Prostate qu's: curing Stage IV, Zytiga in adv dz

[scarbrtj]

Two prostate qu's/ruminations, somewhat related

1) These guys make a comment (and some of the guys are rad oncs obv) which I think is positive but still unorthodox, "A sequentially applied multimodal treatment strategy can eliminate detectable disease in selected patients with metastatic spread at diagnosis. The end point of undetectable PSA after testosterone recovery should be considered when evaluating new approaches to rapidly set priorities for large-scale testing in early metastatic disease states and to shift the paradigm from palliation to cure." So I guess we as oncologists need to be doing more of this (ie multimodal tx) in Stage IVA/B CaP? That would include having the bravery to say things like "shifting the paradigm from palliation to cure" in tumor board?

2) Given number one above, and re: the STAMPEDE and LATITUDE trials.
a) We all see guys with metastatic prostate cancer. I'm seeing these guys who are just on Lupron only. Should we be telling their urologists to add Zytiga? That's now the standard of care, correct: ADT+Zytiga, versus ADT alone?
b) We know ADT+XRT is better than XRT in high risk localized prostate cancer and also I know many rad oncs (me included) willing to treat Stage IVA CaP like Stage III CaP. The STAMPEDE had a small portion of patients that were non-metastatic. They saw a benefit, but the HR crossed over 1 (ie p=NS). I know nothing about if they got XRT, surgery, etc., although I guess that'd be germane. Be that as it may, I heard this guy on the study say that the benefit of abiraterone "was similar for metastatic and nonmetastatic patients. We saw the same magnitude of effect, and so we think the effect applies across the whole trial population." In my mind, I would think Zytiga+ADT+XRT has to be the "new thinking" although I don't see this being mentioned or advocated, and obv there's not going to be any data *right now* on plus-minus XRT. But we should be thinking about giving Zytiga plus XRT here right?
c) Given 'b,' can we as rad oncs extend this whole line of argument to the high risk post-op setting (FWIW, for anyone I ever see who has an indication for postop XRT, they almost always have an indication for postop XRT+ADT in my mind).


http://www.goldjournal.net/article/S0090-4295(16)30850-0/fulltext
ASCO 2017: STAMPEDE Trial: Adding Abiraterone to Standard Treatment Improves Survival in Advanced Prostate Cancer - The ASCO Post
ASCO 2017: LATITUDE Trial: Addition of Abiraterone to Standard Hormonal Therapy Improves Outcomes in Newly Diagnosed Metastatic Prostate Cancer - The ASCO Post

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[medgator]

Stampede was presented at the most recent asco and yes I interpreted it to mean that adjuvant zytiga should be standard of care in high risk as well in metastatic patients.

The issue is getting it paid for. Europe has approved it while afaik that is not the case here surprisingly.

EC extends license for Zytiga to treat earlier stage prostate cancer

The question I have is how to integrate zytiga and docetaxel in these populations.... after radiation, how do we decide who gets one or maybe both?

Not sure about radiation for M1 patients.... waiting for data on that one

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[seper]

Agree with above, but there is another issue: how does Firmagon (degarelix) play into this? I see newly diagnosed patients on it all the time.

 

[DoctwoB]

Stampede was presented at the most recent asco and yes I interpreted it to mean that adjuvant zytiga should be standard of care in high risk as well in metastatic patients.

The issue is getting it paid for. Europe has approved it while afaik that is not the case here surprisingly.

EC extends license for Zytiga to treat earlier stage prostate cancer

The question I have is how to integrate zytiga and docetaxel in these populations.... after radiation, how do we decide who gets one or maybe both?

Not sure about radiation for M1 patients.... waiting for data on that one

Sent from my LG-H910 using SDN mobile

The data from Stampede and Latitude is highly compelling, however the data for up front docetaxel in metastatic hormone sensitive prostate cancer from the docetaxel arms of stampede and CHARTED trials is equally compelling. I’d argue giving either abietarone or docetaxel with ADT is definitely the current evidence based standard of care.

