(1st UPDATE) Enzalutamide

Commentary by Sandy Srinivas, MD, Prostate Cancer Site Editor for JNCCN 360

Professor of Medicine, Stanford University Medical Center

Enzalutamide first gained U.S. Food and Drug Administration (FDA) approval for patients with metastatic castration-resistant prostate cancer who had received prior docetaxel. Later, enzalutamide demonstrated improvement in overall survival when administered before chemotherapy. Using novel hormonal drugs, such as enzalutamide, in earlier lines of therapy has been beneficial to many patients, including in metastatic castration-naive as well as nonmetastatic castration-resistant prostate cancers. Trials evaluating enzalutamide’s use in localized disease with radiation are ongoing. Other drugs in this same category have also gained approval from the FDA. Significant cross resistance occurs across these agents, but they have slight differences in toxicity profiles, allowing for some individual selection.

DISCLOSURES

Dr. Srinivas has received clinical research support from or served on a data safety monitoring board for AstraZeneca, Bayer HealthCare, Bristol Myers Squibb, Clovis Oncology, Eisai, Exelixis, Genentech, Merck, Pfizer, Seattle Genetics, and Tracon Pharmaceuticals and has served on a scientific advisory board or as a consultant or expert witness for Bayer HealthCare, Eisai, Genentech, Janssen, and Merck.

In October 2018, a new indication was approved for the use of enzalutamide in patients with metastatic castration-naive (also called hormone-sensitive) prostate cancer following the results of the pivotal ARCHES study.¹ Accounting for up to 5% of annual prostate cancer incidence in the United States, metastatic castration-naive prostate cancer is defined as a metastatic disease that has not yet been treated with—or is continuing to respond to—hormone therapy.² The approval of enzalutamide plus androgen-deprivation therapy (ADT) for the treatment of metastatic castration-naive prostate cancer represents an alternative to the standard regimen of docetaxel or abiraterone plus ADT.³

Study Data Behind Expanded Indication

The ARCHES study was a double-blind, phase III trial that included men with metastatic castration-naive prostate cancer who were randomly assigned to receive ADT plus either enzalutamide at 160 mg daily or placebo.⁴ Overall, enzalutamide plus ADT significantly reduced the risk of radiographic disease progression or death by 61% compared with ADT alone. This result was consistent across subgroups, regardless of metastatic disease volume and prior treatment with docetaxel. Overall survival data are still immature and not yet reported.

As for safety, the rates of grade 3 or greater adverse events were similar in the enzalutamide and placebo groups (24.3% vs. 25.6%), and no unexpected adverse events were reported. Notably, the high baseline level of quality of life reported at the beginning of the study was maintained throughout treatment.

Based on the significant improvement in disease progression and positive safety results, the independent data safety monitoring board recommended allowing patients treated with placebo plus ADT to cross over to enzalutamide plus ADT. Moreover, in December 2019, the FDA approved the regimen of enzalutamide plus ADT for the treatment of metastatic castration-naive prostate cancer.¹ The ARCHES trial was the first to demonstrate clinically meaningful benefits of a second-generation nonsteroidal antiandrogen in combination with ADT. By including a subgroup of men who were previously treated with docetaxel, the study “provided unique insight into this important patient subgroup with unmet clinical needs.”⁴

Additional Evidence of Benefit

Another recent study produced similar outcomes; in the phase III ENZAMET trial, men with metastatic castration-naive prostate cancer were assigned to either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy in addition to ADT, plus docetaxel where deemed appropriate.⁵ After nearly 3 years of follow-up, there were fewer deaths in the enzalutamide group: 102 versus 143 deaths in the standard-care group (P = .002). Enzalutamide also significantly improved prostate-specific antigen progression-free survival and clinical progression-free survival. However, the beneficial effect of enzalutamide on survival appeared to be smaller among stratified subgroups who received bone antiresorptive therapy, planned early docetaxel treatment, and had a high disease volume.

Adding early enzalutamide to ADT was associated with a higher frequency of toxic effects, especially peripheral neuropathy, which was associated with the concomitant use of docetaxel. Fatigue was reported more frequently, and more patients treated with enzalutamide discontinued therapy before disease progression.

