Dr. Neal D. Shore spoke at the 24th International Prostate Cancer Update on Saturday, February 22, 2014 on “Multimodal Treatment of mCRPC: Potential Sequencing of New Agents.” In his presentation, Dr. Shore discusses multimodal treatment options, new agents, and the need for more data.

Presentation

Keywords: abiraterone, mCRPC, radium-223, enzalutamide, therapies, prednisone, sipuleucel-t, docetaxel, cytotoxic chemotherapies

How to cite: Shore, Neal D. “Multimodal Treatment of MCRPC: Potential Sequencing of New Agents.” Grand Rounds in Urology. January 22, 2015. Accessed Aug 2019. https://grandroundsinurology.com/prostate-cancer-neal-d-shore-multimodal-treatment-of-mcrpc/.

Transcript

Multimodal Treatment of mCRPC: Potential Sequencing of New Agents

Okay, so a lot of what I’m going to present, much of it has already been presented very nicely by Dan and Peter Mulders and Lenny Gomella so I will kind of skip through those parts and just try to give some areas of controversy and areas of unmet need. This is courtesy of Bill Owen. We really have gone from having nothing into what many have called an embarrassment of riches, but it has also created a lot of confusion. The sequencing is challenging because we lack a lot of appropriate data, combinatorial data, and even good sequencing data so that is a challenge but it is actually a really good thing. Many of us in this room, hopefully all of us in this room, are going to get involved in those studies so that we get the data and we can have a factual review of level one evidence. I think it is really important, and looking at this complicated slide, for urologists who are attending here to recognize that this is your time. I was talking with Mike Glodé and it’s true that medical oncologists have really led the way in a lot of the pioneering work for these protocols and studies, but that said, if you really want to take care of a patient with advanced prostate cancer, and you don’t look at this as a dalliance but you really look at it as a commitment, it is a wonderful time to expand your clinical center of excellence and help patients. Someone will be at the top of this pyramid and you have to ask yourself, who will that be? The characteristics that we make our decisions on and this is really—if you were to look at the AUA CRPC guidelines, you would see all of these things. There are morbidity issues, there are radiographic issues, there are issues of cost which I haven’t put in here but that is always somewhat of a significant issue. Then there are biomarkers and cross resistance and how are we going to fathom our way through all of this, and combine different mechanisms of action.

Let’s just look about sipuleucel-T or Provenge, you talked about that earlier. You have seen this and here is just a quick summary of its timeline, and its mechanism of action. It is very safe and we know that. It has a unique mechanism of action and hopefully it will be additive. We see this three to five month survival benefit on phase III trials and what we know is it is not a pure additive summary of overall survival benefit but perhaps in certain patients, if we do better selection and biomarker analysis and genetic analysis, we can find who they are. We saw this slide earlier; I think it is extremely compelling despite the fact that it is post – – analysis, especially in identifying patients earlier. The paper that Dave Crawford is the first author on called, “From the RADAR Group,” coming out in urology really speaks to the importance of appropriate timing of our diagnostic radiographic testing in addition to our laboratory parameters, and finding patients early to have the discussion. I think it is really important that we have that ability to have that discussion.

Here is some work that we have done in terms of combinatorial studies—Eric Smalls the first author—and this was looking at combining abiraterone with prednisone and sipuleucel-T and – – the P11-3 trial and what we essentially looked at was if you can give Zytiga abiraterone 10 mg prednisone daily with sipuleucel-T. Long and short of our study, 30 patients in that arm concomitant; two weeks later, the same 30 patients to receive Zytiga two weeks after a course of Provenge. The product characteristics were not altered so you are able to deliver them on the Provenge. Efficacy data is still pending and we’re following those patients out and that is really the long and short here. There is a real need for investigator-initiated studies and they are ongoing, not just with sipuleucel-T, now with enzalutamide but as Dan Petrylak alluded to, other studies with radium-223 as well.

So the immunotherapy challenges I showed you on an earlier slide are present for review so I won’t go over this too much except to recognize that our historical understanding of therapies may be different from therapies that have a more static or dampening progression. I think that is an important clinical construct that we need to be aware of. The check point inhibitors are very, very hot items right now not just in prostate cancer, but in lung, skin, kidney, GI and we are going to see a lot more of these checkpoint inhibitors, whether it is where the PD1, program cell 1 or ligand 1. The thing about combining them together and sequencing them is going to be very, very important. How do we take a checkpoint inhibitor where we take our foot off the break, so to speak, and avoid the systemic reactions that those can cause; we don’t want that to have those toxicities, those somewhat autoimmune-type related toxicities of the GI tract, the skin, and endocrine, and even liver issues, and combine those with an active immunotherapeutic such as Prostvac and Provenge. Again, cost will certainly be an issue but if we can ultimately design that combinatorial strategy that will be particularly interesting for certain patient subgroups.

