Despite treatment advances in prostate cancer, it is associated with approximately 79,000 deaths in Europe and 34,000 deaths in the USA each year, presenting a clear unmet need.1,2 Most patients with metastatic castration-resistant prostate cancer (mCRPC) are ≥ 70 years of age and the median age of those who die from the disease is 80 years.3,4
Older patients with prostate cancer often have a complex clinical profile with comorbidities and functional and cognitive limitations.3,5 Furthermore, although several treatment options are available for patients with mCRPC, the optimal treatment sequence is still unclear. Consequently, in daily clinical practice, this presents clinicians with the challenge of selecting the appropriate treatments and sequence that will both increase survival outcomes and have acceptable safety profiles.
Progressed ≤ 12 months. CI=confidence interval; HR=hazard ratio; mCRPC=metastatic castration-resistant prostate cancer; PFS=progression-free survival; yr, year.
The CARD study investigated the efficacy and safety of cabazitaxel (25 mg/m2 plus prednisone and granulocyte colony-stimulating factor [G-CSF]) versus abiraterone (1000 mg plus prednisone) or enzalutamide (160 mg) in patients with mCRPC who had previously received docetaxel and progressed within 12 months on the alternative androgen receptor (AR)-targeted therapy (abiraterone or enzalutamide).6 The study demonstrated improved radiographic progression-free survival (rPFS) and overall survival (OS) in patients who received cabazitaxel compared with the alternative AR-targeted therapy (rPFS: 8.0 versus 3.7 months; OS: 13.6 versus 11.0 months). The results of the CARD study provided clear evidence that patients with mCRPC who have received prior docetaxel and progressed within 12 months on an AR-targeted therapy should receive cabazitaxel over another AR-targeted therapy. Although the primary CARD data provided evidence to support clinicians with decision-making regarding treatment sequencing in this setting, this subsequent analysis investigated the impact of age on efficacy and safety in this population (rPFS [primary endpoint] and safety by age were prespecified; others were post hoc).
In the 255 patients enrolled in the CARD study, 135 (53%) were ≥ 70 years of age and were used as the “older” subgroup. The cut-off of ≥ 70 years of age for the older population was selected based on the International Society of Geriatric Oncology guidelines.7 We found that patients ≥ 70 years of age had similar outcomes to the overall population. Among patients ≥ 70 years of age, median rPFS was significantly longer in patients who received cabazitaxel compared with the alternative AR-targeted therapy (8.2 versus 4.5 months; p = 0.012). The median OS was also longer among patients ≥ 70 years of age who received cabazitaxel compared with the alternative AR-targeted therapy (13.9 versus 9.4 months; p = 0.084). Although this difference was not statistically significant, the study was not statistically powered to detect differences in the OS endpoint. Furthermore, prostate-specific antigen and pain responses were significantly improved in patients ≥ 70 years of age who received cabazitaxel compared with the alternative AR-targeted therapy. These data provide convincing evidence that in patients ≥ 70 years of age with mCRPC who have received prior docetaxel and progressed within 12 months on the alternative AR-targeted therapy, subsequent cabazitaxel treatment improves efficacy compared with the alternative AR-targeted therapy.
In CARD, we also found that the median rPFS was similar for patients who received cabazitaxel aged ≥ 70 years compared with those aged < 70 years (8.2 versus 7.4 months). Age-related efficacy and safety data have been reported in post hoc analyses of the AFFIRM and COU-AA-301 studies investigating enzalutamide or abiraterone in older patients (≥ 75 years of age) with mCRPC who received prior docetaxel, respectively. In AFFIRM, the median rPFS was similar for patients receiving enzalutamide aged ≥ 75 years compared with those aged < 75 years (9.9 versus 8.3 months).8 Likewise, in COU-AA-301, median rPFS was similar for patients receiving abiraterone regardless of age (6.6 versus 5.6 months).9 Although direct comparisons between CARD, AFFIRM, and COU-AA-301 cannot be made, all three studies suggest that age does not affect the efficacy of cabazitaxel or AR-targeted therapy.
An acceptable safety profile is a priority for any cancer treatment. However, achieving this can be particularly challenging in older patients with mCRPC. In this study, grade ≥ 3 treatment-emergent adverse events (TEAEs), grade ≥ 3 serious TEAEs, and treatment discontinuations due to adverse events were more frequent in patients ≥ 70 years of age compared with patients < 70 years of age; this was seen in both treatment arms. Despite the increased frequency of TEAEs among patients ≥ 70 years of age, the safety of these regimens was manageable. These data suggest that close management of patients ≥ 70 years of age with TEAEs are required to ensure optimal patient care.
