Darolutamide

Globally, prostate cancer is the second most common cancer among men.¹ It is the most frequently diagnosed cancer and second most frequent cause of cancer deaths in U.S. men, with an estimated 288,300 new cases and 34,700 deaths in 2023.² At diagnosis, ~77% of patients have localized, ~14% regional, and ~8% distant disease, with the latter group having a 5-year survival rate of ~30%.² Recently, prostate cancer incidence rates have been declining for local-stage disease but increasing for regional- and distant-stage disease.³ Moreover, a substantial proportion of patients with localized disease develop progressive disease despite prostate-directed definitive therapy.⁴

Advanced prostate cancer comprises a spectrum of disease states that can be distinguished by the presence or absence of metastasis and sensitivity or resistance to androgen-deprivation therapy (ADT).⁵

Metastatic Castration-Sensitive Prostate Cancer

The incidence of metastatic castration-sensitive prostate cancer, which accounts for ~50% of prostate cancer–related deaths, is increasing.^6,7 The metastatic disease extent and time of development are strong prognostic factors; patients with low-volume disease have a better prognosis than those with high-volume disease, and patients with metachronous metastatic disease (ie, those with metastatic relapse after definitive therapy for localized disease) have a better prognosis than patients with synchronous (ie, de novo) metastatic disease.⁸

Current guideline-recommended care for fit patients with metastatic castration-sensitive prostate cancer (both with synchronous or metachronous metastases) comprises lifelong ADT (ie, luteinizing hormone-releasing hormone analog- or surgery-based castration) with either six cycles of docetaxel or certain androgen receptor (AR) signaling inhibitor (abiraterone acetate plus prednisone [AAP], enzalutamide, apalutamide [ie, doublet combination therapies]), or a recently added combination of docetaxel with either AR signaling inhibitor darolutamide or AAP (ie, triplet combination therapies).⁹ ADT with radiation to the primary tumor is also an option for patients with a low metastatic burden. Use of ADT alone is discouraged and should be used when doublet or triplet intensification therapy is clearly contraindicated. However, although ADT intensification is being increasingly used, in the real-world practice setting, it is still underutilized, and there is an unmet need for improved adherence to guideline-recommended treatment options.¹⁰

ARASENS: A Pivotal Trial in Metastatic Castration-Sensitive Prostate Cancer   

Darolutamide, a structurally distinct new-generation AR inhibitor with low blood-brain barrier penetration and limited potential for clinically relevant drug-drug interactions,^11-13 has shown potent antitumor efficacy in the phase III ARAMIS trial in patients with nonmetastatic castration-resistant prostate cancer.^14,15

The U.S. Food and Drug Administration (FDA) approval of darolutamide for patients with metastatic castration-sensitive prostate cancer was based on the efficacy and safety data from the double-blind, placebo-controlled, phase III ARASENS trial.^16,17

The primary analysis involved 1,306 patients, 86.1% of whom had de novo disease. The risk of death was lower by 32.5% in the darolutamide group than in the placebo group (hazard ratio [HR] = 0.68; P < .001), despite a high percentage of patients in the placebo group receiving subsequent life-prolonging systemic therapies. Darolutamide was also associated with consistent benefits with respect to the secondary endpoints, including the time to development of castration-resistant disease (HR = 0.36; 95%; P < .001), time to pain progression (HR = 0.79; 95%; P = .01), symptomatic skeletal event–free survival (HR = 0.61; P < .001), time to a first symptomatic skeletal event (H =, 0.71; P = .02), and the time to the initiation of subsequent systemic antineoplastic therapy (HR = 0.39; P < .001), as well as across most prespecified subgroups.¹⁷

Moreover, the subgroup analyses of ARASENS showed that the darolutamide triplet therapy improved overall survival in high-volume, high-risk, and low-risk disease; the data also suggested a survival benefit in the smaller subgroup with low-volume disease.¹⁸ As for the delayed time to pain progression, the darolutamide triplet therapy provided clinically meaningful benefit, notably in patients with high-volume disease.¹⁹