You have heard a lot about abiraterone; here is just a simple summary slide. It is an oral drug, now approved in both pre- and post-chemotherapy, and it clearly has a well-described mechanism of action. The 302 which allowed for approval of abiraterone in December of last year is just a little over a year out and so there is always some period of adoption that has to occur. How can we combine this drug with other therapeutics? Does the 5 mg prednisone b.i.d. have an impact? I alluded to the fact that some are not using b.i.d., some are using lower dose or no dose at all and I think that has to be further documented and well described, as well as even taking it potentially with food or without food. The label right now says you take it without food in a non-fed state with 10 mg b.i.d. Enzalutamide just released its fascinating data that has already been presented here now; it just came out just a few weeks ago with GU ASCO.

I will go through my next few slides quickly and I put together some tables to sort of compare and contrast the data of the 302 and the PREVAIL. Here is the PREVAIL schema which you have all seen already. It is very similar in concept design to the 302. Here are some of the key study design differences between the PREVAIL and the 302. In terms of control group, the PREVAIL was a placebo, Cougar 302 is prednisone. Visceral disease was allowed in PREVAIL, but not in Cougar 302. There were some mild differences in terms of exclusion regarding hypertension. Some subtle differences but yet real in terms of heart failure allowance and allowance as well for some cardiac arrhythmia in the PREVAIL group. Then of course an exclusion for seizures in patients in the PREVAIL group as well. Some of these issues are going to come into play when people love to ask the question, which drug are you going to use? I think a lot of it, like many things, is you have to individualize it to the patient.

Let’s look at the demographics in the disease characteristics. They are very, very comparable in both studies. You can see as you look along here whether it was the age or some of the performance laboratory values as well, or radiographic findings. Exposure to drug is also fairly comparable. You will see a little bit of a difference between the change in the placebo group versus the placebo prednisone group in terms of progression-free survival and that ultimately, with radiographic progression, probably had some implications as to why you see that difference. Subsequent therapies is becoming a scourge throughout a lot of these trials especially in the western world because we have all this access to these approved therapies which dampen survival in the control arm. So the concept now of hanging one’s hat, I think, on overall survival becomes somewhat muddied and that has to be discussed and looked at a little bit more carefully. We have seen challenges with this. I alluded to it in the last talk regarding the post-chemo trial. We have seen the same problem in the Tak-700 study. When you look at sub-segments that don’t have areas in the world that don’t have exposure to these approved therapies, you don’t see this crossover and thus you see a better result in your overall survival data, or at least a clear separation of the data.

Here is the efficacy data against—I’m trying to make it a little bit clearer to you in terms of the PREVAIL and the abiraterone 302 or the Cougar 302 trial and one can see the PFS , the – – cytotoxic therapy, PSA progression and some additional data that is going to come out. We have presented this previously at AUA in terms of fact-P . Now most of us don’t do fact-P and validated questionnaire and pain scores in the clinic; they are cumbersome and they are too difficult to do but the data is the data. A lot of the third party agencies like to see that for reimbursement purposes but at the end of the day, it really is important in terms of quality of life impact and I think those are things that are going to be further teased out between these two drugs, and I think they are very important.

I found this article Chuck Rine which was a retrospective analysis of a post-chemo abiraterone trial known as the 301; it was very interesting. I put this up here because looking at the baseline testosterone levels, and this again is a post-chemo group CRPC so it had to have a T-level less than 50, if you stratify out and you just tease out the differences in T-levels in the group that received abiraterone versus the group that was in the control, one sees some differences in survival. It goes back to an important theme that Dave Crawford has been championing for years: Number 1, not only check T in your androgen-sensitive patient population but also in your hormone-resistant or your endocrine-resistant population because it certainly can have potential impacts on drug selection. In the pre-docetaxel setting, I just put together some thoughts. I’m sure we will talk about this a little bit more in our panel. Which one do you want to give first? I don’t think there is a really clear answer to this. These are both excellent oral therapeutics. You can see the different lists. Enzalutamide doesn’t require steroids, it can be taken with or without food, and it was less restrictive regarding issues of congestive heart failure. Glucose dysregulation should not come into play. Many have had a lot more experience with using abiraterone first; it is not precluded in seizure patients. Perhaps there are some other neurocognitive issues which one needs to consider. What is the implication for that T-level as it is basically shutting down the ligands T and DHT that ultimately stimulate the androgen receptor.

