Roundtable Discussion: Dreicer Speaks to the Importance of Therapeutic Sequencing in mCRPC

During a Targeted Oncology™ Case-Based Roundtable event, Robert Dreicer, MD, MACP, professor of Medicine and Urology at the University of Virginia School of Medicine, as we as the section dead in Medical Oncology, associate director for Clinical Research, and deputy director, University of Virginia Cancer Center, and codirector, Paul Mellon Urologic Cancer Institute in Charlottesville, VA, discussed the case of a patients with metastatic castration-resistant prostate cancer with a group of peers.

APOSTOLOVA: Since his cancer is metastatic and castration-resistant, I would add denosumab or other bone agents.

DREICER: [If someone were to choose] abiraterone [Zytiga], can you give us a sense of why you would pick it over enzalutamide [Xtandi]?

SANDHU: I typically go for abiraterone because of the central nervous system effects that we see sometimes with enzalutamide. A lot of our patients are older; [I am concerned about the] risk of falls.

Also, comfort level: Most of the time, I’ve used abiraterone in the frontline setting. It was approved before enzalutamide.

DREICER: How about some BIERENBAUM: I generally prefer enzalutamide. I think the lack of need to coadminister with steroids is helpful. We’ve generally found it to be a bit better tolerated, although I don’t see a drastic difference.

DREICER: Obviously, there’s no right answer, so those are absolutely appropriate reasons.

DRIECER: [The National Compre-hensive Cancer Network guidelines] provide you the ability to pretty much make any judgment based on evidence; there’s certainly no right or wrong answer here.1 Let’s assume for the sake of argument that you are seeing a patient with mCRPC and they’ve received no prior therapy. So all things are on deck in terms of your ability to make a choice. And the patient is symptomatic, mildly, like this patient—so, not drastic. What would drive you, as a clinician, to use docetaxel [Taxotere] in lieu of either abiraterone or enzalutamide?

EFIOM-EKAHA: I would look at the volume of disease. I think in patients who have very high volume, especially visceral disease, I may go in with my 6 cycles of docetaxel and then sequence that with enzalutamide thereafter. I wouldn’t do it concurrently because that’s probably not a good idea. I think for low-volume disease, I’d be OK going with enzalutamide alone.

DREICER: This gentleman did have next-generation sequencing done. There were no actionable mutations.... Obviously there are some clinical factors there, performance status, overall fitness; in addition to that, comorbid conditions, patient preference, etc.

Can a colleague who opted to cross over to abiraterone and prednisone share their rationale?

ROTKOWITZ: I’m thinking it’s a marathon, not a sprint, and I’m trying to sequence all my agents accordingly. I would definitely evaluate for the biomarkers, as noted, for microsatellite instability high. I’d definitely look for the ability the use a PARP inhibitor, at least, if not now, then further down the line. But with the neuropathy, I would be a little concerned about a secondary taxane, and—with a minimal burden of progression of disease—consider exhausting all my androgen receptor inhibitors before moving on to another type of systemic chemotherapy.

DREICER: Fair enough. Can a colleague who picked cabazitaxel [Jevtana] share their rationale?

EFIOM-EKAHA: I picked cabazitaxel. It is relatively well tolerated, and I think it would be a reasonable option. I don’t favor using abiraterone after enzalutamide. But I think there may not be a lot to gain with the sequencing of the secondary drugs. This patient’s disease is progressing, and so I would go straight to alternate chemotherapy.

DREICER: [Overall survival (OS) data from the CARD trial showed that the hazard ratio for death with cabazitaxel vs androgen signaling–targeted inhibitor was 0.64 (95% CI, 0.46-0.89; P = .008), with] an improvement in OS of [approximately] 2.5 months in patients receiving cabazitaxel as opposed to an androgen receptor inhibitor.2 The progression-free survival data also favor cabazitaxel.The PSA, objective tumor response, pain response, and time to symptomatic skeletal events data favor cabazitaxel.^3,4

Grade 3 or greater adverse events were similar in both groups, and treatment discontinuation was twice as high in the cabazitaxel arm.² Adverse events leading to death [were] actually higher—but probably not statistically so—in the androgen receptor inhibitor group. Two validated quality-of-life metrics also suggest a benefit with cabazitaxel.⁵

DREICER: One other thing about the CARD trial that’s important to point out: We all see patients who’ve had surprisingly long responses to these drugs, right? So when people ask me: “Do [you] always sequence in a patient whose disease has blown through an androgen receptor inhibitor? [Are you] going to go to cabazitaxel?” My answer is, “What happens if the patient has been on abiraterone for 3.5 years and now they’re progressing?” I’m a lot more likely to use enzalutamide because it’s an androgen receptor inhibitor phenotype.

But in this study, the patients had to progress within a year, so they did not have long-term response. So—in a sense—they’re cherry-picking a group in which maybe this is not the way to go for these patients. This isn’t definitive; it’s just to look at the data. In prostate cancer, there’s so little level 1 evidence with sequence, we at least need to know what it is, whether or not it always [affects] our practice.

DREICER: [Let’s discuss] your general experience with cabazitaxel in terms the major [adverse] effects. Is there something specific about cabazitaxel that you talk to your patients about or that you and your team spend time worrying about?

JI: The only thing is the myelosuppression. We learned that, as you pointed out earlier, we don’t have to go to the full dose. I tend to pick up a moderate dose, and then next time, if the marrow reserve is there, I increase the dose a little bit. It’s a palliative treatment, after all.

DREICER: One of the things that we know about essentially all the diseases we treat, but certainly prostate cancer, is that it is very heterogeneous. I’m a urologic oncologist, but I used to treat breast cancer—for a while, until it got really complicated, you knew what the sequence was.

There were 4 things and you did them in a row. Prostate cancer has never been that way. As heterogeneous as breast cancer is, I think prostate cancer is actually more heterogeneous. One of the challenges [to] keeping up with this disease is that you can’t just build on a sequence. We all start with testosterone suppression. But beyond that, now you intensify testosterone suppression in most patients. When the patient develops castration-resistant disease, there are a bunch of approved therapies and you can use essentially all of them immediately.

How do you make choices when you don’t have evidence? This is the challenge. The CARD study is at least a little bit of data [saying] that if a patient fits into the criteria of that trial—and many patients do—you know that you probably will get better bang for your buck in survival benefit by using cabazitaxel. But that’s all it is. It’s not an absolute requirement that every case is managed that way.

_REFERENCES:

_{1. Schaeffer E, Srinivas S, Antonarakis ES, et al. NCCN Guidelines Insights: Prostate Cancer, Version 1.2021. J Natl Compr Canc Netw. 2021;19(2):134-143. doi:10.6004/jnccn.2021.0008}

_{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. de Wit R, Kramer G, Eymard JC, et al. CARD: randomized, open-label study of cabazitaxel (CBZ) vs abiraterone (ABI) or enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2019;30(suppl 5):v851-v934. doi:10.1093/annonc/mdz394.040}

_{4. Fizazi K. Pain response and health-related quality of life analysis in patients with metastatic castration-resistant prostate cancer. Poster presented at: Genitourinary Cancers Symposium; February 13-15, 2020; San Francisco, CA. Abstract 16.}

_{5. 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, open-label, phase 4 study. Lancet Oncol. 2020;21(11):1513-1525. doi:10.1016/ S1470-2045(20)30449-6}