Adverse events were similar in the darolutamide and placebo groups, and the incidences of the most common adverse events were highest during the overlapping docetaxel treatment period in both groups. Among the most frequently reported adverse events of special interest for patients receiving AR inhibitors, the incidences of vasodilation and flushing (20.4% with darolutamide vs. 21.7% with placebo) and diabetes mellitus and hyperglycemia (15.2% and 14.3%) were also similar in the two groups.¹⁷

Management Considerations

Maha Hussain, MD, FACP, FASCO, shared her thoughts on the ARASENS data with JNCCN 360: “ ARASENS data clearly showed clinical benefit across patient subgroups including those with high- and low-volume disease²⁰ and high- and low-risk disease.²¹ The decision regarding patient management, including whether to use darolutamide triplet therapy, or the AAP triplet with ADT and docetaxel as per PEACE-1 trial,²² must integrate all clinically relevant factors. In other words, one must consider the overall condition of the patient, the health status of the patient, comorbidities, age, safety, and the merits of the therapy being considered,” she noted.

At the end of the day, patients need to be engaged in a shared decision-making process.

Dr. Hussain continued: “For example, if I have a patient who is 85 years old, who was diagnosed when he was 65 and now has a very few bone lesions with few lymph nodes involved (low volume), I favor doublet therapy. On the flip side, if I had a patient who is in his 70s, who just got diagnosed with de novo metastatic hormone-sensitive prostate cancer, even if it is low-volume disease, I would likely favor triplet therapy. However, at the end of the day, patients need to be engaged in a shared decision-making process.” Dr. Hussain is the Genevieve Teuton Professor of Medicine in the Division of Hematology-Oncology, Department of Medicine, and the Deputy Director, at the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine.

“When it comes to choosing between darolutamide- versus AAP-based triplet therapy for patients with metastatic hormone-sensitive prostate cancer,” Dr. Hussain said, “I like using both, as they are both generally well tolerated. The choice between the two often revolves around insurance coverage, co-pay issues, and drug-drug interactions. In my experience, however, I have to say that darolutamide is a bit easier to handle because one does not need to worry about electrolytes, liver function tests, taking a pill on an empty stomach, or taking prednisone. But, again, because we have so much experience with AAP, we continue using it quite often. In the end, however, if there are no contraindications and/or potential for drug-drug interactions, I give patients the choice and let them decide on whatever they think will work better for them.”

Dr. Hussain also shared these thoughts with JNCCN 360: “With regard to the assessment of volume and risk of disease, some of the challenges that occasionally emerge in clinical practice stem from the increased use of prostate-specific membrane antigen positron-emission tomography (PSMA-PET) imaging. Because we are now able to pick up many more lesions with PSMA-PET,” she explained, “the question becomes, how does one manage patients with low-volume disease on conventional imaging who have lots of disease on PSMA-PET scan? Along those lines, another scenario for which we need more clarity, in terms of the optimal management, are patients with no disease on conventional imaging, who have a few lesions on PSMA-PET scan. In some of these cases that are not clear-cut, we typically discuss the possible treatment strategy within the tumor board setting.”

When it comes to managing patients with nonmetastatic castration-resistant prostate cancer, Dr. Hussain told JNCCN 360 that “the choice among enzalutamide, apalutamide, and darolutamide needs to take into account any possible contraindications based on the different safety profiles of these drugs and a potential for drug-drug interactions.^12,23 Also, one needs to think about the risk of cardiovascular issues (eg, hypertension, arrhythmia, and congestive heart failure), hemorrhagic strokes, risk of falls (eg, enzalutamide and apalutamide are associated with an increased risk of falls), renal failure, cognitive impairment (eg, with its lower blood-brain barrier penetration, darolutamide seems to be associated with a lower risk of cognitive impairment), and, finally, issues around insurance coverage and co-pay issues. When thinking about some of these issues, we are fortunate to have pharmacists with whom we work closely when deciding on the optimal therapy for each individual patient.”

