The 2021 Genitourinary (GU) Cancers Symposium was held in a virtual format on February 11–13 and featured the latest developments in the understanding and treatment of genitourinary cancers. The impact of prostate cancer therapies on outcomes in older adults continues to be a growing area of research, and numerous studies presented at the meeting shed light on treatment approaches in this population. Here we review key oral presentations and posters.
Localized Prostate Cancer
Upfront use of docetaxel chemotherapy is part of standard care for localized prostate cancer, based on data from the RTOG 0521 and -STAMPEDE trials, which showed improved overall survival and progression-free survival, respectively.1,2 However, real-world data presented at the meeting suggest that these benefits may not extend to older adults.
GUEST EDITOR
Stuart M. Lichtman, MD, FASCO
A retrospective national cancer center database review of patients aged 65 years or older with high-risk localized prostate cancer from 2004 to 2015 (n = 11,734) showed that only a minority of older patients (n = 128) were treated with adjuvant chemotherapy in addition to androgen-deprivation therapy and radiation therapy, and no overall survival benefit was observed.3 Patients aged at least 75 years were less likely to receive adjuvant chemotherapy, and this group had a worse overall survival, although the difference was not statistically significant (0.47 vs 0.69 at 60 months; P = .08).
Nonmetastatic Castration-Resistant Prostate Cancer
Novel androgen receptor inhibitors for localized or nonmetastatic castration-resistant prostate cancer have shown a significant metastasis-free survival benefit in pivotal phase III trials such as ARAMIS, SPARTAN, and PROSPER.4-6 That said, the effects of androgen receptor inhibitors in older adults with cancer remain limited.
A post hoc subgroup analysis of data by age from the PROSPER trial demonstrated a similar overall survival benefit with enzalutamide in patients aged ≥ 70 years compared with those aged < 70 (hazard ratio [HR] = 0.73; 95% confidence interval [CI] = 0.58–0.9 vs HR = 0.72; 95% CI = 0.5–1.04), with consistent overall safety between age groups.7 However, patients aged ≥ 70 treated with enzalutamide experienced more exposure-adjusted adverse events per 100 person-years including fatigue (17.2 vs 14), falls (7.2 vs 4.1), and fractures (7.2 vs 4.6). Although these increased rates were not statistically significant in the multivariate model, it is important for clinicians to be aware of these adverse events in older patients, given they can cause significant morbidity and mortality in this population.8
Metastatic Prostate Cancer
In the setting of metastatic disease, data from clinical trial and real-world populations were presented with a focus on safety in older adults. A secondary analysis of the CHAARTED trial based on age showed an overall survival benefit with the addition of docetaxel to androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer.9 Patients aged ≥ 70 (n = 177, 22.4%) had improved overall survival (HR = 0.45, 95% CI = 0.25–0.80) comparable to patients aged < 70. Although patients aged ≥ 70 were more likely to have an impaired performance status and to have had prior local therapy, they were able to complete all six cycles of docetaxel (82.6% vs 87.1%, P = .28), with similar rates of grade 3 to 5 adverse events (36.8% vs 26.8%, P = .69) and grade 4 to 5 adverse events (14.9% vs 11.9%, P = .46).9
Nabiel Mir, MD
Sindhuja Kadambi, MD
In contrast, a Canadian real-world retrospective analysis of 399 men aged ≥ 66 with metastatic hormone-sensitive prostate cancer who received docetaxel and androgen-deprivation therapy (median age = 72, interquartile range = 68–76; mean Charlson Comorbidity Index = 0.15, standard deviation = 0.72) found that only 44% of patients were able to complete six cycles of treatment, 43% of patients required dose reductions, and 16% experienced febrile neutropenia requiring hospitalization or an emergency department visit.10 However, only 7.3% of patients in the analysis received growth-factor support, despite current ASCO guidelines recommending the use of colony-stimulating factors in patients aged 65 or older.11
At the GU Cancers Symposium, researchers also presented a final analysis of the TITAN study of the androgen receptor inhibitor apalutamide (n = 525) vs placebo (n = 527) in patients with metastatic hormone-sensitive prostate cancer receiving androgen-deprivation therapy. With a median follow-up of 44 months, apalutamide was shown to reduce the risk of death by 35% (HR = 0.65, P < .0001), and this effect on overall survival was seen across age groups, including patients aged 75 and older. The cumulative incidence of adverse events such as fatigue, falls, and fractures was noted to be similar in the apalutamide and placebo groups. No information, however, was provided on adverse events specifically in older adults.