Which one is entirely up for debate as their is limited sequencing data. Docetaxel proponents argue that your patient may not be a candidate for cytotoxic therapy when their disease progresses in 4 years so better to give it now and save the novel hormonal agents. It is also significantly cheaper. Abiretarone proponents will argue that it had a significantly improved risk profile compared to docetaxel and many patients may die of other causes before progressing and requiring cytotoxic therapy. FWIW if it were my father I would recommend zytiga. By the time he progresses there may well be new hormonal agents or better data regarding hormonal agent sequencing or targeting therapy to specific subsets of patients who progress.

 

[medgator]

The data from Stampede and Latitude is highly compelling, however the data for up front docetaxel in metastatic hormone sensitive prostate cancer from the docetaxel arms of stampede and CHARTED trials is equally compelling. I’d argue giving either abietarone or docetaxel with ADT is definitely the current evidence based standard of care.

Which one is entirely up for debate as their is limited sequencing data. Docetaxel proponents argue that your patient may not be a candidate for cytotoxic therapy when their disease progresses in 4 years so better to give it now and save the novel hormonal agents. It is also significantly cheaper. Abiretarone proponents will argue that it had a significantly improved risk profile compared to docetaxel and many patients may die of other causes before progressing and requiring cytotoxic therapy. FWIW if it were my father I would recommend zytiga. By the time he progresses there may well be new hormonal agents or better data regarding hormonal agent sequencing or targeting therapy to specific subsets of patients who progress.

Agreed, docetaxel for 6(?) cycles doesn't sound like something I'd want to do if there is an option for zytiga first

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[nkmiami]

Also, zytiga will be generic in a few months, so its use could really take off.

 

[Palex80]

Sequence of therapies in prostate cancer is a great unknown.
Of course first line chemotherapy with ADT is more toxic than first line abiraterone with ADT, however we do not fully know of chemotherapy will work as well in abiraterone pre-treated patients like abiraterone will work in chemotherapy pre-treated patients.
There is data for example pointing out that abiraterone doesn't work in patients who have encalutamide. Response rate is really low.

For me both abiraterone and chemotherapy are valid options in first line metastatic patients. Perhaps, but only perhaps, chemotherapy is more suited in patients with visceral metastasis or higher gleason tumors. But noone really knows.
Chemotherapy will probably become s.o.c. soon together with ADT for first line non-metastatic high risk prostate cancer patients undergoing RT. The RTOG trial should be reaching the point where the data is mature and the French trial has shown promising results too.

I still do not think we are at the point of saying we can CURE stage IV patients with bone or visceral metastasis.

 

[medgator]

.
Chemotherapy will probably become s.o.c. soon together with ADT for first line non-metastatic high risk prostate cancer patients undergoing RT. The RTOG trial should be reaching the point where the data is mature and the French trial has shown promising results too.

I still do not think we are at the point of saying we can CURE stage IV patients with bone or visceral metastasis.

Rtog study was reported within the last year iirc and showed an OS benefit to chemo. Chemo is therefore mentioned in the nccn guidelines as an option after radiation in fit patients.

I refer all high risk pts to med onc after xrt in light of the rtog and stampede data

 

[Chartreuse Wombat]

Also, zytiga will be generic in a few months, so its use could really take off.

nkmiami nailed it...radoncs should be prepared to prescribe and know the toxicities

"Zytiga's composition patent expired in December 2016 in the US and generic entry is expected in October 2018. Therefore, J&J will have approximately one year to capitalise on these latest results."

Loss of exclusivity to limit J&J gain after Zytiga label extension - Pharmaceutical Technology

 

[medgator]

nkmiami nailed it...radoncs should be prepared to prescribe and know the toxicities

"Zytiga's composition patent expired in December 2016 in the US and generic entry is expected in October 2018. Therefore, J&J will have approximately one year to capitalise on these latest results."

