Clinical Commentary: The Treatment Landscape of Metastatic Hormone-Sensitive Prostate Cancer

Nancy Dawson, MD

Medical Oncologist

Norton Cancer Institute

Assistant Professor

University of Louisville School of Medicine

Louisville, KY

EVENT SUMMARY:

At a live virtual event, Nancy Dawson, MD, discussed the treatment of patients with metastatic hormone-sensitive prostate cancer and what important aspects of treatment clinicians should home in on. Dawson, director of clinical research at the Georgetown Lombardi Comprehensive Cancer Center, discusses the clinical trials that looked at treatment with docetaxel or abiraterone and the impact of triplet regimens. Moreover, Dawson looks at the adverse events profile to look out for.

The molecular testing [for patients with] hormone-sensitive disease is only useful in terms of deciding whether you want to put the patient on a clinical trial or not. There are several clinical trials that are looking at PARP inhibitors, but only on the clinical trial setting right now for hormone-sensitive disease.

The thing about tumor volume is that it is sort of a negative thing and if [a patient has] high-volume disease, then certain therapies might be more beneficial to them. For example, usually the benefits of chemotherapy in the combination of docetaxel plus androgen-deprivation therapy [ADT] over ADT alone were only seen in patients with high-volume disease.¹

This was not seen in [patients with] low-volume disease, whereas with some of the oral therapies like apalutamide [Erleada] and enzalutamide [Xtandi], it does not matter whether your patient has high- or low-volume disease because in either case it is beneficial. So high volume is important in that it determines some other things that [a clinician might do]. For example, you would not radiate someone’s prostate if they had de novo metastatic disease or if they had high-volume disease.

In the trials of docetaxel they found that older patients seem to tolerate it and benefit like younger people do.² They tolerated and preferred cabazitaxel [Jevtana] but we do not do that usually in this setting, but frailty is still one factor to consider.

Trials Establishing the Foundation of Treatment

In the CHAARTED [NCT00309985] and STAMPEDE trials [NCT00268476], both were associated with increased overall survival [OS] in the chemotherapy arms and had about 15% discontinuation rate for adverse events [AEs].³ Again, in the CHAARTED trial it was only about [patients with] high-volume patients who benefited, but then you have the addition of abiraterone [Zytiga] in the LATITUDE [NCT01715285] and the STAMPEDE trials. Again, both of those trials showed that adding abiraterone significantly improved OS, and OS in the LATITUDE trial was positive in favor of adding abiraterone [Table³].

Both the ENZAMET trial [NCT02446405], which added ADT plus a first-generation antiandrogen like bicalutamide or flutamide vs adding enzalutamide, and the ARCHES trial [NCT02677896], which was ADT plus enzalutamide vs placebo, updated data showed significant improvement in OS by adding enzalutamide and had a relatively low AE discontinuation rate of 6% to 7%, respectively.

The TITAN trial [NCT02489318] also has updated OS data showing a significant improvement in OS by adding apalutamide to ADT. There are also the 2 triplet regimen trials, PEACE-1 [NCT01957436], which was the ADT-docetaxel plus abiraterone trial, and the ARASENS trial [NCT02799602], which looked at ADT plus docetaxel plus or minus darolutamide. Both of those trials showed significant improvements in OS with an HR of 0.75 [95% CI, 0.59-0.96, P = .021] in the PEACE-1 trial and an HR of 0.68 [P < .001].

Real-World Analysis and Results of Prostate Cancer Treatments

[In a post hoc and real-world analysis of the TITAN study] researchers looked at the apalutamide data from a group of 69 patients from urology practices also looking at what happens if a patient is on ADT vs what happens if they are on apalutamide in terms of their prostate-specific antigen [PSA] kinetics.⁴ What we see at 3 months, 6 months, and 12 months is the percentage of patients have significant drops in their PSA level at [89% to 58%, 90% to 68%, and 90% to 71%, respectively].

If we look at the relativeness of ADT vs ADT plus apalutamide we are going to see that significantly more patients have a 90% drop in their PSA and significantly more of them have a PSA that becomes basically undetectable, and patients who have those undetectable or significant drops in PSA also have a better survival outcome.

Now, in trying to interpret these data, why is it not OK to just take the apalutamide when you progress vs take it up front? Some of the impact of these combinations up front is that they have a significant impact on the patient’s PSA, which translates to a significant impact on their survival.