Jennifer L. Lloyd, APRN, of the Huntsman Cancer Institute at Utah University in Salt Lake City, told JNCCN 360 that at her institution, when it comes to disease volume and risk stratification, they use, in addition to the CHAARTED and LATITUDE criteria,^20,21 results of genomic profiling. “For example, we look into the PTEN, RB, or TP53 mutations and/or deletions [for metastatic hormone-sensitive disease]. If we see aberrations in any two of those genes, we consider that as high-risk disease and tend to treat it more aggressively. In patients who are younger, fit, with good functional status and no comorbidities,” she observed, “we tend to go with a triplet therapy. In other patients, we take a more tiered approach, starting with ADT, then adding either docetaxel or AR inhibitors; then, if those are tolerated well, we add the third component (ie, either docetaxel or AR inhibitors). The reason being that, if you start with the triplet therapy in those patients and it is not well tolerated, it is not always easy to adjust it.”

More on Safety and Drug-Drug Interactions

In terms of the differential safety profiles of AR inhibitors, Ms. Lloyd explained that “although they are all relatively well tolerated, there are some differences. But, most importantly, each individual patient may respond to them in their own unique way. As for the adverse events associated with darolutamide triplet therapy, as seen in the ARASENS trial, most of them come from the chemotherapy. However, the one that seems to be associated with darolutamide, as well as other AR inhibitors, that we see relatively frequently is fatigue, which for some patients can be debilitating—they may have difficulty working and performing their daily activities. We also occasionally see some patients experience diarrhea, nausea, and vomiting,” she added, “although they are typically more frequently associated with chemotherapy.”

In the case of darolutamide, dose adjustments are relatively easy, as it comes in 300-mg tablets.

Ms. Lloyd continued: “The relatively mild cases can often be managed with supportive care medications per institutional guidelines, without any need for dose adjustments. However, for more severe cases, dose adjustments or temporary therapy holds should be considered. In the case of darolutamide, dose adjustments are relatively easy, as it comes in 300-mg tablets. So, instead of taking two tablets in the morning and then two tablets in the evening, we recommend taking one tablet twice daily.”  

“Also, as many of these patients take medications for chronic comorbidities,” she added, “one needs to be acutely aware of the potential for drug-drug interactions. We are lucky to have exceptional pharmacists on our team who help us navigate that and make sure we stay away from any significant drug-drug interactions.”

Key Takeaways

Dr. Hussain shared some closing thoughts: “We have made great progress in terms of many novel agents being developed and successfully introduced into clinical practice. As a result of that, patients nowadays are experiencing tangible benefits, including significantly increased overall survival, as compared with a decade or so ago, and better and longer cancer control. We now need to try to better understand various mechanisms of resistance to these novel therapeutic approaches, especially as they move into the earlier disease setting. Achieving that and translating it to clinical practice will require a large collaborative effort. Luckily, today there is great interest in research in this area, and I feel confident that we will keep making progress. My hope is that in the future, we will be able to turn advanced disease into a more chronic one and even cure some patients.”

We now need to try to better understand various mechanisms of resistance to these novel therapeutic approaches, especially as they move into the earlier disease setting.

Ms. Lloyd offered these key takeaways: “Clinical guidelines are wonderful resources to help us navigate management of a very challenging disease with an increasingly complex therapeutic landscape. But what is important to keep in mind always is that what matters most is the actual person in front of us. Each patient is unique, and the defining factors in terms of what therapy we are eventually going to go with will have to suit that individual.” 

Disclosures

Maha Hussain, MD, FACP, FASCO, has served on advisory boards for GSK, Novartis, and Bayer; has received honoraria for serving as an invited lecturer at educational events from Merck, AstraZeneca, and several organizations sponsoring such events; and has received institutional clinical trial funding from Genentech, Bayer, and Arvinas.