Relationship of Prostate Cancer Therapies to Geriatric Outcomes
The meeting brought together several studies that evaluated outcomes important to older adults such as effects on function, cognition, and quality of life (QOL).
Although androgen-deprivation therapy has been known to be associated with serious adverse effects that can lead to increased morbidity and mortality in older adults, including sarcopenia, falls, and frailty, little is known about the long-term effects of abiraterone and enzalutamide on older adults.12 Naimi et al performed a retrospective single-center study of patients with metastatic castration-resistant prostate cancer who received abiraterone (n = 29, median age = 75) or enzalutamide (n = 29, median age = 69) for more than 1.5 years.13 Using the computed tomography–derived Psoas Muscle Index (PMI) as a marker of sarcopenia, the investigators reported that patients on either abiraterone or enzalutamide had a significant decline in PMI at 24 months compared to baseline.
Yang et al conducted a multicenter prospective observational cohort study of men aged ≥ 65 with metastatic castration-resistant prostate cancer starting docetaxel (n = 70), abiraterone (n = 38), enzalutamide (n = 67) and radium-223 (n = 23) to assess physical function, falls, and frailty over time with treatment.14 They found that at 3 and 6 months after treatment initiation, treatment type alone was not associated with significant changes in functional measures. Although frail patients had baseline functional deficits compared to fit patients, they experienced greater improvements in physical function and well-being over time.
The symposium further explored the cognitive and psychological health effects of androgen-deprivation therapy on older adults. Roupret et al conducted a prospective, longitudinal study of patients aged ≥ 60 with prostate cancer on gonadotropin-releasing hormone agonists (GnRHa).15 Using the Mini Mental State Evaluation (MMSE) questionnaire (with MMSE score < 26 indicative of cognitive impairment), they found that patients aged ≥ 75 had significantly lower MMSE scores (mean = 26.2; 95% CI = 25.6–26.8) than patients aged 60 to 75. The prevalence of cognitive impairment in patients aged ≥ 75 (30%) was nearly double that of patients aged 60 to 70 (15.3%) and 70 to 75 (14.7%). There was no significant change in MMSE scores globally at 6 months after initiating GnRHa therapy between age groups.
In a retrospective cohort study of veterans diagnosed with localized prostate cancer (n = 32,194), 25.7% screened positive for depression using Patient Health Questionnaire (PHQ)-2 and PHQ-9 screenings between 6 months and 5 years after diagnosis.16 Of those veterans who were diagnosed with depression, 30.5% of patients received an antidepressant. Veterans with depression, compared to those without, had higher all-cause mortality (adjusted HR = 1.30; 95% CI = 1.25–1.35). Black veterans were more likely than White veterans to be diagnosed with depression (adjusted HR = 1.12; 95% CI = 1.05–1.19) but less likely to receive antidepressants (adjusted HR = 0.84; 95% CI = 0.75–0.94).16 Association between depression and all-cause mortality was significantly greater in Black veterans than in White veterans (adjusted HR = 1.05; 95% CI = 0.97–1.13). Receipt of antidepressants did not improve mortality regardless of race.
Financial Toxicities of Prostate Cancer Treatment
Several studies highlighted the financial and racial barriers to high-quality care among older adults with prostate cancer. Schwartz et al explored out-of-pocket costs for patients prescribed abiraterone or enzalutamide (n = 219); they found that patients with Medicare Part D coverage (61%) had higher out-of-pocket costs for oral antiandrogen therapies, with an average of $582 out-of-pocket per month and 22% with an initial cost greater than $1,000 for the first 30 days.17 Nearly one-third of patients required financial assistance, which was associated with delays in initiating treatment.
Similarly, 30% of patients enrolled in the nonprofit Cancer Support Community’s Cancer Experience Registry spent $250 or more per month on out-of-pocket costs.18 A majority of patients reported that their physicians did not discuss cost of treatment (67%) or financial distress (77%).
Closing Thoughts
In summary, the studies presented at the 2021 GU Cancers Symposium provided important data on the effects of prostate cancer treatment on older adults and highlighted the importance of assessing frailty, cognition, psychological health, and financial toxicity in these patients. They also demonstrate the need for additional such studies to further improve the care of older adults with prostate cancer.
