The American Society of Clinical Oncology (ASCO) 2020 meeting was held virtually this year due to the COVID-19 pandemic. Despite this, there were hundreds of abstracts, posters and presentations. In an interview, Axel S. Merseburger, chairman of the Department of Urology at the University Hospital Schleswig-Holstein in Lübeck, Germany, considered the presentations on prostate cancer to be one of his personal highlights.
Non-metastatic, castration-resistant prostate cancer (nmCRPC) represents about 5-7% of prostate cancer cases in clinical practice.1 The standard approach to nmCRPC has been to continue androgen deprivation therapy (ADT), observe patients, conduct imaging tests on a regular basis, and then to intervene when a patient first develops a detectable metastasis.1 Since progression to metastatic disease inevitably occurs,2 this has been an important unmet need. However, recent years have transformed the management of nmCRPC, with the approval of three agents – apalutamide, darolutamide and enzalutamide – in this treatment setting.
The SPARTAN (Study of Apalutamide in Men With Non-Metastatic Castration-Resistant Prostate Cancer) Phase III study (NCT01946204) evaluated the efficacy and safety of the androgen receptor inhibiting agent apalutamide (ErleadaÒ,Johnson & Johnson) in 1,207 men with high-risk nmCRPC. Patients were randomised to apalutamide or placebo plus ongoing ADT. Results were published in the New England Journal of Medicine in 2018 and showed that metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo.3 As a result, apalutamide became the first agent to be approved in the setting of nmCRPC.
Since patients with nmCRPC often live more than 5 years, around 2 years longer than patients with metastatic CRPC, treatment will result in longer drug exposure. Long-term follow-up data from the SPARTAN study was, therefore, greatly anticipated, and would also determine whether the metastasis-free survival benefits observed in the primary analysis would translate to clinically meaningful benefits in overall survival (OS). At ASCO, the final OS analysis of data from SPARTAN, with a follow up of 52 months, was presented. Apalutamide showed a significant OS benefit compared with placebo, corresponding to a 22% reduction in death. These benefits were maintained despite a 19% crossover from placebo to the treatment group after unblinding at the primary analysis. The safety profile of apalutamide was consistent with previous reports; grade 3/4 treatment-emergent adverse events (TEAEs) included rash (5.2%), fractures 4.9%, falls (2.7%), and ischemic heart disease (2.6%). There was one TEAE leading to death (myocardial infarction) that was considered potentially related to apalutamide.4
Approval of apalutamide for men with nmCRPC was soon followed by that of enzalutamide (XTANDIÒ, Astellas), an androgen receptor inhibitor that was already approved for treating metastatic CRPC patients either before or after chemotherapy. Approval was based on the findings of the PROSPER (Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer) study (NCT02003924; n=1,401), in which enzalutamide treatment plus ongoing ADT led to a clinically meaningful and significant lower risk of metastasis or death than placebo.5 In the final analysis of the OS data, which was presented at ASCO and simultaneously published in the New England Journal of Medicine, the risk of death associated with enzalutamide was 27% lower than with placebo. The safety profile was consistent with the primary analysis and the established safety profile of enzalutamide. The most common TEAEs that occurred more frequently in the enzalutamide treatment arm included fatigue (37%), hypertension (17%), asthenia (10%), back pain (13%), dizziness (12%), diarrhoea (12%), nausea (13%), hot flush (14%), fall (18%), arthralgia (13%), constipation (13%), haematuria (10%), headache (11%) and decreased appetite (12%). 6
Another androgen receptor inhibiting agent, darolutamide (NubeqaÒ, Bayer), received FDA approval in 2019 based on the findings of the ARAMIS (Efficacy and Safety Study of Darolutamide in Men With High-risk Nonmetastatic Castration-resistant Prostate Cancer) study, (NCT02200614 ) in which 1,509 patients with nmCRPC were randomised to darolutamide or placebo while continuing ADT.7 The final OS analysis was conducted after 254 deaths were observed (15.5% of those receiving darolutamide and 19.1% of placebo patients), and was presented at ASCO. Darolutamide showed a significant OS benefit (31% reduction in death) compared with placebo. As in the primary analysis, TEAEs with ≥5% frequency were comparable between the treatment and placebo arms.8
