Prostate Cancer Treatment: From Monotherapy to Sequencing

Prostate Cancer Treatment: From Monotherapy to Sequencing

Thinking back to this, what are some of the patient characteristics for busy clinicians to consider when we make our therapeutic decisions? Well, first and foremost perhaps is it pain? What’s the level of pain? Is there no pain? Asymptomatic to minimally symptomatic to severely symptomatic. Dan did a nice job in describing what’s high volume, low volume bone disease? Are visceral metastases present? And it’s absolutely essential in our trial designs because sometimes we really, we ham string ourselves and we have really effective drugs but where we put in the wrong inclusion/exclusion criteria. Performance status, a traditional ECOG. That’s a good trial definition but there are some murkiness I sometimes still find between a 1 and 2 and we also have outliers in those, but we look at performance status. Neuropathy, definitely something to consider. It’s a fairly devastating complication for many men and women. And we certainly need to advance in our ways to prevent and/or treat neuropathy.

Comorbidities of course, whether there’s insulin resistance, glycemic issues, heart failure issues, cognitive seizure issues, a lot of these things come into play, myelosuppressive issues. When you give therapies early or late, prior therapies, exposure response, and really the big Holy Grail is response biomarkers, and we’ve heard a lot of talk about that. We certainly need to do a lot better. We’re getting great biomarkers, and our decisions about who to biopsy, who to avoid a repeat biopsy, genomic assays, proteomic assays, and newly diagnosed stratification in terms of low risk to high risk. But we really need better biomarkers besides PSA and alkaline phos, LDH and hemoglobin. We’re looking at CDCs, there’s some really exciting work on ARV7 but it’s certainly not yet ready for prime time. Then of course the overall phenotype of tumor characteristics.

What are some of the other key questions that you would be asking yourself if you’re in the armamentarium and the space for treating CRPC or advanced cancer? Well something get better if I give it earlier? I certainly try to make that proposition about immunotherapy yesterday. Are some things better is we give them later or not? Well, is the efficacy of a prior therapy diminished by subsequent treatment? And Dan showed you some nice work about use of abiraterone and then subsequent docetaxel, there’s now some very interesting work that may be very provocative about the benefits of cabazitaxel in that space.

Is the administration of later agents diminished by their precedence and that’s really one of the key things we’re learning more about. We don’t have great level 1 evidence yet, we have some single institution data but not large prospective multi institution.

And can resistance be modulated by specific concurrent targeted therapy? We’ll talk more about that. Characteristics, biomarkers, I already mentioned that.

We’ve seen this, this is just again a snapshot of the remarkable growth that we’ve had. We really were in the desert prior to 2004, and the incredible seminal work done by Dan Petrylak and getting our first chemotherapy to really show a survival advantage. Then we had a six year hiatus until the explosion of therapies in the last five years. With this embarrassment riches as it’s been called, this kind of created a little bit of confusion, but not really. These are very well described therapeutics with distinct mechanism of action, very well recognized and characterized safety profiles, but yet we don’t have a lot of level 1 evidence of how to sequence. I’ll try to give you some thoughts on this and we can certainly talk about it at the panel.

The disease continuum, it’s just remarkable what’s happened in the last five years thanks to trial accrual, great scientific work and the patients who have dedicated themselves to being enrolled in these studies.

Looking back to 2004 to 2009 prior to 2010 look how simple this was. We had ADT and we talked about, and it was shown earlier, certainly in the urology community, we’d be remising and supplementing as Lenny point out, vitamin D and calcium as well as antiresorptives. We certainly can do better there, but we had some secondary hormonal maneuvers, and then we got docetaxel. And that made a really big difference for many of our patients, and also mitoxantrone for palliation, but not as survival benefit.

Bam, fast forward now, look at that and then suddenly here’s where we are. You kind of look at this, this explosion of colors and options. We do ADT, we do bone prevention strategies, and now what can one do and I think that certainly we could have a panel and one could make a case for all three of these strategies to move forward with but we can talk more about that.