When we talk about triplet therapy, [the question] is: Does docetaxel by itself [provide] your patient a benefit, and then does adding apalutamide do no more than the docetaxel did? If you already may have the benefit from the docetaxel, does adding apalutamide to docetaxel have your patient do any better than if you just did the apalutamide alone? So how much contribution do we have from the docetaxel vs how much we get from the second-generation anti-androgen, androgen-blocking, and antigen-inhibiting drug apalutamide? In my mind it may be that you already got what you are going to get from the docetaxel.

Managing Challenges With Treatment

Enzalutamide came out with a 40-mg tablet and it is quite tiny because people complained about the 40-mg capsules. The abiraterone tablets are still too big. Docetaxel, of course, is given in your vein, and you have to give prednisone with the docetaxel as well as with the abiraterone, but it is different, slightly less when it is for hormone-sensitive patients than for those who are castrate resistant. Then you have all these different things that they warn you about that are quite different, and they do influence how you manage these patients in terms of their AEs and what you are looking for.

For example, we know with abiraterone, we are worried about mineralocorticoid excess and hepatotoxicity and fluid retention, so you do not have to worry about what their ejection fraction is.⁵ You do not have to worry about what their liver function is. You will have to monitor it every few weeks for at least the first couple of months, where on the other end you have enzalutamide and apalutamide, both of which are associated with falls and seizures.

Enzalutamide now is associated with ischemic heart disease,⁶ and then you have docetaxel, which can be associated with the AEs of chemotherapy. Patients can get paresthesia, neutropenic fever, and they can get quite significant neutropenia. These are sort of the practical considerations when you are telling these patients about these drugs, that they are different.

Now, looking at the guidelines, bone-targeted therapy is recommended in castrate-resistant patients and not those with hormone-sensitive disease.⁷ There was a large, randomized trial I participated in where they looked at the use of zoledronic acid [Zometa] vs placebo to prevent skeletal-related events in patients with hormone-sensitive disease, and there was no difference in the skeletal-related events.⁸

A similar trial was not done with denosumab [Xgeva], but the reason, I think, is that in patients with hormone-sensitive disease they might be more likely to have a responsive disease, but the data do not support that adding a targeted therapy in the hormone-sensitive setting helps.

_References

_{1. Sweeney C, Chen Y, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-746. doi:10.1056/NEJMoa1503747}

_{2. Wong HL, Lok SW, Wong S, Parente P, Rosenthal M. Docetaxel in very elderly men with metastatic castration-resistant prostate cancer. Prostate Int. 2015;3(2):42-46. doi:10.1016/j.prnil.2015.03.003}

_{3. Ong S, O’Brien J, Medhurst E, Lawrentschuk N, Murphy D, Azad A. Current treatment options for newly diagnosed metastatic hormone-sensitive prostate cancer-a narrative review. Transl Androl Urol. 2021;10(10):3918-3930. doi:10.21037/tau-20-1118}

_{4. Chi K, Saad F, Chowdhury S, et al. Prostate-specific antigen kinetics in patients with advanced prostate cancer treated with apalutamide: results from the TITAN and SPARTAN studies. J Urol. 2021;206(suppl 3):e587. doi:10.1097/JU.0000000000002038.11}

_{5. Attard G, Merseburger AS, Arlt W, et al. Assessment of the safety of glucocorticoid regimens in combination with abiraterone acetate for metastatic castration-resistant prostate cancer: a randomized, open-label phase 2 study. JAMA Oncol. 2019;5(8):1159-1167. doi:10.1001/jamaoncol.2019.1011}

_{6. Kulkarni AA, Rubin N, Tholkes A, et al. Risk for stroke and myocardial infarction with abiraterone versus enzalutamide in metastatic prostate cancer patients. ESMO Open. 2021;6(5):100261. doi:10.1016/j.esmoop.2021.100261}

_{7. Saad F, Hotte SJ. Guidelines for the management of castrate-resistant prostate cancer. Can Urol Assoc J. 2010;4(6):380-384. doi:10.5489/cuaj.10167}

_{8. So A, Chin J, Fleshner N, Saad F. Management of skeletal-related events in patients with advanced prostate cancer and bone metastases: incorporating new agents into clinical practice. Can Urol Assoc J. 2012;6(6):465-470. doi:10.5489/cuaj.12149}