Dr. Mir is a fellow in Geriatric Oncology at the University of Chicago Medical Center. Dr. Kadambi is a fellow in Geriatric Oncology at the Wilmot Cancer Institute at the University of Rochester Medical Center.
DISCLOSURE: Dr. Mir and Dr. Kadambi reported no conflicts of interest.
REFERENCES
1. Rosenthal SA, Hu C, Sartor O, et al: Effect of chemotherapy with docetaxel with androgen suppression and radiotherapy for localized high-risk prostate cancer: The randomized phase III NRG Oncology RTOG 0521 trial. J Clin Oncol 37:1159-1168, 2019.
2. James ND, Spears MR, Clarke NW, et al: Survival with newly diagnosed metastatic prostate cancer in the “docetaxel era”: Data from 917 patients in the control arm of the STAMPEDE trial (MRC PR08, CRUK/06/019). Eur Urol 67:1028-1038, 2015.
3. Akhtar K, Formica MK, Madhira B, et al: High-risk nonmetastatic prostate cancer in the elderly: Does adjuvant chemotherapy affect survival? J Clin Oncol 39(6 suppl):229, 2021.
4. Fizazi K, Shore N, Tammela TL, et al: Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med 380:1235-1246, 2019.
5. Hussain M, Fizazi K, Saad F, et al: Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med 378:2465-2474, 2018.
6. Smith MR, Saad F, Chowdhury S, et al: Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 378:1408-1418, 2018.
7. De Giorgi U, Hussain MHA, Shore ND, et al: PROSPER subgroup analysis by age and region: Overall survival and safety in men with nonmetastatic castration-resistant prostate cancer receiving androgen deprivation therapy plus enzalutamide. J Clin Oncol 39(6 suppl):84, 2021.
8. Sattar S, Haase K, Kuster S, et al: Falls in older adults with cancer: An updated systematic review of prevalence, injurious falls, and impact on cancer treatment. Support Care Cancer 29:21-33, 2021.
9. Lage DE, Michaelson MD, Lee RJ, et al: Outcomes of older men receiving docetaxel for metastatic hormone-sensitive prostate cancer. J Clin Oncol 39(6 suppl):82, 2021.
10. Shayegan B, Wallis CJD, Hamilton RJ, et al: Real-world utilization of docetaxel among men with de novo metastatic castration-sensitive prostate cancer: A population-based study in men aged 66 or older. J Clin Oncol 39(6 suppl):47, 2021.
11. Smith TJ, Bohlke K, Lyman GH, et al: Recommendations for the use of WBC growth factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 33:3199-3212, 2015.
12. Winters-Stone KM, Moe E, Graff JN, et al: Falls and frailty in prostate cancer survivors: Current, past, and never users of androgen deprivation therapy. J Am Geriatr Soc 65:1414-1419, 2017.
13. Naimi MF, Khan M, Carvajal JRB, et al: Comparative analysis of sarcopenia induced by long-term abiraterone versus enzalutamide therapy in men with metastatic castration-resistant prostate cancer. J Clin Oncol 39:69(6 suppl):2021.
14. Yang H, Breunis H, Timilshina N, et al: Impact of treatment and frailty on elder-relevant physical function outcomes in older adults with metastatic castration-resistant prostate cancer. J Clin Oncol 39(6 suppl):76, 2021.
15. Roupret M, Rozet F, Hennequin C, et al: Cognitive status of prostate cancer patients aged 60 years and older after a six-month gonadotropin-releasing hormone agonist therapy, according to age groups: Secondary analysis of PRISME study. J Clin Oncol 39(6 suppl):56, 2021.
16. Parikh RB, Gallo JJ, Cashy J, et al: Racial disparities in depression incidence, management, and mortality after prostate cancer diagnosis. J Clin Oncol 39(6 suppl):201, 2021.
17. Schwartz EB, Jeong A, Roman A, et al: Evaluating financial burdens of oral hormonal therapies for patients with prostate cancer. J Clin Oncol 39(6 suppl):70, 2021.
18. Kranzler EC, Miller MF, Fortune EE, et al: Financial toxicity and patient-provider communication about cancer-related cost among prostate cancer patients and survivors. J Clin Oncol 39(6 suppl):215, 2021.
