Carducci Recommends Weighing QOL, Survival Benefit When Selecting Therapy for Second-line or Later CRPC

Michael A. Carducci, MD

Michael A. Carducci, MD, AEGON professor of Prostate Cancer Research, Johns Hopkins University School of Medicine, associate Cancer Center director for Clinical Research, and Regional Research director for the National Capital Region, Johns Hopkins Sidney Kimmel, Comprehensive Cancer Center, provided recommendations for treatment of a 75-year-old man with castrastion-resistant prostate cancer (CRPC) during a Targeted Oncology Case Based Peer Perspectives event.

Targeted Oncology™: Would you recommend the addition of an osteoclast-targeting agent?

CARDUCCI: I tend not to use them this early.The disease is metastatic and castration resistant. I’m a believer that most of the therapies that we’re going to start with, when you look at their background and labels, also reduce skeletal-related events. If they’re more symptomatic or one of the fi rst-line therapies don’t work, that’s when I start adding the [osteoclast-targeting agents].

For first-line therapy for metastatic disease, what would you next offer to this patient?

If I’ve already used docetaxel in the hormone-sensitive group,I [wouldn’t] go right to docetaxel at this point based on his relatively low-volume, manageable pain. I would pick one of the hormone agents to move to next.If they’re physically well and have time to squeeze in sipuleucel-T [Provenge], I do it; but my sense is that data suggest that they’re not going to have a drop in PSA.You’re going to need to have a backup [plan]. They’re going to progress by PSA and it doesn’t really delay the time until your next therapy,\ so you almost have to have what you’re going to do next [lined] up if you use it.But if they’re physically well and can go through the process, I think the sipuleucel-T makes sense up front.I would pick between abiraterone acetate [Zytiga] and enzalutamide [Xtandi].

What would you do next for a patient such as this?

Now that he’s progressed after having had enzalutamide and 4 doses of docetaxel, [I would consider] doing a test for molecular sequencing to see if they have a DNA repair [deficiency] or MSI [microsatellite instability]. I think that’s a reasonable approach, knowing about 20% to 25% of patients may fall into that category—more of the DNA repair deficiency rather than the MSI-high category for prostate cancer.

I do test it a bit earlier just so I know....If the patient is progressing multiple times, I might get new tissue to see if it changes.But for the most part, it’s something that I’ve already done earlier, at least germline testing, if it’s available.

If you’re going to...use abiraterone and you want to know... their likelihood of benefitting from it, AR-V7 [androgen receptor splice variant 7 test] may help you with that.A negative result [means] that abiraterone may work; if the AR-V7 is positive, then you know that it’s less likely to work at all. Some folks use that as a decision if it’s a test that you can get in your clinics.

Radium 223 [dichloride (Xofigo)] could be an option in this gentleman.He has adenopathy. The label says you can go up to 3 cm pelvic as long as it’s growing at a slow rate because radium 223 is not going to target that.

Really, you are left with the decision between abiraterone or cabazitaxel [Jevtana] for this patient using approved labels rather than moving to some of the other agents based on certain circumstances^.1

What do you think about cabazitaxel for a patient who poorly tolerated docetaxel?

There are different toxicities, less neuropathy with cabazitaxel but more issues with blood counts [versus other options in this setting].We know how to handle that with growth factor support.

Which data led to the approval of cabazitaxel in this setting?

The CARD study [NCT02485691], and this was published in the New England Journal of Medicine² and presented last year at the European Society for Medical Oncology 2019 Congress.³ This was a study that took men with CRPC who, in the past 12 months, had progressed on a prior androgen receptor– targeted agent and could have had docetaxel. Some of that may be related to timing and hormone-sensitive disease. They were randomized to cabazitaxel at 25 mg—that was the starting dose that was recommended in this study—or to the other hormonal agent that they did not receive [in a prior line of therapy]. If they had abiraterone before, then they were randomized to enzalutamide. If they had enzalutamide, they were randomized to abiraterone. Radiographic progression-free survival [rPFS] was the primary end point, with a number of secondary end points.

Prostate cancer is a disease of the elderly....Greater than 35% of the patients who went on this study were [older than] 75 years of age.Knowing that you can give this agent in these elderly individuals, there’s a slight difference in how patients were processing their pain or how they were presented [on scans].There were more patients who had M1 disease in the abiraterone or enzalutamide arm [47.6%] versus cabazitaxel [38.0%]. In the first line, 43% had abiraterone and 55% [had] enzalutamide in the cabazitaxel arm.

Looking at the primary end point, there was a statistically significant difference in radiographic PFS [rPFS] with a hazard ratio of 0.54 [95% CI, 0.40-0.73; P < .0001] favoring cabazitaxel, so a 46% reduction in risk for progression on scans. For cabazitaxel, the median rPFS was 8.0 months, and for abiraterone/enzalutamide, it [was] 3.7 months.

If you look at rPFS on the forest plot [for preplanned subgroups], it favors cabazitaxel whether the patients are older, have visceral [metastases];in all cases, it seemed that the cabazitaxel arm had an improved outcome for rPFS.

[For] overall survival, the P value is significant, and there is a 37% reduction in the risk of death [HR, 0.64; 95% CI, 0.46- 0.89; P = .0078].The difference in survival for cabazitaxel was at 13.6 months versus 11.0 months for the abiraterone or enzalutamide. This is second- and third-line disease, so when you’re talking about a patient’s survival being in the range of 11 to 14 months, we’re favoring cabazitaxel in this one.

PFS by different measurements, not just radiographic, showed a 2-month difference [4.4 months vs 2.7 months; HR, 0.52; 95% CI, 0.40-0.68; P < .0001].

If you look at all the secondary end points, more patients responded with PSA declines, objective tumor response in those with measurable disease, and pain responses, which were all more significantly improved. The time to a second skeletalrelated event was lower for the cabazitaxel group. In this case, [there was a] a fairly clear difference between starting second-line chemotherapy versus second-line hormonal agents.

More patients did have to discontinue the therapy they were assigned with cabazitaxel [19.8%] versus [8.9%] for abiraterone/enzalutamide.

What were the effects on quality of life (QOL) with cabazitaxel?

[QOL] was the same throughout the study.If you [compare] cabazitaxel versus abiraterone/enzalutamide, you can see that [probability of deterioration] stays stable throughout.From those perspectives, they are equal in terms of their benefit and in quality of life.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 2.2020. Accessed July 15, 2020. https://bit.ly/30gVbHR}

_{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):25062518. doi:10.1056/NEJMoa1911206}

_{3. de Wit R, Kramer G, Eymard J, 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}