Jennifer L. Lloyd, APRN, has served as a consultant to Pfizer.

References

1. Bergengren O, Pekala KR, Matsoukas K, et al. 2022 Update on prostate cancer epidemiology and risk factors—a systematic review. Eur Oncol May 16, 2023 (early release online).
2. Cancer Stat Facts: Prostate Cancer. National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program. Available at https://seer.cancer.gov/statfacts/html/prost.html. Accessed June 27, 2023.
3. Jemal A, Culp MBB, Ma J, Islami F, et al. Prostate cancer incidence 5 Years after US Preventive Services Task Force recommendations against screening. J Natl Cancer Inst 2021;113:64–71..
4. Rebello RJ, Oing C, Knudsen KE, et al. Prostate cancer. Nat Rev Dis Primers 2021;7:9.
5. Hamid AA, Sayegh N, Tombal B, et al. Metastatic hormone-sensitive prostate cancer: toward an era of adaptive and personalized treatment. Am Soc Clin Oncol Educ Book 2023;43:e390166.
6. Desai MM, Cacciamani GE, Gill K, et al. Trends in incidence of metastatic prostate cancer in the US. JAMA Netw Open 2022;5:e222246.
7. Mittal A, Srikala SS, Ong M, et al. Triplet therapy in metastatic castrate sensitive prostate cancer—a potential new standard of care. Curr Oncol 2023;30:4365–4378.
8. Francini E, Gray KP, Xie W, et al. Time of metastatic disease presentation and volume of disease are prognostic for metastatic hormone sensitive prostate cancer. Prostate 2018;78:889–895.
9. Schaeffer EM, Srinivas S, An Y, et al. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 1.2023—September 16, 2022. To view most recent version, visit NCCN.org.
10. Gebrael G, Thomas VM, Swami U, et al. The management of metastatic castrate-sensitive prostate cancer: from guidelines to real-world practice. Oncologist April 4, 2023 (early release online).
11. Zurth C, Koskinen M, Fricke R, et al. Drug-drug interaction potential of darolutamide: in vitro and clinical studies. Eur J Drug Metab Pharmacokinet 2019;44:747–759.
12. Boujonnier F, Lemaitre F, Scailteux LM. Pharmacokinetic interactions between abiraterone, apalutamide, darolutamide or enzalutamide and antithrombotic drugs: prediction of clinical events and review of pharmacological information. Cardiovasc Drugs Ther May 1, 2023 (early release online).
13. Williams SCR, Mazibuko N, O’Daly O, et al. Comparison of cerebral blood flow in regions relevant to cognition after enzalutamide, darolutamide, and placebo in healthy volunteers: a randomized crossover trial. Target Oncol 2023;18:403–413.
14. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med 2019;380:1235–1246.
15. Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med 2020;383:1040–1049.
16. Nubeqa (darolutamide) prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212099Orig1s000lbl.pdf. Accessed June 27, 2023.
17. Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone‐sensitive prostate cancer. N Engl J Med 2022;386:1132–1142.
18. Hussain M, Tombal B, Saad F, et al. Darolutamide plus androgen-deprivation therapy and docetaxel in metastatic hormone-sensitive prostate cancer by disease volume and risk subgroups in the phase III ARASENS trial. J Clin Oncol February 16, 2023 (early release online).
19. Smith MR, Tombal BF, Saad F, et al. Darolutamide and time to pain progression by disease volume in ARASENS. 2023 ASCO Annual Meeting. Abstract e17075.
20. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015;373:352–360.
21. Fizazi K, Tran NP, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 2017;377:352–360.
22. Fizazi K, Foulon S, Carles J, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet 2022;399:1695–1707.
23. Shore N, Garcia-Horton V, Terasawa E, et al. Safety differences across androgen receptor inhibitors in nonmetastatic castration-resistant prostate cancer. Future Oncol 2023;19:385–395.