Efstathiou Explains How She Uses Steroids in Patients With Metastatic CRPC

Eleni Efstathiou, MD, PhD

During a virtual Targeted Oncology Case-Based Roundtable event, Eleni Efstathiou, MD, PhD, associate professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the case of a 75-year-old patients with metastatic castration-resistant prostate cancer (mCRPC).

Targeted Oncology^TM: Have you had issues getting advanced imaging at baseline approved by insurance? How would you have handled this patient?

EFSTATHIOU: It’s getting better. With recurrence I’ve had more luck, but because this is a [case similar to] usually the cases on Medicare, we have the opportunity to do up to 3 [scans]. But you have to pick when you want it. Now that he has mCRPC there is no point, but we might have been able—hindsight is 20/20—to do some advanced imaging in the beginning because he had the pain, or even an MRI with the musculoskeletal protocol for the bones and the pelvis, and we would have seen that he had metastases. We might have introduced enhanced androgen [receptor] signal inhibition, meaning giving him abiraterone [Zytiga] from the beginning, that is now generic, or enzalutamide [Xtandi] or apalutamide [Erleada]. Based on the STAMPEDE data [NCT00268476], we would probably still offer radiation of the primary [tumor] in metastatic disease. These are things that I think will become more mainstream in the future, pending financial resolution.

Which imaging modality would you use?

There is the practical consideration and there is the actual academic medical consideration of what is the best. Right now, it looks that prostate-specific membrane antigen PET is the best when it comes to not just the sensitivity part, because then it would be comparable with fluciclovine; I think it is also more specific. Having said that, we only have 3 institutions that got the FDA approval, which means that practically, at least in Houston, Texas, and the greater area of Houston, we don’t have reimbursement. So I might offer fluciclovine or, to be somewhere between conventional and enhanced, as I suggested for this patient, I would have at least done an MRI of the pelvic bone area where he had [those lesions]. Trying to find what would be more feasible, I have had great success in getting reimbursement for PET fluciclovine for patients over the age of 64 who are on Medicare. For the rest, it has been 50/50 for me but it is getting better. Hopefully, PET will become more available for prostate-specific membrane antigen and we will have access soon enough.

What did you think of these poll results? Can you speak to the steroid use needed for patients given abiraterone?

We have a patient who had mCRPC per conventional imaging oligometastatic; he had a limited response to initial treatment with ADT. Even if we admit that he was metastatic from [the] beginning, he received radiation per STAMPEDE—nothing wrong with that—and received ADT, but he still progressed within roughly a year and a half.

I voted abiraterone. At MD Anderson Cancer Center, even if you have no coverage, right now we have this generic deal for abiraterone that costs $200 to buy it [outright with] no insurance. We have found great deals for the patients, so the coverage is full.

I use 0.5 mg of dexamethasone with abiraterone, and I measure morning adrenocorticotropic hormone—that way I get away with a minimal dose of the steroid. If you go for a generic dose, you may be overgiving the steroid and have the impacts [associated with steroids], which add on to the bone density loss, gaining weight, resistance to insulin. It can be messy.

With enzalutamide, my problem has always been that, especially in men over the age of 75, there is so much fatigue in the central nervous system that it has been concerning. I have not been able to give full dosing.

But either way, I think abiraterone and enzalutamide are within the same mechanism of action, more or less, and docetaxel [Taxotere] is a different mechanism of action. Arguably, there may have been a point for docetaxel because this patient progressed quickly. He may have a more aggressive phenotype. Based on the old data on mCRPC and docetaxel, we could potentially go up to 10 [cycles], or based on the study that was done, we could do chemotherapy holidays. I do it for some patients, 4 [cycles] and then another 4 [cycles] 6 months later, if need be. There is a lot to play with here.

Does this patient’s updated case worry you?

This patient has one of those diseases that become pretty scary because he is showing resistance to enhanced androgen signal inhibition and he is showing resistance to the docetaxel early on.

How do you feel about these polling results?

Nobody would go for abiraterone. I am pleased to see that, really, because we have now established that moving from one agent to the other that is targeting the same mechanism of action may not be the prudent way to go, especially for those who have this type of resistance.