Loss of exclusivity to limit J&J gain after Zytiga label extension - Pharmaceutical Technology

I guess it depends on your comfort level.... zytiga requires prednisone administration with it iirc.

Personally I prefer med onc to see high risk pts to discuss taxotere vs zytiga. They can prescribe whichever they like along with lupron

 

[nkmiami]

I guess it depends on your comfort level.... zytiga requires prednisone administration with it iirc.

Personally I prefer med onc to see high risk pts to discuss taxotere vs zytiga. They can prescribe whichever they like along with lupron

I havent prescribed zytiga, but the prednisone is just a very low dose to "make up" for cortical steroid that the zytiga depletes.

 

[radtothebone]

One thing most men hate about taking abiraterone is the need to take it Wilhite fasting. However this study suggests taking it with food may be just as effective, eliminate the abdominal complaints seen with fasting and bring about cost savings with a 75% lower dose allowed...

http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.6_suppl.176

 

[Palex80]

Regardless of systemic therapy /etc Im quite interested in RT to the prostate for metastatic disease (STAMPEDE is looking at it i think in one of their arms). Do you have much experience with it in the US?

Indeed, I heard results of this comparison will be made public in 2018. If it shows a benefit for local RT in the metastatic setting, it's going to be a game changer.
Another trial is looking at this too, albeit with a different design: A Phase III of ADT +/- Docetaxel +/- Local RT +/- Abiraterone Acetate in Metastatic Hormone-naïve Prostate Cancer. - Full Text View - ClinicalTrials.gov

 

[radtothebone]

It's all still up in the air I reckon. STAMPEDE currently have an arm looking at enza/abi combined upfront (few patients I've seen on it seem to have their PSAs under control for the last 2 years at least). Also theoretically upfront enza should be no worse than upfront abi, and the ENZAMET trial is looking at enza upfront combined with Taxotere. Regardless I quite like giving Taxotere upfront especially since the LATTITUDE data for abi is no better than Taxotere, cause its just 6 cycles and then youre done. Also Taxoter 75mg/m2 is pretty well tolerated. I reckon though upfront abi (or enza maybe in the future?) is good for crumbly old guys who you worried about giving even Taxotere 60mg/m2 to....

I wonder what the impact of RTOG 0521 will be in the PET-PSMA/Choline/etc era though? cause prob alot of these high risk guys had mets that were being missed on istope bone scans and CTs i suspect?

Regardless of systemic therapy /etc Im quite interested in RT to the prostate for metastatic disease (STAMPEDE is looking at it i think in one of their arms). Do you have much experience with it in the US?

Regarding RTOG 0521, I have heard that final results regarding OS may differ from the ASCO abstract and this has hindered its publication. Not surprising given that the OS benefit seemed to at least somewhat driven by non prostate cancer death.

 

[medgator]

I wonder what the impact of RTOG 0521 will be in the PET-PSMA/Choline/etc era though? cause prob alot of these high risk guys had mets that were being missed on istope bone scans and CTs i suspect?

Isn't that still investigational? I thought those isotopes/tracers weren't really in widespread use yet?

 

[Haybrant]

i wonder if people would be wiling to describe what is your workup right now for patients that are referred for high risk prostate cancer. Do you get MRI's, bone scan, Isotope PETs? All refer to med onc then start 2 months post initiation of adt? Treating nodes for pts w 2 or more high risk features?

 

[scarbrtj]

i wonder if people would be wiling to describe what is your workup right now for patients that are referred for high risk prostate cancer. Do you get MRI's, bone scan, Isotope PETs? All refer to med onc then start 2 months post initiation of adt? Treating nodes for pts w 2 or more high risk features?

