Garmezy Reviews Efficacy, Safety, and Quality of Life for Cabazitaxel in mCRPC

Benjamin Garmezy, MD

Assistant Director of Genitourinary Research

Sarah Cannon Research Institute

Tennessee Oncology

Nashville, TN

CASE SUMMARY

• A 75-year-old man presented with intermittent left hip pain.
• The physical exam was unremarkable except for a prostate nodule on the rectal exam.

Clinical workup

• Prostate-specific antigen (PSA): 16.2 ng/mL
• Transrectal ultrasound scan-guided biopsy: biopsy Gleason: grade 5 + 4, group 5
• Negative bone scan and abdominal/pelvic CT scan
• X-ray of pelvis indicated osteoarthritis.
• Stage cT2N0M0
• Germline and somatic testing were negative for pathogenic alterations.

Treatment and follow-up

• External beam radiation therapy plus androgen-deprivation therapy (ADT) was initiated, planned for 24 months.
  • Undetectable PSA level at 6-month follow-up; asymptomatic
  • Patient did not return for regularly scheduled PSA follow-up after completion of 24 months of therapy.

Thirty-six months later

• The patient experienced progression and received ADT plus enzalutamide (Xtandi) 160 mg by mouth daily with initial PSA decreased to nadir of 3.9 ng/mL and symptom response.
• The patient spent a significant amount of time traveling and did not return for routine PSA monitoring.
• He developed metastatic castration-resistant prostate cancer (mCRPC) shown on imaging/PSA progression and was started on docetaxel 75 mg/m² intravenously every 3 weeks and prednisone 10 mg per day.
  • Patient clinically responded with resolution of pain and improved energy, with a declining PSA.
  • Four cycles completed; patient developed worsening bilateral digital neuropathy throughout therapy, so therapy was stopped before cycle 5.
  • Three months later, the patient had rising PSA, new back pain, and shortness of breath on exertion.
  • Abdominal/pelvic CT showed enlargement of known pelvic lymph nodes and 1 new liver lesion (< 2 cm).

Targeted Oncology: What is the evidence for using cabazitaxel ( Jevtana) in a patient such as this with mCRPC?

GARMEZY: There was a phase 1/2 trial [NCT01505868] of cabazitaxel plus or minus carboplatin in patients with mCRPC.¹ The inclusion criteria were anyone with metastatic prostate adenocarcinoma, but also small cell or neuroendocrine prostate cancers were allowed. They had to have an ECOG performance status of 0 to 2; I commend them for including the 2.

They were randomly assigned 1:1 to cabazitaxel at 25 mg/m², which was the dose that was initially used when cabazitaxel went up against mitoxantrone.^1,2 Then cabazitaxel at 25 mg/m² plus carboplatin at an AUC [area under the curve] of 4.¹ The primary end point was progression-free survival [PFS]. They made some key secondary end points as well, including OS [overall survival] and PSA decline.

How did patients do on this trial in terms of efficacy?

The PFS was statistically significant, with an HR of 0.69 and a 95% CI of 0.5 to 0.95 [P = .018]. There was pretty good separation of the Kaplan-Meier curves for some time until they collapse. [We are] not curing any patients with these types of therapies in mCRPC.

OS, though, was not statistically significant, with an HR of 0.89. You could argue maybe a trend at the beginning, but the P value was insignificant, at .5. The CI at the [high end] was at 1.25.

For the treatment effect for OS, [the investigators] worked on developing this aggressive variant prostate cancer [AVPC] signature. The easiest way to think about it is one criterion is the molecular signature of these patients; you have to have 2 of 3 aberrations: TP53, RB1, or PTEN. If you have 2 of 3, then you meet this molecular variant signature for AVPC. But they also had some other criteria as well, looking at if patients had certain visceral metastases, predominantly lytic bone lesions instead of blastic bone lesions, etc. There’s about 7 criteria, but the most popular one is this molecular signature.

The subgroups for AVPC were either through ctDNA [circulating tumor DNA] or through IHC [immunohistochemistry]. For those patients who had that AVPC signature, the HR for OS [0.39; 95% CI, 0.21-0.73; P = .0024] looks a lot better than those that didn’t [HR, 1.45; 95% CI, 0.82-2.55; P = .20]. That’s significant, telling us that this regimen is probably a good option for patients with AVPC, and may be less necessary in patients without aggressive variant disease.

What kind of adverse events (AEs) were seen in this trial?

When you add the carboplatin to cabazitaxel, you add in toxicity. But the key here is, you look at number of cycles received, and patients who got the doublet received more cycles than patients who got cabazitaxel monotherapy. Median duration of treatment was longer, 4.9 vs 3.8 months, and they basically received more therapy because they progressed less quickly, which is a good thing.

These patients had higher rates of cytopenias: anemia, thrombocytopenia, and neutropenia; all those grade 3 or 4 AEs are considerably higher. Grade 3 to 4 anemia was at 22%, but you also get more GI [gastrointestinal] AEs as well. So it’s not just the cytopenias, but they have increased fatigue, increased nausea, and other increased GI AEs. I think most of us are familiar with carboplatin in other tumor types as well, whether or not they’ve given it in prostate cancer, but it has that expected toxicity when you add it to cabazitaxel.

Can you discuss the CARD study (NCT02485691) for mCRPC?

This was a study of patients who have mCRPC who have progressed on prior docetaxel, as well as a novel hormonal antagonist, or the ARTA [androgen-receptor–targeted agent].³ It didn’t matter what sequence in which they got those therapies, whether they got the chemotherapy first in the mHSPC [metastatic hormone-sensitive prostate cancer] setting, or whether they got it later. Then they were randomized to cabazitaxel or the switch, from abiraterone [Zytiga] or enzalutamide [Xtandi].