Which trials looked at cabazitaxel (Jevtana) in this patient population?

There was a retrospective report at the 2020 European Society for Medical Oncology meeting that suggested cabazitaxel may also work better in patients who have DNA damage repair mutations.1 It was a big report [with 190] patients.

There [was also the] CARD trial [NCT02485691].² We all know that we shouldn’t go from abiraterone to enzalutamide or from enzalutamide to abiraterone. Guess what? Everyone was going from abiraterone to enzalutamide because we didn’t have real proof that there was this overlap in activity and it was easy to do, especially in urology practice. So even though I thought that this was not a big deal of a trial—in fact, it was really hard to accrue as a trial—not only did it pan out to be an important trial, it got plenary sessions and then went to the New England Journal of Medicine; these were things I did not expect. But it was a great trial because we were able to collect a lot of biomarker data that we are going to be reporting soon. There were not a lot of patients, about 250. There was an effort to do a similar trial in the United States, but it did not accrue.

How was this trial designed?

There was a randomization for those men who had received either abiraterone or enzalutamide to get the [opposite], so abiraterone to enzalutamide and enzalutamide to abiraterone versus being randomized to cabazitaxel with granulocyte colony-stimulating factor support. The full dose, 25 mg, was what we had to initially use and try. The primary end point was radiographic progression-free survival [rPFS]. Secondary end points were overall survival [OS], PFS, PSA response, tumor response, the biomarkers that we are going to follow, and quality of life. Stratification was based on performance status and time to progression from the prior agent that was used.

What was the efficacy in the CARD study?

By using cabazitaxel you essentially double the median rPFS [8.0 vs 3.7 months; HR, 0.54; 95% CI, 0.40-0.73; P <.0001]. It is not that trivial; it is quite impressive, but it was expected.

In the transition from abiraterone to enzalutamide [or vice versa]—within the first 3 months you lose half the patients. Half of your patients are going to progress right through it. They were progressing even with pain and the like. So essentially, for at least half of these patients, transitioning from abiraterone to enzalutamide [or vice versa] would be the equivalent of a placebo. We saw that with the PROfound trial [NCT02987543]. You have to be careful. The only patients that I have seen that this transition works [for] in my practice have been patients who have been on abiraterone or enzalutamide for years and then I transition, and I do some enhanced imaging to find where the progression is, and I add a bit of radiation in the site of the progression. It needs tweaking if you are going to do it.

Regardless, all the groups had benefit [with cabazitaxel], so no concerns there. The OS, even though it was a secondary end point, [showed] benefit with cabazitaxel [13.6 vs 11.0 months; HR, 0.64; 95% CI, 0.46-0.89; P =.0078]. Same thing with PFS [4.4 vs 2.7 months; HR, 0.52; 95% CI, 0.40-0.68; P <.0001].

This is supported by all other secondary end points, including a very important one, the serious skeletal events, which are always our biggest fear [median time to serious skeletal events, not reached vs 16.7 months; HR, 0.59; P =.05].

There was not a huge difference [in toxicity]. There is a difference…but it is not a huge difference, and I would argue that a lot of us will adopt a dose of 20 mg, if need be.

Quality-of-life data, presented and published more recently…suggested that cabazitaxel, even though it’s a chemotherapy, is giving better results with regard to wellbeing and at least does not impose on our patient.³

References:

Aldea M, Lam L, Perez CL, et al. Cabazitaxel (CBZ) activity in men with metastatic castration resistant prostate cancer (mCRPC) with and without DNA damage repair [DDR] defects. Ann Oncol. 2020;31(suppl 4):S507-S549. doi:10.1016/annonc/annonc275

2. de Wit R, de Bono J, Sternberg CN, et al; CARD Investigators. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381(26):2506-2518. doi:10.1056/NEJMoa1911206

3. Fizazi K, Kramer G, Eymard JC, et al. Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel versus abiraterone or enzalutamide (CARD): an analysis of a randomised, multicentre, openlabel, phase 4 study. Lancet Oncol. 2020;21(11):1513-1525. doi:10.1016/S1470-2045[20]30449-6