Cabazitaxel Fits into Treatment Paradigm for Patients With mCRPC

Case Summary

• A 75-year-old man presented with intermittent left hip pain​.
• Physical exam: unremarkable except for a prostate nodule on rectal exam​
• ECOG performance status: 1​

Clinical workup ​

• Prostate-specific antigen (PSA) level: 16.2 ng/mL​
• Gleason score 5 + 4, grade group 5​ per transrectal ultrasound–guided biopsy
• Bone scan and abdominal/pelvic CT scan​ were negative.
• X-ray of the pelvis indicated osteoarthritis.
• The patient was diagnosed with category cT2N0M0​ prostate cancer.
• Germline and somatic genetic 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). Six months after initiation of therapy, PSA was undetectable and the patient was asymptomatic​.
• Unfortunately, the patient did not return for regularly scheduled PSA follow-ups, and​ 36 months later, he experienced progression.
• The patient received ADT plus enzalutamide (Xtandi) 160 mg once daily before noon; his initial PSA (nadir, 3.9 ng/mL) and symptom response​ were good.
• Because of a busy travel schedule, the patient did not return for routine PSA monitoring​.
• He developed metastatic castration-resistant prostate cancer (mCRPC) and was started on docetaxel 75 mg/m2 IV once every 3 weeks plus prednisone 10 mg once a day.
• The patient responded clinically to treatment (ie, resolution of pain, improved energy, and declining PSA)​.
• He completed 4 cycles of treatment but developed worsening bilateral digital neuropathy throughout therapy. Therapy was stopped, and cycle 5 was not administered.​
• Three months later, the patient showed 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^TM: Would cabazitaxel (Jevtana) be considered preferential treatment even if we knew that the tumor is prostate-specific membrane antigen (PSMA) positive?

MEHMET A. BILEN, MD: Technically, yes. PSMA-positivity and being eligible for [177Lu-PSMA-617 (Lu 177)] technically doesn't exclude patients for a composite toxin, so those options are available. I think it depends on availability and whether you have access to Lu 177…but, ultimately, I think patients receive both of them, either Lu 177 first then cabazitaxel or cabazitaxel then Lu 177. It just depends on [the access to treatment].¹

Most of the time, I look at the patient’s PSMA expression, and if this is a very high PSMA-positive patient I may go with Lu 177, but I worry about the liver metastasis [in a patient like this] because those kinds of patients have either neuroendocrine or a neuroendocrine-like prostate cancer. This means this is the time they stop producing PSMA, and that [kind of patient can have more disease progression] during Lu 177 treatment.²

Mehmet A. Bilen, MD​

Associate Professor, Department of Hematology and Medical Oncology

Director, Genitourinary Medical Oncology Program

Winship Cancer Institute of Emory University​

Atlanta, GA

Please discuss the makeup of the phase 1/2 trial (NCT01505868) that looked at combining cabazitaxel with chemotherapy.

This trial was started at the University of Texas MD Anderson Cancer, and was a single-arm phase 1/2 study, [which recently published data in Lancet Oncology].3 In that trial, a patient with metastatic prostate cancer or small-cell prostate cancer were eligible to enroll. After [enrollment], the patient received either 25 mg/m2 of cabazitaxel alone [n = 79] or 25 mg/m2 of cabazitaxel plus carboplatin [n = 81] with an area under the curve [AUC] of 4.

The primary end point for this trial was progression-free survival [PFS], but there were multiple secondary end points including PSA response rate, safety/toxicity, and overall survival [OS]. In this trial, they certified the patient based on…[if they had] variant prostate cancer, or anaplastic high grade prostate cancer, using genomic markers including RB1, PTEN, or TP53. If a patient had 2 or more of these biomarkers, they [classified them as having variant prostate cancer], otherwise they did not classify them as such.³

What were the efficacy and safety outcomes of the trial?