New Data Support Use in Castration-Resistant Disease

The release of the final overall survival analysis from the PROSPER trial confirmed prolonged survival in men with nonmetastatic castration-resistant disease who received ADT plus enzalutamide compared with standard ADT alone (67.0 vs. 56.3 months, P = .001); the risk of death associated with enzalutamide was 27% lower than with placebo.⁶ The study results also indicated that men taking enzalutamide were able to delay the use of a new subsequent antineoplastic therapy compared with those receiving placebo (66.7 vs. 19.1 months). The exposure-adjusted rate of grade ≥ 3 adverse events was similar between the groups (17 vs. 20 per 100 patient-years), but higher rates of falls and fractures were reported with enzalutamide.

Sequencing Therapy

Now that enzalutamide has been established as a mainstay of therapy for castration-resistant prostate disease, researchers are determining how to maximize its impact in therapy. Using a sequencing strategy of abiraterone acetate followed by enzalutamide in patients with newly diagnosed metastatic castration-resistant disease appeared to provide the greatest clinical benefit compared with giving enzalutamide first, according to an open-label phase II Canadian study.⁷ For patients treated with abiraterone until PSA progression followed by enzalutamide, the time to second PSA progression was significantly longer compared with those treated with the opposite sequencing strategy (19.3 vs. 15.2 months, P = .036). PSA responses to second-line therapy were seen in 36% of patients treated with enzalutamide compared with just 4% of those who received abiraterone (P < .0001), indicating that unlike abiraterone, enzalutamide showed activity as a second-line novel androgen receptor pathway inhibitor after progression on a different androgen receptor pathway inhibitor. [Editor’s Note: According to the results of the CARD clinical trial, cabazitaxel is preferred in this setting, rather than another novel androgen receptor pathway inhibitor.⁸ Moreover, patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene mutation may benefit from PARP inhibition.⁹]

Future Research

Growing evidence has confirmed the benefit of enzalutamide in the treatment of patients with both castration-naive and -resistant prostate cancer. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) now include enzalutamide with ADT as a category 1 (based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate) option for first-line treatment of metastatic castration-naive prostate cancer, nonmetastatic castration-resistant prostate cancer with a PSA doubling time of at least 10 months, and first-line metastatic castration-resistant prostate cancer (adenocarcinoma).¹⁰

Nonetheless, several mechanisms of enzalutamide resistance have been identified that may limit its long-term effectiveness—including genetic mutations and splice variants of the androgen receptor, signaling pathways that bypass androgen signaling, and intratumoral androgen biosynthesis.¹¹ A greater understanding of these processes may lead to targeted approaches for preserving the efficacy of enzalutamide in prostate cancer.

References

1. U.S. Food and Drug Administration: FDA approves enzalutamide for metastatic castration-sensitive prostate cancer. December 16, 2019. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide-metastatic-castration-sensitive-prostate-cancer. Accessed September 29, 2020.
2. Scher HI, Solo K, Valant J, et al. Prevalence of prostate cancer clinical states and mortality in the United States: estimates using a dynamic progression model. PLoS One 2015;10:e0139440.
3. Firwana B, Sonbol MB, Mahmoud FA, et al. Treatments for metastatic hormone-sensitive prostate cancer: a systematic review. J Clin Oncol 2018;36:346.
4. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol 2019;37:2974–2986.
5. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med 2019;381:121–131.
6. Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med 2020;382:2197–2206.
7. Khalaf DJ, Annala M, Taavitsainen S, et al. Optimal sequencing of enzalutamide and abiraterone acetate plus pednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. Lancet Oncol 2019;20:1730–1739.
8. de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med 2019;381:2506–2518.
9. U.S. Food and Drug Administration. FDA approves olaparib for HRR gene-mutated metastatic castration-resistance prostate cancer. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer. Accessed October 7, 2020.
10. Schaeffer E, Srinivas S, Antonarakis E, et al. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 2.2020. Accessed September 29, 2020. To view the most recent version of the guidelines, visit nccn.org.
11. Vander Ark A, Cao J, Li X. Mechanisms and approaches for overcoming enzalutamide resistance in prostate cancer. Front Oncol 2018;8:180.