells.
Conclusions
Post-progression treatment with APC8015F may have extended the survival of control subjects in the IMPACT study. Adjusting for use of APC8015F resulted in an increase in median OS benefit with sipuleucel-T of up to 7.8 months. These results suggest a greater treatment effect of sipuleucel-T than reported in IMPACT, and should be factored into future studies without APC8015F crossover."
aua2012.org/abstracts/proce...
In ASCO 2012 was presented ABSTRACT "Overall survival (OS) benefit with sipuleucel-T by baseline PSA: An exploratory analysis from the phase III IMPACT trial." It show that patients with PSA<22.1 has OS 13 months.
asco.org/ASCOv2/Meetings/Ab...
it has been proven scientifically to extend over all survival time in those who get it. Those who get it live longer than those who don't, some live years long. The earlier it is given the better it works. This is why if the MDs are on top of things and putting their patients well being first, they will give Provenge first and then CHEMO and androgen depriving oral medications like ZYTIGA, XTANDI.
I would like recommend to read article that was published in Onclive "Robust Sipuleucel-T Immune Activity Is Detailed in Pooled Data Analysis". From this article:
"Patients who received sipuleucel-T (Provenge) developed immune parameters that correlated with improved overall survival, giving researchers a better understanding of how the immunotherapy works at a cellular level and suggesting that these parameters should be the focus of further studies on the treatment...
The study results should help put such concerns to rest, said Daniel P. Petrylak, MD, one of the authors of the paper. “This is evidence,” he said, “that this product works...
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. “This is not going to change how we use the therapy, but it may change how some people view it...
Petrylak added that researchers should focus on how to sequence Provenge and four other therapies available to CRPC patients.
“We don’t understand the biology as well as we should,”Petrylak said. “We need good tests to tell us which drug is the best one to use in a given situation. There’s no scientific way of doing this, at this point, and that’s really what the disappointment is. But that tells us where we have to work in the next couple of years to figure this out.”
onclive.com/publications/On...
In advanced prostate cancer ,it is all about sequences of drugs and put them in right order.
There is interesting ONCLIVE PEER EXCHANGE FOR PROSTATE CANCER
This discussion was among prominent urologists, broken in several pieces and posted on ONCLIVE:
Immunotherapy for Castration-Resistant Prostate Cancer:
"The role of immunotherapy for men with castration-resistant prostate cancer (CRPC) is an area that has garnered a great deal of discussion among physicians. E. David Crawford, MD, agrees with the NCCN guidelines, which suggest that sipuleucel-T (Provenge) should be the FOUNDATION and FIRST-LINE choice for minimally or asymptomatic CRPC.
Crawford foresees a large paradigm shift in the future for urologists treating CRPC. Multiple new therapeutics, which are easily given by urologists, are rapidly becoming available, such as the immunotherapy sipuleucel-T and the investigational agent radium-223, which Crawford describes as a game changer. Recently approved agents include abiraterone acetate and enzalutamide with TAK-700 (orteronel) and lyase inhibitors rapidly approaching in the development pipeline..."
onclive.com/peer-exchange/p...
Optimal Treatment Sequencing for Advanced Prostate Cancer:
"...However, the question facing many physicians is how to sequence these new therapies.
Paul R. Sieber, MD, believes that it may take a decade before reliable evidence-based information is available on sequencing. Additionally, he questions the future role of cytotoxic therapies, as newer and less toxic options become available.
Rudimentarily Sieber's practice has pushed the use of sipuleucel-T (PROVENGE) earlier in the treatment paradigm. Following this treatment, many physicians are using abiraterone acetate (Zytiga) in the prechemotherapy space with the possibility of also administering enzalutamide (Xtandi) in the future. Additionally, throughout the course of these treatments the management of skeletal-related events can easily be accomplished using denosumab (Xgeva) and zoledronic acid (Zometa). However, Sieber believes that the role cytotoxic agents play is still largely unclear."
onclive.com/peer-exchange/p...
Therapeutic Options for Advanced Prostate Cancer
"Neal D. Shore, MD, provides details on the multiple therapies that are approved for patients with advanced prostate cancer. In general, androgen deprivation therapy (ADT) with leuprolide or GNRH antagonists remains a first-line therapy for patients who are still sensitive to androgen. For these patients, the antiresorptive agents denosumab and zoledronic acid can be used to help manage skeletal-related events (SREs).
Once patients show radiologic evidence of disease, the immunotherapy sipuleucel-T( PROVENGE) can be given in a 30 to 40-day completion with a very acceptable tolerability and safety profile, for asymptomatic castration-resistant prostate cancer (CRPC). Following progression, the cytotoxic agents docetaxel and cabazitaxel can be administered sequentially.
In the post chemotherapy space, two new oral agents have gained approval, abiraterone acetate and enzalutamide. The agent abiraterone acetate is an androgen biosynthesis inhibitor and lowers testosterone and testosterone metabolite levels by impacting the binding domain of the androgen receptor. The other agent, enzalutamide, directly binds to the androgen receptor and further prevents translocation at the level of the nucleus in the DNA..."
onclive.com/peer-exchange/p...
You tell that you will start CHEMO soon. 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;
ncbi.nlm.nih.gov/pmc/articl...
Right sequences of drugs can give patient many years of life . You still have other drugs ahead( CHEMO, ZYTIGA, XTANDI,).
Remember your immune system become stronger and other drug will work better. I wish you the best and remember , you did right choice going with PROVENGE first. You can consider even try hormone therapy again and maybe it will start work again."
Moving forward with treatment: Xtandi and Provenge
Preparing for Provenge
Provenge - is it worth it?