There was a significant improvement in PFS [for patients on cabazitaxel plus carboplatin] at a median 7.3 months [95% CI, 5.5-8.2] compared with 4.5 months [95% CI, 3.5-5.7], and an observed HR of 0.69 [95% CI, 0.50-0.95; P = .18]. However, when looking at OS, the results [were similar between both arms, at a median of 18.5 months (95% CI, 16.7-21.9) in the combination arm compared with 17.3 months (95% CI, 13.8-21.9), and an HR of 0.89 (95% CI, 0.63-1.23, P = .50)]. This is a small study and is not powered for OS, but based on this analysis, there is no significant improvement in OS…. For patients who have molecular marker positivity, there was more benefit with the combination therapy vs if the patient was negative; [those patients] had similar outcomes between the cabazitaxel monotherapy and cabazitaxel plus carboplatin arms.³

Of course, adverse event [AEs] are important to observe. The median cycles of treatment were similar between each arm [at 5.0 in the monotherapy group and 6.0 in the combination arm], but in terms of reasons for discontinuation, it was mainly progression of disease, more so on the cabazitaxel alone arm vs cabazitaxel and chemotherapy [at 49% vs 32%, respectively]. However, if you look at toxicity [that led to treatment discontinuation] there was a slight increase in the combination arm at 12% versus 10%. Looking at the most common AEs [in the combination arm], everything is expected, including fatigue [63%], diarrhea [59%], neutropenia [2%], but nothing extraordinary. Overall, this is a reasonably well-tolerated combination that I use in my patient population.

Where does the CARD trial (NCT02485691) fit into this treatment landscape?

This was a phase 4 trial published in The New England Journal of Medicine a couple of years ago, and was a multicenter, randomized, off-label study that enrolled patients between 2015 and 2018. Just think about it, what was the landscape of prostate at that time? We didn’t have as many options then as we do today.⁴

So, a patient with mCRPC who progressed on an AR-targeted therapy less than 12 months before or after docetaxel was eligible, and they enrolled close to 250 patients [that met this criteria]. Cabazitaxel was given at 25 mg/m² [once every 3 weeks plus] prednisone and granulocyte colony-stimulating factor [GCSF] versus 1000 mg of abiraterone [Zytiga] and prednisone or 160 mg of enzalutamide [Xtandi]….

All patients received prior docetaxel and received prior androgen receptor­ [AR]-targeted therapy. In the overall distribution of patients, 16.3% [in the cabazitaxel arm] and 19.8% [in the comparison arm] had visceral metastasis, which we know those are a high-risk feature. The majority of patients expressed pain progression and the median duration of their prior AR-targeted therapy was about 8 months in both arms.⁴

What were the outcomes of the CARD trial?

The primary end point for this trial was radiologic PFS [rPFS], and…the median rPFS was 8.0 months [95% CI, 5.7-9.2] with cabazitaxel vs 3.7 months [95% CI, 2.8-5.1] with a HR of 0.54 [95% CI, 0.40-0.73; P < .001]. Across all subgroups rPFS favored cabazitaxel as well. OS also favored cabazitaxel vs abiraterone or enzalutamide at a median of 13.6 months [95% CI, 11.5-17.5] vs 11.0 months [95% CI, 9.2-12.9], and the HR was 0.64 [95% CI, 0.46-12.9] with a significant P value of .008.⁴

Again, rPFS in all subgroups favored cabazitaxel, but patients with visceral metastases were smaller population [within the trial at] 46 patients vs 209 patients without, therefore their CI is larger [with an HR of 0.79 (95% CI, 0.41-1.52).⁴ For patients who have…liver metastases, if you worry about a their PSA getting low vs imaging progression and no neuroendocrine differentiation, then I think bringing in carboplatin may help this patient population.^2,3

^References

^{1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 3.2023. Accessed August 11, 2023. https://bit.ly/3xNDAcB}

^{2. Bilinski P, Webb M. An exceptional response to 177LuPSMA undermined by neuroendocrine transformation. Urol Case Rep. 2020;34:101467. doi:10.1016/j.eucr.2020.101467}

^{3. 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.}

^{4. 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}