1) I get an MRI for all prostate patients: this is for tx planning purposes (fiducial fusion to CT and contouring), but it also can be helpful for staging obv
2) I get a bone scan in all high risk
3) I never get any other scans in high risk
4) I never refer to med onc in high risk
5) I never treat nodes in high risk unless I have evidence of N1
I am open to changing #3 and 4 especially; I may never change #5

 

[evilbooyaa]

1) I get an MRI for all prostate patients: this is for tx planning purposes (fiducial fusion to CT and contouring), but it also can be helpful for staging obv
2) I get a bone scan in all high risk
3) I never get any other scans in high risk
4) I never refer to med onc in high risk
5) I never treat nodes in high risk unless I have evidence of N1
I am open to changing #3 and 4 especially; I may never change #5

1) Agree
2) Agree
3) Agree. Do not feel that there is a role for it outside of the recurrent setting.
4) At my institution med-onc does hormonal therapy, so there are referrals sent for that.
5) Not 100% sure what my practice will be as an attending - it's split here amongst the attendings between never and essentially always (in high-risk at least)

 

[Radiated_GuineaPig]

So at the end of the day Stampede had few details regarding the radiation treated high risk subgroup. I agree it's very earth shaking data, but radiation was mandatory to patients with N- non-metastatic disease and it was dealer's choice for N+ non-metastatic disease. These are two different subgroups that are treated with radiation. Thus there are a lot of unanswered questions with regards to radiation and abiraterone.

However the ASCENDE-RT trial was a radiation trial, and showed a very large PFS benefit with a brachytherapy boost. The order of magnitude for PFS is not that different than adding Abi. We clearly know who got radiation and what fields were used. At ASTRO the GU high command was calling brachytherapy boosts "true dose escalation". Do people give brachy boosts for their high risks? if not they should, there is a well designed radiation trial with level 1 evidence showing benefit.

 

[Palex80]

However the ASCENDE-RT trial was a radiation trial, and showed a very large PFS benefit with a brachytherapy boost. The order of magnitude for PFS is not that different than adding Abi. We clearly know who got radiation and what fields were used. At ASTRO the GU high command was calling brachytherapy boosts "true dose escalation". Do people give brachy boosts for their high risks? if not they should, there is a well designed radiation trial with level 1 evidence showing benefit.

The problem is however that toxicity also rose sharply in ASCENDE-RT with LDR-boost.

Grade III urinary toxicity was 18.4% vs. 5.2%. That's more than 3 times higher and grade III toxicity is a relevant issue. I do not know if I would risk that.

 

[medgator]

The problem is however that toxicity also rose sharply in ASCENDE-RT with LDR-boost.

Grade III urinary toxicity was 18.4% vs. 5.2%. That's more than 3 times higher and grade III toxicity is a relevant issue. I do not know if I would risk that.

The ldr purists will hate to admit this but hdr would probably have better numbers there

 

[Radiated_GuineaPig]

The problem is however that toxicity also rose sharply in ASCENDE-RT with LDR-boost.

Grade III urinary toxicity was 18.4% vs. 5.2%. That's more than 3 times higher and grade III toxicity is a relevant issue. I do not know if I would risk that.

Agreed, urinary toxicity was higher in the LDR arm, but the number to focus is on is prevalence at 5 years, which was 8.6% vs 2.2% at 5 years. The difference is due to the fact that many of these events were reversible with a dilation or a TURP. Yes having a grade 3 tox is no joke, but if they are reversible with a outpatient procedure, its a risk that I and alot of patients I believe are wiling to take for treating high risk disease. Also with this regime you save on one year of ADT (compared to what many of us would with EBRT alone), which pretty much all men like and will decrease cardiovascular and bone problems. Ultimately the PFS difference was substantial (HR=2) and there is a good chance that in another 5 years we'll see an OS difference. Might I also point out that grade 3-5 toxicities from abi included 10% vs 4% grade 3-5 cardiovascular disorders and 7% vs 1% grade 3-5 hepatic disorders (9 vs 3 patients died from the Abi combination as well).