These data have been well received, since the original study endpoints of metastasis-free survival was controversial. Overall survival is a more established endpoint in evaluating therapies for PC. These results, therefore, confirm previous evidence supporting the efficacy of apalutamide, enzalutamide and darolutamide in the treatment of nmCRPC. While no direct comparative studies have yet been performed, the three studies are comparable in terms of the size and patient characteristics of the populations studied, and the efficacy results in terms of metastasis-free survival and OS benefit. However, the safety profiles differ, since darolutamide has a reduced risk of crossing the blood-brain barrier compared with apalutamide and enzalutamide.10 An analysis presented at ASCO found that darolutamide had a statistically significant lower risk of falls, fracture, and rash compared to apalutamide, and a lower risk of falls, dizziness, mental impairment, fatigue, and severe fatigue compared to enzalutamide.9 Choice of therapy is likely to depend on the patient’s medical history, possible drug-drug-interaction, patient choice and drug cost.10
Other promising agents in the treatment of CRPC include the poly ADP ribose polymerase (PARP) inhibitor olaparib (LynparzaÒ, AstraZeneca), which has shown significant and clinically meaningful OS benefits compared with enzalutamide or abiraterone in the metastatic disease setting in men with BRCA1/2 or ATM gene mutations.11 Olaparib is among the agents being investigated in the TAIPUR (Targeted Agent and Profiling Utilization Registry) study, a Phase II study that is evaluating a number of currently available therapies in patients with advanced cancers with genomic alterations. Data presented in ASCO showed that olaparib treatment resulted in disease control in 68% and an overall response rate of 36% in 29 heavily pretreated patients with advanced PC with BRCA1/2 inactivating mutations.
These data confirm that the treatment landscape for nmCRPC has changed dramatically. The future is bright in terms of therapeutic choices for advanced PC, and this should lead to improved clinical outcomes.
- Liede A, Günther O, Bennett B, Wong S. Prevalence of non-metastatic castration-resistant prostate cancer in Europe. Ann Oncol. 2012;23(suppl 9):Abstr IX298.
- Smith MR, Kabbinavar F, Saad F, et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol. 2005;23:2918–25;10.1200/jco.2005.01.529;15860850.
- Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378:1408 18;10.1056/NEJMoa1715546;29420164.
- Small EJ, Chowdury S, Oudard S, et al. Final survival results from SPARTAN, a phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2020;38(suppl):Abstr 5516.
- Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378:2465–74;10.1056/NEJMoa1800536;29949494.
- Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2020;10.1056/NEJMoa2003892;32469184.
- Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer, N Engl J Med, 2019;380:1235-46;10.1056/NEJMoa1815671;30763142.
- Fizazi K, Shore ND, Tammela T, et al. Overall survival (OS) results of phase III ARAMIS study of darolutamide (DARO) added to androgen deprivation therapy (ADT) for nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2020;38 (suppl):Abstr 5514.
- Jiang S, Terasawa E, Garcia Horton V, et al. Safety outcomes of darolutamide versus apalutamide and enzalutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC): Matching-adjusted indirect comparisons. J Clin Oncol. 2020;38 (suppl):Abstr 5561.
- Williams J. Nonmetastatic PCa: A changing landscape. Urology Times. Spetember 2019 https://www.urologytimes.com/sites/default/files/legacy/mm/digital/media/ut0919_ezine.pdf Accessed 3 June 2020.
- de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382:2091-102;10.1056/NEJMoa1911440;32343890.
Disclosure: Axel S Merseburger has no conflicts of interest to declare in relation to this article.
Support: Commissioned and supported by Touch Medical Media.
Published: 4 June May 2020