Let’s kind of review of where we are on therapeutic by therapeutic. We see here sipuleucel-T, the first immunotherapeutic approved in any metastatic solid tumor, and what you see down at the bottom is the highlighting of what I presented yesterday and this is work done by Dave Crawford and Paul Schellhammer which really shows if you look back retrospectively, at the base quartiles of PSA, patients with lower tumor burden reflective of lower PSAs, their overall survival difference was quite markedly different, again post hoc retrospective analysis. But it goes with the line of thinking that patients who are less immunosuppressed, less tumor burden will do better with immunotherapeutic. I think this will be brought out and validated with the prospect ongoing trials and other immunotherapeutic trials. I think it’s pretty clear that that’s something that we need to be cognizant of.

Key questions for sipuleucel-T. Is it better given early? I would say yes, and that’s certainly been my clinical practice. I don’t believe in giving it post-chemotherapy or later on after multiple other CRPC therapies.

Is it designed to work better later? I don’t think the answer is yes. I think it’s no because there’s more immunosuppression and there’s less time for the immunotherapeutic to take hold. A lot of our other therapies work fairly quickly as long as we’re giving them. Immunotherapeutics need time to unfold.

Are they diminished by precedence like steroids and cytotoxics? Well, I remarked on some of that data using it in combinatorial trials with abiraterone, enzalutamide, and to date in short-term analysis we see that the product characteristics. And I think the same is true when we were looking at PROSTVAC that the product characteristics are not diminished but we need long term efficacy to see that. The doses of steroids are very low dose, and it’s been somewhat murky as to whether or not this will have any impact whatsoever so thus the maybe.

Administration of later agents. Probably not diminished by earlier, but long term evidence is still unfolding in this. We have the PROCEED registry trial which we’re following, we’re have 2,000 patients that we’re monitoring for this.

Resistance modulated by specific concurrent targeted therapies. Well, perhaps ongoing AR pathway signaling characteristics we’ll continue to look at.

And finally, regarding immunotherapeutics, a big challenge as I alluded to yesterday, is we don’t see much PSA modulation so what’s a scalable commercial biomarker? Is it an antigen antibody panel? Is it a particular gene signature? That continues to evolve and hopefully that will occur so we can understand our responder analyses.

We go where the money is, and the money has really as it relates to prostate cancer is the androgen receptor and that’s where some of the great advances have been, and here’s the endocrine access. We talk about paracrine and autocrine accesses as well. And where did we first… first oral to get approved both post and pre-chemo was abiraterone, followed by the work on MDV31 also known as enzalutamide. We have other androgen biosynthesis inhibitors that we’ve looked at. Orenterol or TAK700, which was certainly an active drug but I think further development is in abance [phonetic] because of a recent failed trial. VT464 is an interesting metalloenzyme platform also an androgen biosynthesis inhibitor. Dan and I are very involved in the trial development for that. It doesn’t require prednisone. It may have some interesting advantage with ARV7 but that’s also in trial development.

We have androgen receptor signaling inhibitors, the first one out of the trial development space into commercial improvement has been enzalutamide, now approved both after and before chemotherapy. ARN509 another signaling inhibitor has been shown to be very successful in phase 2 studies. There are phase 3 trials ongoing. Galaterone, being developed by Tokai which is sort a combination simplistically put of an ABSI and an ARSI, it may also have some interesting potential advantages with splice variant populations. And then ODM201, another androgen receptor signaling inhibitor – – presented some of that work at the posters the other night which has its own unique organic chemical structure and has potential interesting advantages and less blood brain barrier penetration. And an earlier phase 2 study showing less fatigue and interestingly, less elevation of testosterone but again also in trial development.

The final overall survival analysis that was presented this year at ESMO by Chuck Ryan for the COUGAR 302 in pre-chemo shows a 4.4 month survival benefit which is really quite remarkable looking at really almost the entire totality of that patient population. The RPFS, a virtual doubling from 16.5 to 8.2.

So where are we with abiraterone acetate? Is abiraterone better given early? I think the answer to that is almost certainly most likely and we see that because of the advantages of that trial, 4.4 months survival benefit, oral drug, very well tolerated.

Designed to work better later in CRPC? Well, it really depends on what you’re giving beforehand. And it depends in what some of the precedence are.

