Approaching Therapy for mCRPC

Jorge A. Garcia, MD, FACP: If the question is how we decide which of the 4 buckets to use—oral therapy, immunotherapy, cytotoxic, or radiopharmaceuticals, in no particular order—you’ll find different pockets of practice in North America. I would argue that if this patient was seen in a urology-driven practice and was not seen by a medical oncologist, this patient could in fact actually be started on sipuleucel-T and then sequenced down the road to an oral agent. It’s fair to say that although the challenge of using sipuleucel-T in men with metastatic castration-resistant disease is the lack of PSA [prostate-specific antigen] reduction for most patients or serological response and the lack of objective disease measurements—meaning that we don’t know if sipuleucel-T can actually impact. But we do know that one should expect to see radiographic improvement when you use sipuleucel-T in the context of that patient population.

But at the end of the day, the primary outcome of that data was survival benefit. I would not be opposed to the use sipuleucel-T for someone in that castration-resistant setting. The concern for me personally about using sipuleucel-T for this particular patient is 2-fold. No. 1 is his Gleason score—he has high-grade disease. No. 2 is his time from initiation of ADT [androgen deprivation therapy] until he developed castration-resistant disease to me is a bit too short. That actually is almost less than 9 months when the patient actually started developing serological progression and ultimately developed objective progression. I’m not sure this, in my opinion, would actually be the right or the ideal patient in my personal practice to start sipuleucel-T right off the bat. I would probably use sipuleucel-T for someone who has a bit more of an indolent disease nature.

That brings me to the question of prognosis. How do I know how patients will do when they develop castration-resistant disease? Well, it is fair to say that in the contemporary data that we have right now in the United States and throughout the European system as well—universally, I should say—is very clear. We now have very compelling and contemporary data that allows us to actually allocate patients to the median survival when they walk in the office with metastatic disease. We have plenty of data with the STAMPEDE and CHAARTED trials. We also have the data with the TITAN and ENZAMET trials.

Data with LATITUDE trial clearly demonstrated that if you walk in the office with metastatic disease and you receive ADT alone, androgen suppression therapy—which is obsolete for those patients today, in 2020—the median survival for those patients is around 44 months. If you start segregating patients by high or low volume, those numbers obviously tend also to be a bit different—high volume more aggressive, low volume less aggressive. Therefore, survival tends to be longer.

But if you look at the median outcome for most patients in the castration-resistant space, it really depends on the presence or absence of metastatic disease and also the presence or absence of symptomatic disease. We have neat statistical tools that can be utilized for patients or can be used by patients in this context. We have the Susan Halabi nomogram and the Memorial Sloan Kettering Cancer Center nomogram, so clearly we are actually using patients’ features to make that set of decisions as to how you can counsel a patient for prognosis. Also, we would be using laboratory features such as albumin, hemoglobin, Gleason, and so on to give you a census to how people will do over time.

The truth of the matter, sadly, is that men who develop metastatic castration-resistant prostate cancer, with the best data that we have, have a median survival of 3 to 5 years. We are pushing the envelope a bit more these days, obviously with the advent of so many new agents. But the reality of it is if you look at existing data with PREVAIL, with COU-AA-302—DOCE [docetaxel] and CABAZI [cabazitaxel] might have been a bit obsolete today. But there are compelling data right now, and some contemporary for that matter, demonstrating that most patients when they develop castration-resistant disease—especially if he’s symptomatic and objective in nature—will have a median survival of 3 to 5 years.

You do want to make the best of your time. That’s why understanding the right patient phenotype, understanding the right and the most appropriate treatment option sequence for your patients, is so important. Sadly, the data that we have thus far have never sequenced patients in that context, with the exception of 2 recent contemporary trials, 1 in the European region and perhaps actually the data with PARP inhibitors that clearly demonstrated that in a metastatic castration-resistant prostate cancer space, the sequence for an oral agent No. 1 to an oral agent No. 2 is not ideal.