The primary end point was imaging-based PFS.³ Baseline characteristics were similar across the groups, very well balanced. About half had received the abiraterone and half had received enzalutamide, so a good mix there. A bit more had received the novel hormonal after docetaxel than prior to docetaxel, which was more common back then.

If you look at the imaging-based PFS, you can see cabazitaxel obviously beat the switch of androgen-signaling–targeted inhibitor, at a median of 8 months vs 3.7 months, with an incredibly significant P value [HR, 0.54; 95% CI, 0.40-0.73; P < .001].³ There was clear separation on those Kaplan-Meier curves. The OS benefit, which is the most important, was 13.6 months vs 11 months. So it’s a modest but a very clear benefit, especially when you look at those curves and how well separated they are, with an HR of 0.64 [95% CI, 0.46-0.89; P = .008].

What did the subgroup and quality-of-life (QOL) analyses show in the CARD trial?

These trials aren’t powered to address any 1 particular subgroup, so you don’t want to overinterpret these forest plots. What you want to see is if there’s a true benefit, that you’re consistent, and if anything strikes you as odd, and can you explain it? The interesting thing here is maybe the patients without visceral metastases got just as much improvement as the patients who did. We normally think for patients who have visceral metastases, we need to give them chemotherapy. But the patients who didn’t have visceral metastases, if anything, had a more improved response, which may be suggestive that their disease was more controllable and able to be cytoreduced. I think that’s an important thing to keep in mind. Don’t only think visceral metastases, taxane; but taxanes can be pretty helpful in patients with bone-only disease as well.

For the QOL metrics, the PSA50 responses were 35.7% with cabazitaxel and 13.5% with either abiraterone or enzalutamide [P = .0002]. The objective tumor response was higher at 36.5% vs 11.5%, respectively [P = .004]. Then pain reduction was at 45% with cabazitaxel vs 19.3% with a hormonal agent [P < .0001]. What that tells me is cabazitaxel is active in this refractory patient population, and that statistically significant QOL indicators are real for our patients. We talk about wanting them to live well, and sometimes, providing chemotherapy can help them do so if it’s reducing pain.

Then for the time to symptomatic skeletal event [SSE], the median was not reached [NR] vs 16.7 months in patients who got cabazitaxel vs the control arm [HR, 0.59; 95% CI, 0.35-1.01; P = .05].³ There was a clear separation of the curves, so it’s preventing progression and preventing a very painful way to progress. Developing an SSE in the hip can be a life-altering consequence of mCRPC, so these are something to keep in mind.

There were statistically significant improvements. We know the control here, the switch of the novel hormonal, is not a very active control, but it is a real-world control, especially for a lot of these clinics where patients have higher comorbidities, and they have more refractory and tougher-to-treat cancers.

Looking at health-related QOL is important to do, but they’re always flawed in the way they’re conducted, too. So they’re not perfect, but they’re helpful, and if you look at prostate-specific concerns around well-being, it didn’t reach statistical significance [P = .11]. But if you look at pain, there was a statistically significant difference [P < .001]. Pain is one of the more important things we think about when we think about our patient population.⁴

The FACT-P [Functional Assessment of Cancer Therapy- Prostate] for patients on cabazitaxel on the CARD trial showed higher QOL in almost every metric.⁴ They don’t all reach statistical significance, and a lot of them are more similar than different, but the key is, it’s not causing harm in the QOL and there may be a benefit, especially when it comes to pain.

So that’s something to keep in mind to have those conversations with patients, and know that by providing the chemotherapy, you’re not necessarily going to make life worse. A lot of us have given chemotherapy to patients who are on the brink, and it’s a discussion between hospice and trial of a second taxane. You provide the second taxane and they wake up for a bit, and they do better for a bit, and they’re able to spend some more meaningful time with their family and their loved one. So I think it’s something to keep in mind, that chemotherapy doesn’t always cause a detriment to the health of our patients.

What was the toxicity profile for these patients?

We look at CARD trial safety, and the key here is to look at any AEs that are high in both groups: 98% for cabazitaxel, 94% for the hormonal agents for any AEs.³ Greater than grade 3 is similar, at 56% vs 52%, respectively. The AEs leading to treatment discontinuation had more with cabazitaxel [19.8% vs 8.9%, respectively], and that’s not surprising. That’s the taxane toxicity, whether that’s a bad cytopenia that’s leading to discontinuation, or a fever, something like that. But if the cabazitaxel is causing more AEs leading to treatment discontinuation, why are the AEs so balanced between groups? It’s basically because of progression.

If the patient is progressing on therapy, then they’re going to develop, more likely, AEs related to the cancer, not related to the treatment. AEs leading to death was different, 5.6% vs 11.3% for cabazitaxel vs control, respectively, so you are substituting delayed cancer progression for some AEs to therapy.³ That’s the conversation you have to have with patients about what’s right for them.

_REFERENCES

_{1. Corn PG, Heath EI, Zurita A, et al. Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers: a randomised, open-label, phase 1-2 trial. Lancet Oncol. 2019;20(10):1432-1443. doi:10.1016/S1470- 2045(19)30408-5}

_{2. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147-1154. doi:10.1016/S0140-6736(10)61389-X}

_{3. de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381(26):2506-2518. doi:10.1056/NEJMoa1911206}

_{4. 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}