Is efficacy of abi diminished by subsequent treatment? We have really limited evidence of this. There is this classic sort of view right now that if you’re looking at oral agents, abi and enza are the ones that are available, whichever one go second doesn’t do as well as the one that goes first. And that’s the issue regarding precedence.

Can therapeutic resistance be modulated by specific concurrent therapy? Perhaps, but that remains to be seen and we’re certainly looking at various dosages of steroids.

Are there patient characteristics or biomarkers that help match patients and specific therapies? Well, not currently, but again the whole world of looking at splice variants, wild type androgen receptor and better ability to document where those variants are will help us delineate both with abi and enza and other orals coming down the pipe, primary versus acquired resistance.

Here’s the PREVAIL, the overall survival, which is a 2.2 but that was in its first analysis and we’ll see if there will be additional analyses that are presented but certainly landmark again in the prechemotherapy population. Also a dramatic differential in PFS as well, which was highly statistically significant.

So enzalutamide, I think much like abi, same questions given early clearly I think yes, now available pre as well as post-chemotherapy. I think that if we’re going to try to give it later, after a multitude of therapies, it’s probably not going to see the same effect as giving it early as well. And really for purposes of time I think you can go through and look at some of the similar comments I made regarding abiraterone.

Again, one of the biggest questions that’s asked is, do I give one before the other? And we really don’t have any large scale perspective, multi-institutional studies to say which ones should be given before or after. We’re certainly learning more about that in terms of both splice variants as well as potential issues regarding testosterone and other ligand levels.

Dan did a wonderful job of presenting this. I’ll go through this pretty quickly. This is the landmark work that he did, and Ian Tannock as well, in giving us chemotherapy.

But at eight years later and this is just one snapshot of one of those concomitant trials, and as the overlay and the unfortunateness of all the couple of trials, none of them have worked, and it’s with rather great disappointment that that’s happened. And it certainly could be because of limitations in dosaging or potential limitations in our inclusion/exclusion criteria, but sufficed to say we’ve never developed a cuplar [phonetic] trial with docetaxel that’s been beneficial as of yet so there’s a graveyard of failed studies along the way. It doesn’t mean that we won’t eventually find one but it’s certainly looking less promising, maybe it’s going to be with cabazitaxel.

This as Chris Sweeney has presented at ESMO, I think this is just an unbelievable find. This certainly is game changing and despite the fact I don’t think it’s in anyone’s guidelines yet, it certainly is in my practice that patients who present with androgen sensitive metastatic disease, high volume for sure, four more bone lesions and/or visceral disease are getting started on six cycles of docetaxel chemotherapy at the 7 mg/m2 dose. Seventeen month median overall survival is compared to the control arm is rather impressive to say the least.

And that’s what this slide pretty much summarizes. We don’t yet know if low volume disease will have the same result. Low volume as defined by four, well less than four bone lesions and no visceral metastases. Very well tolerated, younger patient population, six cycles and I think it really is a game changing trial.

The key questions on docetaxel, is it better given early? Well, I think undoubtedly it’s a resounding yes as the CHAARTED study showed you in those newly diagnosed patients. And as Dr. Letran showed in the Philippines, it may be upwards of 50% of his population. That’s certainly true for areas in Asia and Middle East, Eastern Europe, and the U.S. in North America and Western Europe we see 5% to 10% of our patients presenting this way.

Is docetaxel designed to work better later? Possibly. But it’s mostly used in symptomatic patients and one can argue in good performance status patients with really aggressive parameters, we are potentially doing a disservice by not giving it earlier.

Is it diminished by subsequent treatments? There’s limited evidence. There’s certainly very interesting evidence coming along now that giving abi and enza before may further diminish the effects of docetaxel because of its use or potential mechanism of action on androgen receptor translocation. There’s some additional work being done in cabazitaxel which may show it to be a better agent in that particular state.

Are there patient characteristics or biomarkers that help match? The answer is no, we can look at CTCs and I certainly do look at them, and we see when they’re present and they’re not always present in advanced prostate cancer patients, but when they are present and they are above typically 7 per serum aliquot, and then you see that declination, that’s a good prognostic sign.