Febrile neutropenia (FN) is a hematological toxicity that can lead to serious infections and is potentially life-threatening, and a patient’s risk of FN can be increased following treatment with taxanes, such as cabazitaxel.10 Furthermore, advanced age is an independent predictor of grade ≥ 3 neutropenia and/or neutropenic complications.11 In CARD, the frequency of FN was not higher in patients ≥ 70 years of age compared with patients < 70 years of age who received cabazitaxel (3.1% versus 3.2%). The overall frequency of grade ≥ 3 FN among patients who received cabazitaxel was 3.2%, this is lower compared with the incidence reported among patients receiving 25 mg/m2 cabazitaxel in the TROPIC (8%), FIRSTANA (12%), and PROSELICA (9.2%) trials.12-14 The reduced FN rate reported in the CARD study may be the result of compulsory G-CSF use during Cycle 1 of cabazitaxel treatment, in earlier trials use of G-CSF during Cycle 1 was either not allowed or avoided if possible. This is supported by an earlier study of 746 patients with mCRPC who received cabazitaxel (25 mg/m2 plus prednisone), who had a 30% reduction in grade ≥ 3 neutropenia and/or neutropenic complication risk associated with G-CSF.11 These findings suggest that among patients with mCRPC receiving cabazitaxel, use of G-CSF during Cycle 1 of treatment may reduce the risk of FN.
This study provides evidence that the overall results of the CARD study are applicable to patients aged ≥ 70 years of age. Patients with mCRPC, regardless of age, who have received prior docetaxel and progressed within 12 months on an AR-targeted therapy should receive cabazitaxel over another AR-targeted therapy. Treatment decisions in older patients with mCRPC should be aligned with the guidelines and made not just on chronological age but in the broader context of fitness, vulnerability, and frailty.3
Written by: Cora Sternberg MD, FACP, Englander Institute for Precision Medicine, Division of Hematology and Oncology, Weill Cornell Medicine, Sandra and Edward Meyer Cancer Centre, New York, NY, USA
Cora N. Sternberg certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Cora N. Sternberg has provided a consulting or advisory role for Bayer, Merck Sharp & Dohme, Pfizer, Roche, Incyte, AstraZeneca, Sanofi, Merck Serono, Medscape, UroToday, Janssen, Immunomedics (now Gilead), Astellas Pharma, and BMS.
Medical writing assistance was received from Mark Cockerill of MediTech Media, funded by Sanofi. The CARD study was funded by Sanofi.References:
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- Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin 2021;71:7-33.
- Caffo O, Maines F, Rizzo M, Kinspergher S, Veccia A. Metastatic castration-resistant prostate cancer in very elderly patients: challenges and solutions. Clin Interv Aging 2016;12:19-28.
- Boyle HJ, Alibhai S, Decoster L, et al. Updated recommendations of the International Society of Geriatric Oncology on prostate cancer management in older patients. Eur J Cancer 2019;116:116-36.
- Colloca G, Tagliaferri L, Capua BD, et al. Management of the elderly cancer patients complexity: The radiation oncology potential. Aging Dis 2020;11:649-57.
- de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med 2019;381:2506-18
- Droz JP, Aapro M, Balducci L, et al. Management of prostate cancer in older patients: updated recommendations of a working group of the International Society of Geriatric Oncology. Lancet Oncol 2014;15:e404-14.
- Sternberg CN, de Bono JS, Chi KN, et al. Improved outcomes in elderly patients with metastatic castration-resistant prostate cancer treated with the androgen receptor inhibitor enzalutamide: results from the phase III AFFIRM trial. Ann Oncol 2014;25:429-34.
- Mulders PF, Molina A, Marberger M, et al. Efficacy and safety of abiraterone acetate in an elderly patient subgroup (aged 75 and older) with metastatic castration-resistant prostate cancer after docetaxel-based chemotherapy. Eur Urol 2014;65:875-83.
- Shiota M, Yokomizo A, Takeuchi A, et al. Risk factors for febrile neutropenia in patients receiving docetaxel chemotherapy for castration-resistant prostate cancer. Support Care Cancer 2014;22:3219-26.
- Heidenreich A, Bracarda S, Mason M, et al. Safety of cabazitaxel in senior adults with metastatic castration-resistant prostate cancer: results of the European compassionate-use programme. Eur J Cancer 2014;50:1090-9.
- 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;376:1147-54.
- Oudard S, Fizazi K, Sengelov L, et al. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: A randomized Phase III trial-FIRSTANA. J Clin Oncol 2017;35:3189-97.
- Eisenberger M, Hardy-Bessard AC, Kim CS, et al. Phase III study comparing a reduced dose of cabazitaxel (20 mg/m2) and the currently approved dose (25 mg/m2) in postdocetaxel patients with metastatic castration-resistant prostate cancer-PROSELICA. J Clin Oncol 2017;35:3198-206.
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