Combination is clearly very interesting and there has been some great work in that but again, we need more safety toxicity data and of course cost might be of an issue. Regarding cross-resistance, one of the things that my own personal experience has been that whichever one of these two drugs goes first, whether it is abiraterone or enzalutamide, or enzalutamide then abiraterone, clearly the second drug’s duration of efficacy and benefit is somewhat diminished compared to the first. There is no surprise there; they are all working on the androgen receptor access. Here is a series—a compilation of various authors and investigators that looked at PSA kinetics; they looked as if it went first or if Zytiga goes first. They are all small studies and we need larger studies to further compile and really get a handle for this. Part of it is probably going to be access, and part of it is going to be describing and looking at some of those other patient characteristics. Maybe there are some laboratory things we could be looking at. Maybe it is not just T but also some other biomarkers as well, perhaps CTCs, but we certainly need some other help in making those decisions. Again, especially in patients, the second drug tends to take a back seat to the first.

In my conclusion, we need more data. Some of the suggestion appears to be that abiraterone, when given before enzalutamide, that combination again in smaller numbers seems to do a little bit better but we don’t really know and don’t have enough experience to make a solid conclusion about that. In radium-223, and Dan spoke and gave a great presentation on the radioisotopes as well as the antiresorptives, I think this is a wonderful opportunity for both oncologists and urologists to once again expand your treatment horizon. What I love about this product is how well it is tolerated. It is a 45 second infusion and it really has minimal impact on patient quality of life with the exception of low-grade diarrhea in a small number of patients. It appears to be extremely well-tolerated and we are really looking forward to seeing a lot of combinatorial studies especially with the oral agents and how one could use this and fit this into your treatment paradigm to delay more toxic therapies such as docetaxel or cabazitaxel. That said, the cytotoxic chemotherapies still have a strong place and still have a purpose, there is no doubt about it. Here is the ALSYMPCA trial that you have seen already. Here is the KM , the 3.6 month OS , but what I wanted to show you was this next slide, particularly for urologists which breaks down the OS in the patients in the ALSYMPCA, pre-chemo versus post-chemo. One sees a 4.6 month overall survival benefit for patients prior to chemotherapy. One of the key things about it is if you are going to use this is this takes one infusion once a month. A course of therapy is six cycles, so you have to be judicious in trying to find that window of time where your patients are not going to be progressing very rapidly in the middle of that course of therapy and ultimately require, and potentially benefit from docetaxel or eventually cabazitaxel. It is rather interesting to see how well patients did in the pre-chemo therapy arm.

I think Dan really addressed very nicely some of the data that we have in terms of myelosuppression, regarding future use of chemotherapy after radium-223. In terms of prescribing and administering it, it can clearly be prescribed by a urologist or medical oncologist or radiation oncologist. Nuclear med radiation oncologists have to administer it because of the handling of the isotope. Dan brought up another great point: Where will the other antiresorptives fit into this? Will they become obsolete? We don’t know that yet. Will they be additive?
Here is just a list of some other studies the PREVAIL trial has completed. Here are others: We talked about the PROSPECT trial with Prostvac, the pre-chemotherapy trial was pending the post-chemo I told you about. The post-chemo Tak-700 trial has completed. There is a pre-chemo Tak-700 that is also pending. Dan did a great job of talking about chemotherapy so I will move on from that. There are some additional ongoing combination trials. I think this is really one of the most exciting times for us and our patients and I am sure we will hear more about the evolution of these trials next year and in years to come here at IPCU.

Here is an additional list of planned combinatorial trials. Many of these are going to be done through investigator initiated studies by a lot of the folks in this room so it will be interesting to look at that. It is certainly a very interesting, unique molecule. The tasquinimod molecule that phase III trial is going to read out sometime soon. Dan talked about custirsen or Clusterin, the OGX-11 product which could be one of the first and only couplet trials to have an impact so we look forward to seeing that. In terms of sequencing and the M-O or the MCRPC, we don’t have any approved therapies; nothing has been shown in a phase III trial. It is a big unmet need, that M-0 CRPC state. It is potentially a shrinking volume of patients as we improve sensitivity of our diagnostic modality such as the various PET scan technologies. It is potentially reasonable if it is a patient who has a very slow PSA velocity. The secondary hormonal therapies has been clearly shown. I think Lenny showed you slides on that. There has never been phase III date to show an overall survival benefit but they have a class C recommendation in the AUA CRPC guidelines. Phase III trials are now ongoing looking both at androgen receptor signaling inhibitors enzalutamide and ARN-509. We just recently completed the imagine trial and Dave is the first author on that. The PI on that, looking at abiraterone and the M-O space with low dose 5 mg prednisone.