Also i totally agree HDR will likely cause a decrease in urinary and there is pretty good rationale to substitute the LDR boost with a HDR boost. I think alot of the LDR purists would actually admit that for a brachy boost. If the boost can be done with HDR then it should be done that way. Also if it were me, i'd throw in a spacer as well.

 

[nkmiami]

Regarding, the spacer- As little regard I have for these with ebrt, I do see a use for them in brachy- why wouldnt you use it?

 

[Radiated_GuineaPig]

I think you misread my response, i would use a spacer.

 

[Chartreuse Wombat]

Agreed, urinary toxicity was higher in the LDR arm, but the number to focus is on is prevalence at 5 years, which was 8.6% vs 2.2% at 5 years. The difference is due to the fact that many of these events were reversible with a dilation or a TURP. Yes having a grade 3 tox is no joke, but if they are reversible with a outpatient procedure, its a risk that I and alot of patients I believe are wiling to take for treating high risk disease. Also with this regime you save on one year of ADT (compared to what many of us would with EBRT alone), which pretty much all men like and will decrease cardiovascular and bone problems. Ultimately the PFS difference was substantial (HR=2) and there is a good chance that in another 5 years we'll see an OS difference. Might I also point out that grade 3-5 toxicities from abi included 10% vs 4% grade 3-5 cardiovascular disorders and 7% vs 1% grade 3-5 hepatic disorders (9 vs 3 patients died from the Abi combination as well).

Also i totally agree HDR will likely cause a decrease in urinary and there is pretty good rationale to substitute the LDR boost with a HDR boost. I think alot of the LDR purists would actually admit that for a brachy boost. If the boost can be done with HDR then it should be done that way. Also if it were me, i'd throw in a spacer as well.

I am going to push back on the assertion that "there is a good chance" that ASCENDE-RT will show a difference in OS. Despite the remarkable difference in bPFS there was no difference in distant metastasis (which is difficult to explain). The trial was small for a prostate study and given competing comorbidities and other cause mortality is will very hard to observe a difference in OS (despite all of the crap in the manuscript saying it might happen). Of course I don't know but OS is very hard in small prostate studies.

 

[Radiated_GuineaPig]

I think we can all agree that the future is uncertain...we may or may not see an OS difference.

But just taking the data at face value, we have often changed our management in prostate cancer (and many other cancers) for much smaller differences in PFS. Often at biochem progression the patient is staring down indefinite ADT which sucks. People worry about the toxicity but you gotta realize that most of these patients were treated with 2D radiation. Thus utilizing modern VMAT, HDR and a rectal spacer may go a long way in optimizing tox.

 

[Chartreuse Wombat]

I think we can all agree that the future is uncertain...we may or may not see an OS difference.

But just taking the data at face value, we have often changed our management in prostate cancer (and many other cancers) for much smaller differences in PFS. Often at biochem progression the patient is staring down indefinite ADT which sucks. People worry about the toxicity but you gotta realize that most of these patients were treated with 2D radiation. Thus utilizing modern VMAT, HDR and a rectal spacer may go a long way in optimizing tox.

I use ASCENDE-RT to support a recommendation that healthy men with lethal prostate cancer should be treated with brachytherapy as a component of treatment (along with ADT and ext beam). I am persuaded; the excess toxicity is a concern but I think much of it is technique related (the implants were very hot; especially at the apex). Additionally many men will accept increased toxicity for increased cure.

 

[radtothebone]

I use ASCENDE-RT to support a recommendation that healthy men with lethal prostate cancer should be treated with brachytherapy as a component of treatment (along with ADT and ext beam). I am persuaded; the excess toxicity is a concern but I think much of it is technique related (the implants were very hot; especially at the apex). Additionally many men will accept increased toxicity for increased cure.