Here’s the TROPIC trial that Dan showed you earlier, Oliver Sartor’s work and Johann de Bono, which that clearly demonstrates a survival benefit in patients who progressed after docetaxel.

Is cabazitaxel better given earlier? Well, earlier than docetaxel. There’s a phase 3 trial, the FIRSTANA which many of us have participated in that style has completely accrued and the readout for that is pending. That’s a head-to-head to trial of different dosages of cabazitaxel versus docetaxel.

Is it designed to work better later in CRPC or not? It’s designed for docetaxel resistance as Dan explained but it might possibly be better at first line. There’s interesting less neuropathy with cabazitaxel versus docetaxel which may give some additional clinical advantages.

Diminished by subsequent treatment? We still have limited evidence there. Diminished by the precedents? Perhaps, but there’s some, as I said earlier, some single institutional work that’s being published in European Urology at – – demonstrating that patients who have been on extensive doses of abi and enza actually have some very good responses to cabazitaxel.

The OGX trial, unfortunately is a failed study which was disappointing, and for docetaxel we’re certainly waiting for it on cabazitaxel and hopefully it will prove positive.

ALSYMPCA, Dave did a great job in reviewing that so this really came on, it’s give us another unique mechanism of action for our therapeutic armamentarium clearly with a survival benefit both before and after chemotherapy in a broad spectrum of patients with symptomatic bone metastases. What we see at least in the post hoc analysis was a 4.6 month survival benefit prior to chemotherapy, 3.1 post-chemotherapy. Very good tolerability on both sides of that distribution.

Is it designed to work better later in CRPC or not? Well, it’s designed for patients with symptomatic bone metastases but before visceral metastases. I think that’s probably still a pretty good recommendation, and I think most of those patients certainly with liver metastases will benefit more significantly with chemotherapy regimens.

Is the efficacy diminished by subsequent treatment? Probably it’s not because of its obvious clear distinct mechanism of action, completely different from everything else that’s there. But we still have limited evidence. Combinatorial strategies and studies are still fairly limited in terms of published information. I think anecdotally clinically it’s being used almost invariably in combinatorial strategies with either abi or enza and we’re working on an open label safety study in both of those two to get that into the peer review literature.

There’s no evidence to suggest it’s diminished by bisphosphonates or denosumab. It is contraindicated with cytotoxic chemotherapies. There’s a trial going on by Mike Morris at Sloan Kettering looking at a dose reduced docetaxel with concomitant radium-223.

Are there patient characteristics or markers that help match patients and specific therapies? Yeah, I think we’re seeing that there’s some very provocative alkaline phosphatase data especially when it’s elevated which really speaks to a biomarker use for radium-223.

Here are the expanding treatment guidelines. It’s busy, but we’re certainly the nice thing about the NCCN is they update them on a regular basis, clearly annually and sometimes semi-annually. One can see all the different recommendations from level 1 evidence to slightly less, and the potpourri of things that we can use. The big challenge is really coming to grips with judging the clinical parameters for the patients. That was the first slide I really presented to you as well as looking at the therapies that are all now approved.

Here’s the AUA CRPC guidelines. It goes to the M0 patient, I’m sorry, this is probably hard to read in the back, but we go to the next index case to patients who are asymptomatic to minimally symptomatic, M1. Then there are the poor performance patients versus good performance patients, and then finally patients prior and after chemotherapy. But for someone wanting to take a start at all this, it really I think they did a great job. Mike Cook [phonetic] and Steve Freedland, others who were on that committee, to look at what the evidence was. It’s very similar basically to the NCCN in terms of saying, okay, what does the literature support and how can I sort of codify into different buckets, various case presentations?

Let me bring this back over here and here’s again your potential sequencing options for patients with metastatic CRPC in today’s date. We do ADT, we do antiresorptive therapies, supplementation, making sure we’re trying to avoid issues of osteoporotic fractures. One can choose these various schemas. It’s still–there certainly each one is respectable and allowable at this point in time. I think on the very green at the very bottom should be cab or enza or abi across the board. I think as we move forward, we’ll have various options that and new approved therapies, new immunotherapeutics, additional oral oncolytics that will certainly make this even more fruitful, and hopefully not at the same time cause confusion. But I think if you look at this and you kind of digest this, you could probably make your own case for individual presentations of patients that you see in your clinic who you might see advantages and disadvantages of any one of these three algorithms.