So this is just a schema. It is not etched in stone. I wouldn’t want to suggest—and that is probably why you see arrows going in both directions and I am going to show you another slide here which is a little more up to date. These were possible therapeutic sequencing concepts in early 2013, and one could certainly use patients who have now rising T level, ADT, calcium, vitamin D, supplementation and antiresorptive when appropriate. Immunotherapeutic is potentially foundational and then looking at some of these other possibilities, but now as we move forward and the PREVAIL shot does show a benefit. Will it be concomitant with abiraterone before or after? That is something that is clearly ripe for discussion. Low-dose keto would probably be in areas of the world where abiraterone and enzalutamide are not available. Dan alluded to the trial which is a head-to-head of cabazitaxel with docetaxel. If it were positive, it could become frontline. Radium-223 could fit before and after docetaxel and in our clinical experience, we are certainly more interested in trying to find the right patients who could benefit from pre-chemotherapy. Then we have the approved therapies, and post-chemotherapy as well.

There are a lot of really important questions. This is certainly not an exhaustive list. How do we figure out how to do best by our patients, and not break the bank at the same time? More importantly is to develop other biomarkers and other data to help us make more informed decisions. We have this broad array of options. We have to somehow streamline the confusion. I think I will stop with that. I have just two ARS questions.

Clinical decision making for sequencing CRPC therapies may be undertaken by urologists, medical oncologists, and radiation oncologists; it requires additional combinatorial and head-to-head trials; has significantly evolved over the last three years; we continue evolving over the next three years. All of the above or should be government regulated?

Okay, great. That must be the FDA person in the back of the room and I hope I didn’t violate another—that was Dr. Raford . Okay, next one please. We would have had 100%.
The following are FDA approved for CRPC; this is a little trickier. The following are FDA approved for CRPC: Radium-223, enzalutamide, Prostvac, abiraterone; enzalutamide, abiraterone, tasquinimod, sipuleucel-T; cabazitaxel, docetaxel, radium-223; sipuleucel-T, cabazitaxel, abiraterone, enzalutamide; or none of the above. Part of the challenge with this is these are just the generics. If I put a little parentheses and gave the trade names, it really becomes a lesson in linguistics. That is one of the challenges I think for many of our colleagues.

Okay, fantastic. Most of you guys got that right, thank you.

References

Bellmunt J, Oh WK. Castration-resistant prostate cancer: new science and therapeutic prospects. Ther Adv Med Oncol. 2010 May;2(3):189-207. http://www.ncbi.nlm.nih.gov/pubmed/21789134

Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012 Jun 28;366(26):2455-65. http://www.ncbi.nlm.nih.gov/pubmed/22658128

Brechbiel MW. Targeted alpha-therapy: past, present, future? Dalton Trans. 2007 Nov 21;(43):4918-28. http://www.ncbi.nlm.nih.gov/pubmed/17992276

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.

El-Amm J, Aragon-Ching JB. et al.The changing landscape in the treatment of metastatic castration-resistant prostate cancer. Ther Adv Med Oncol. 2013 Jan;5(1):25-40. http://www.ncbi.nlm.nih.gov/pubmed/23323145

Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. http://www.ncbi.nlm.nih.gov/pubmed/20525992

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

Madan RA, Gulley JL, Fojo T, et al. Therapeutic cancer vaccines in prostate cancer: the paradox of improved survival without changes in time to progression. Oncologist. 2010;15(9):969-75. http://www.ncbi.nlm.nih.gov/pubmed/20798195

Mostaghel EA, Marck BT, Plymate SR, et al. Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res. 2011 Sep 15;17(18):5913-25. http://www.ncbi.nlm.nih.gov/pubmed/21807635

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64. http://www.ncbi.nlm.nih.gov/pubmed/22437870

Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. http://www.ncbi.nlm.nih.gov/pubmed/21639810

Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013 Jan 10;368(2):138-48. http://www.ncbi.nlm.nih.gov/pubmed/23228172

Ryan CJ, Molina A, Li J, et al. Serum androgens as prognostic biomarkers in castration-resistant prostate cancer: results from an analysis of a randomized phase III trial. J Clin Oncol. 2013 Aug 1;31(22):2791-8. http://www.ncbi.nlm.nih.gov/pubmed/23816964

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

Sharma P, Wagner K, Wolchok JD, et al. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat Rev Cancer. 2011 Oct 24;11(11):805-12. http://www.ncbi.nlm.nih.gov/pubmed/22020206

Shore ND. Chemotherapy for prostate cancer: when should a urologist refer a patient to a medical oncologist? Prostate Cancer Prostatic Dis. 2013 Mar;16(1):1-6. http://www.ncbi.nlm.nih.gov/pubmed/22751145

Taneja SS. A multidisciplinary approach to the management of hormone-refractory prostate cancer. Rev Urol. 2003;5 Suppl 3:S85-91. http://www.ncbi.nlm.nih.gov/pubmed/16985956

Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28;366(26):2443-54. http://www.ncbi.nlm.nih.gov/pubmed/22658127

Tran C, Ouk S, Clegg NJ, et al.Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009 May 8;324(5928):787-90. http://www.ncbi.nlm.nih.gov/pubmed/19359544