Same approach here, with a strong preference for single fraction HDR boost. The British Columbia Cancer Agency implants in trial were quite hot and I also believe this escalated toxicity. Prospective studies with HDR boost frequently show Grade 3 toxicity less than 5%. I use A spacer from time to time with brachytherapy but find that rectal toxicity is low enough that there is little room to improve.

 

[seper]

when comparing prostate HDR to LDR side effects, are there good data?

 

[nkmiami]

I would think HDR would be harder to screw up for someone who does not do a lot of brachy. I am sure in good hands the side effects are comparable.

 

[seper]

Still, there must be some comparison, in both monotherapy and boost scenarios.

 

[Chartreuse Wombat]

Still, there must be some comparison, in both monotherapy and boost scenarios.

There is a retrospective comparison from Alvaro Martinez when he was at Beaumont; HDR better but given the design hard to be dogmatic.

Multiple prospective comparisons ongoing in Canada (of course) available at clinicaltrials.gov

NCT0193688

NCT02692105

NCT02628041

 

[medgator]

STOMP phase II trial

http://ascopubs.org/doi/abs/10.1200/JCO.2017.76.5495

In this multicenter, randomized, phase II study, patients with asymptomatic PCa were eligible if they had had a biochemical recurrence after primary PCa treatment with curative intent, three or fewer extracranial metastatic lesions on choline positron emission tomography–computed tomography, and serum testosterone levels > 50 ng/mL. Patients were randomly assigned (1:1) to either surveillance or MDT of all detected lesions (surgery or stereotactic body radiotherapy).

ADT-free survival was longer with MDT than with surveillance alone for oligorecurrent PCa, suggesting that MDT should be explored further in phase III trials.

http://ascopubs.org/doi/abs/10.1200/JCO.2017.75.4853

 

[evilbooyaa]

STOMP phase II trial

http://ascopubs.org/doi/abs/10.1200/JCO.2017.76.5495








http://ascopubs.org/doi/abs/10.1200/JCO.2017.75.4853

The MDACC trial for NSCLC all over again, except for prostate, except they were placed on observation not chemo. I'm not sure what they thought was going to happen to the observation patients with untreated metastatic pCA? Good to see evidence of some benefit though, although the naysayers will say the OS will be the same (likely true IMO).

Slightly off topic, but anyone familiar with convincing data in this disease process for oligometastatic breast cancer?

 

[Krukenberg]

The MDACC trial for NSCLC all over again, except for prostate, except they were placed on observation not chemo. I'm not sure what they thought was going to happen to the observation patients with untreated metastatic pCA? Good to see evidence of some benefit though, although the naysayers will say the OS will be the same (likely true IMO).

Slightly off topic, but anyone familiar with convincing data in this disease process for oligometastatic breast cancer?

The whole strategy is to delay initiation of ADT, no? My bigger concern is the physician-driven outcome. There have actually been studies on trials with primary outcomes that are driven by physician decisions and they are consistently more positive than one would expect. With the lack of blinding I think there is bias. Maybe a PRO instrument would be a better primary outcome.

 

[Chartreuse Wombat]

STOMP phase II trial

http://ascopubs.org/doi/abs/10.1200/JCO.2017.76.5495








http://ascopubs.org/doi/abs/10.1200/JCO.2017.75.4853

I have a few problems with this study. The major issue is the primary endpoint which is incredibly subjective as Krukenberg states above. Additional concerns include that the study is underpowered and the HR of the intent to treat analysis include 1.0. This is all probably moot since in the US patients with biochemical recurrence are rarely followed until the development of clinical or radiographic metastases. ADT is used very early (too early in my view) which will make any rigorous investigation of this question very difficult to answer since there won't be a lot of patients. The newer imaging tests like PSMA PET will likely detect metastasis sooner but then you have the Will Rogers phenomenon which is impossible to control for. This study will embolden the SBRT/SABR zealots however and perhaps make reimbursement easier (assuming friendly peer-peer).