If you think and go back to this particular patient, and if you start with an oral agent such as enzalutamide or abiraterone acetate, most of us—at least in my practice with existing data—I would not sequence the patient back to an oral agent. Simplistically speaking, if you receive ENZA [enzalutamide] and you progressed, I would not put you on ABI [abiraterone] or vice versa. I would change mechanistically what I do for you. The bigger question becomes, if he gets an oral therapy and he progresses, what would be a sequence to follow? it depends, at least in my personal opinion and in my clinical practice, on how symptomatic you are and whether you really need rapid control of your disease. In this case, hypothetically, if he had progressive disease on an oral agent and he’s developing rapid symptomatic progression, I just don’t think you have the time to invest on 6 months of radium 223 dichloride to control pain and rapid symptomatic control even though it’s effective in nature. Chemotherapy would be in my practice the best option for this patient.

Lastly, if you have the opposite, if you have a patient who’s progressing on a slow and indolent manner, then you have the wiggle room to say, “Well, do I put you on chemotherapy? Or do I put you on a radium 223 type of approach?” It is unfortunate that we have sometimes no head-to-head trials, and oftentimes we are left at the discretion of how we interpret this data, how we practice clinically.

The reality of it is that if you were to actually allocate or explain to a patient, “I’m going to put you on chemotherapy,” or “I’m going to put you on radium 223,” and I explain to the patient how these agents work and also what is the adverse-effect profile of these agents, anybody will pick radium-223. You don’t have the degree of nausea, you don’t have the significant risk for suppression of your hemoglobin, neutropenia, febrile neutropenia for that matter, alopecia, neuropathy, and so on. I’m not saying that you can compare across trials. I’m just simply telling you that if you think of that approach, that in my opinion is not the appropriate approach.

In fact, if you look at the ALSYMPCA data, the median number of cycles given on ALSYMPCA was actually 6 cycles. That’s 6 months, IV [intravenous] given every 4 weeks between radiation oncology and nuclear medicine, it depends on where you practice in the United States. There are different pockets who actually use these agents. I’d like to believe that it’s orchestrated or quarterbacked by a medical oncologist who is the clinician taking care of the patient who understands when to stop, when to continue, when it’s time to scan, or when it’s time to actually move on to something else. But if you make that decision and you have a patient who you believe you can actually at least give him 4 cycles of radium 223 dichloride and you don’t need rapid control of his symptomatic progression, then that will be the type of patient that would probably be in line to actually offer him radium 223 dichloride instead of the predocetaxel space.

It’s very important to remind the audience as well that ALSYMPCA did not allow patients with visceral metastases. Also, it certainly did not allow patients with bulky lymphadenopathy, which in that trial was defined as a greater than 3 cm for lymph nodes. If you really think of that, I would argue that if you have someone with visceral progression, which is very uncommon in prostate cancer, I would argue probably less than 20% of patients we see with visceral disease. But if you happen to have someone with visceral disease in the castration-resistant setting, I would not think of using radium 223 dichloride. I would think more of using chemotherapy, to be transparent with you. Although I would argue that the data with ENZA [enzalutamide] and ABI [abiraterone] could be applicable to those patients, recognizing that 1 of the 2 trials did not allow patients with visceral disease to enroll on the trial.

Transcript edited for clarity.

Case:A 69-Year-Old Man with Advanced Castrate Resistant Prostate Cancer

Initial presentation

• A 69-year-old man presented with intermittent back discomfort and loss of appetite
• PMH: hyperlipidemia controlled on a statin, no known family history of cancer
• PE: DRE revealed asymmetric, boggy prostate; otherwise unremarkable

Clinical Workup

• Biopsy with TRUS showed adenocarcinoma of prostate
  • Stage T2N0M0
  • Grade group 4
• Germline genetic testing: MLH1, MSH2, MSH6, PMS2, BRCA1/2, ATM, PALB2 and CHEK2
• Chest/abdominal/pelvic CT scan showed no evidence distant metastases or lymph node involvement
• Bone scan was negative
• PSA 24.9 ng/mL

Treatment and Follow-Up

• EBRT + ADT was started
• Follow up at 6 months, PSA 11.2 ng/mL
• At 12 months PSA 18.6 ng/mL
  • Patient reported increasing back discomfort and difficulty walking
  • Bone scan at that time showed multiple vertebral lesions at L3/L4
• Treatment with radium-223 dichloride was initiate
  • 6 infusions were completed, treatment was well tolerated