So preferred therapeutic sequencing? The CHAARTED trial clearly shows an early benefit. I think there’s no doubt about it that that should leapfrog and get in there early. I’m a big proponent of sipuleucel-T and all immunotherapeutics to give them as early as possible when there’s less immunosuppression. There’s the issue them next to proceed and at what point in time abi versus enza. Both are excellent oral therapeutics. Then we have a little bit of a conundrum about giving radium-223, Xofigo earlier versus later. In my clinic, we’re giving it earlier for patients once they have symptomatic bone metastases. Docetaxel, an excellent drug, has great benefits and we’ll wait to see what happens with cabazitaxel, whether or not it will leapfrog. Mitoxantrone is still available and still of use in patients who are end line who are suffering and have particular issues of pain palliation. If that head-to-head trial is positive, then cabazitaxel should leapfrog docetaxel potentially in that head to head study, and possibly because of its better use in ARV7 uses. Caboxantinib, actually that trial came and failed and unfortunately I don’t know whether further trial development would go with that.

Here’s just a summary of where we are, broad array level, is not clear of the sequencing. I tried to give you some goals over here. But at the bottom line is really the last bullet is as we get additional evidence, it will allow us to involve our sequencing instead of just using a sort of a gunshot approach.

Chen Y, Clegg NJ, Scher HI. Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target. Lancet Oncol. 2009 Oct;10(10):981-91.
http://www.ncbi.nlm.nih.gov/pubmed/19796750

Choueiri TK, Ross RW, Jacobus S, et al. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol. 2012 Feb 10;30(5):507-12.
http://www.ncbi.nlm.nih.gov/pubmed/22184381

Crawford ED, Eisenberger MA, McLeod DG, et al.
A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989 Aug 17;321(7):419-24.
http://www.ncbi.nlm.nih.gov/pubmed/2503724

de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010 Oct 2;376(9747):1147-54.
http://www.ncbi.nlm.nih.gov/pubmed/20888992

de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-2005.
http://www.ncbi.nlm.nih.gov/pubmed/21612468

Fizazi K, Lipton A, Mariette X, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol. 2009 Apr 1;27(10):1564-71.
http://www.ncbi.nlm.nih.gov/pubmed/19237632

Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010 Jul 29;363(5):411-22.
http://www.ncbi.nlm.nih.gov/pubmed/20818862

Kohli M , Tindall DJ. New developments in the medical management of prostate cancer. Mayo Clin Proc. 2010 Jan;85(1):77-86.
http://www.ncbi.nlm.nih.gov/pubmed/20042563

No authors listed. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. The Leuprolide Study Group. N Engl J Med. 1984 Nov 15;311(20):1281-6.
http://www.ncbi.nlm.nih.gov/pubmed/6436700

No authors listed. Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): results of phase III PREVAILstudy. Clin Adv Hematol Oncol. 2014 Apr;12(4 Suppl 11):3-4.
http://www.ncbi.nlm.nih.gov/pubmed/24870254

Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013 Jul 18;369(3):213-23.
http://www.ncbi.nlm.nih.gov/pubmed/23863050

Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1513-20.
http://www.ncbi.nlm.nih.gov/pubmed/15470214

Rathkopf DE, Smith MR, de Bono JS, et al. Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302). Eur Urol. 2014 Nov;66(5):815-25.
http://www.ncbi.nlm.nih.gov/pubmed/24647231

Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002 Oct 2;94(19):1458-68.
http://www.ncbi.nlm.nih.gov/pubmed/12359855

Schellhammer PF, Chodak G, Whitmore JB, et al. Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. Urology. 2013 Jun;81(6):1297-302.
http://www.ncbi.nlm.nih.gov/pubmed/23582482

Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012 Sep 27;367(13):1187-97.
http://www.ncbi.nlm.nih.gov/pubmed/22894553

Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996 Jun;14(6):1756-64.
http://www.ncbi.nlm.nih.gov/pubmed/8656243

Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1502-12.
http://www.ncbi.nlm.nih.gov/pubmed/15470213