Recap: Updates of Androgen Deprivation Therapy in Prostate Cancer

At an Around the Practice program hosted by CancerNetwork®, experts reviewed the current treatment paradigm of androgen deprivation therapy (ADT) for prostate cancer. The panel was led by Robert Dreicer, MD, MS, deputy director of UVA Cancer Center, director of solid tumor haematology/oncology and professor of medicine and urology with University of Virginia (UVA) Health as well as deputy director of UVA Cancer Center in Charlottesville.

Additional panelists included Saby George, MD, director of Network Clinical Trials and professor of Oncology and Medicine in the Department of Medicine at Roswell Park Comprehensive Cancer Center in Buffalo, New York; and Mark Scholz, MD, executive director of the nonprofit Prostate Cancer Research Institute and an oncologist at Cedars Sinai Marina del Rey Hospital in Marina del Rey, California.

Defining the Role of ADT

Dreicer: Why do we do testosterone suppression in prostate cancer?

George: Prostate cancer multiplies, propagates, and metastasizes dependent on AR [androgen receptor] signaling, or AR signaling by testosterone binding to the AR, and that allows for the cancer cells to multiply and spread. We have seen many new developments in terms of adding more and more to androgen suppression, yet androgen suppression is the mainstay. There are different ways this can be achieved. Surgical bilateral orchiectomy is one of the fastest ways to achieve castrate-range testosterone levels. As soon as you clip the artery feeding to the testicles, they almost reach the level of castration. Then, the most common way is suppression via pituitary testicular access using LHRH [luteinizing hormone-releasing hormone] agonists and LHRH antagonists. LHRH agonists, like leuprolide, take 3 to 4 weeks for castration-range testosterone levels to be achieved, while with newer agents, like with degarelix [Firmagon], 5% of the patients become castrated within 3 days of LHRH antagonist use.

There are other ways to suppress the testosterone signaling by targeting the AR blockers. Novel agents that can block the signaling include enzalutamide [Xtandi], apalutamide [Erleada], and bicalutamide [Casodex]. Those are the newer agents. We have a whole host of different ways of blocking testosterone signaling, binding, and internalization into the nucleus to prevent propagation and multiplication of prostate cancer cells. This is crucial in managing the disease.

Dreicer: What is the distinction between these 2 different forms of blocking
testosterone?

Scholz: My general response is to look at it through the eyes of the patient experience. Sometimes with [degarelix], patients will get rashes. They need to come in every month for a shot. Relugolix has an oral delivery form that we can give indefinitely. In fact, I have patients all over the country and we can prescribe these things over the phone, and they don’t even need an office visit. What’s attractive about these agents compared to the older agents such as leuprolide is the immediate decline in testosterone which, with early-stage disease, may not be that material or concerning, but is clinically more attractive.

Dreicer: [For patients to have] nonmetastatic castration-resistant prostate cancer [nmCRPC], they had to be started on testosterone suppression. This is an interesting disease state because it’s somewhat of an artificial construct. It could come from patients who were treated with radiation therapy for locally advanced disease and were maintained for 2 to
3 years as per prospective level 1 evidence, but then developed biochemical progression in the setting of castration. Many patients may have been started on ADT for PSA [prostate specific antigen]-only disease. It’s in that setting that there’s still a fair amount of controversy since we don’t have level 1 evidence to support that yet. We may at some point; however, nmCRPC includes rising PSA with no evidence of [disease on] conventional imaging, bone scan, or CT.

Patient Case of nmCRPC

Case 1

• A 62-year-old man who is 2 years out from a radical prostatectomy presented with a Gleason score of 9 (4 + 5).
• He has detectable PSA, which led to salvage radiotherapy and ADT.
• PSA level was 7.6 ng/mL; PSA doubling time is 8.8 months.
• Testosterone levels were 33 ng/dL.
• Bone scan showed no evidence of disease; CT of the abdomen/pelvis showed 2 pelvic lymph nodes < 2 cm.
• ECOG performance score: 0

Dreicer: If this patient comes to you, do they get a PSMA [prostate-specific membrane antigen] PET scan?

Scholz: Absolutely. If we have access to these PSMA PET scans, [we should use them]. CTs and bone scans are an antiquated methodology. Where this leads is to the potential advantages of multimodality therapy to go after oligometastatic disease. With a better scan, if you see a limited number of [metastases], which hopefully you will, then the possibility of a meaningful benefit from radiating metastatic lesions using multimodality systemic therapy is more likely to have a bigger payoff.

Dreicer: Let’s first talk about this patient in an environment where PSMA PET is not going to be done for whatever reason. You have…this [patient], will you use next-generation ARIs [androgen receptor inhibitors]? How do you briefly explain the risk and benefit? Again, we all know that the data are compelling. They all showed overall survival [benefit and] the hazard ratios are similar and meaningful. How do you make treatment decisions based on the data? How do you present the information to a patient and how do you then make a clinical judgment about which drug to recommend?

George: Technically that is a patient with nmCRPC. The patient didn’t have any symptoms. All we see are the small lymph nodes. Three studies of
darolutamide [Nubeqa], apalutamide, and enzalutamide had demonstrated that application of these agents early on can prolong the metastasis-free survival [MFS], meaning the time to metastasis can be pushed to roughly 40 months compared with 16 months by not using it. That’s an impressive improvement. MFS was defined based on traditional imaging, bone scan, and regular traditional CT scans. While we do have availability of these newer modalities, they may have a higher sensitivity and specificity; but technically, it’s still the same patient whether you do the scan or not.

It’s still the same space that we’re talking about, but because we are able to detect this micrometastatic or low-burden disease using a newer modality of scan, it doesn’t mean that we should deny them the treatment. It has been shown in 3 large studies that the newer AR-blocking agents like darolutamide, apalutamide, and enzalutamide have the ability to prolong MFS and SSE, or time to symptomatic skeletal events, and improve quality of life. It’s important to apply the data in this space.

Dreicer: What is your routine recommendation in this setting and what’s the rationale for it?

George: I’ve had the most experience with enzalutamide since 2012 or 2013 onward, so that tends to be my default and it’s been around a long time.
Apalutamide came through and darolutamide came afterwards. The difference is that there has been a slight increase in the incidence of seizure disorders or reported seizure disorders with the use of enzalutamide. [In terms of] adverse [effects], darolutamide may have a better edge over the other 2. With a limited experience, darolutamide is probably safer with similar efficacy. Safety is important, especially [as] most of these patients are in their 60s, 70s, and 80s, so we have to be very careful when choosing a drug.

Patient Case of Metastatic Prostate Cancer

• Case 2

• A 70-year-old man received a diagnosis of localized prostate cancer 3 years ago. At that time, he underwent radical prostatectomy with no residual disease on the CT and bone scan.
• The patient now presents with intermittent right hip pain.
• His medical history is otherwise unremarkable.
• Physical exam: right hip tender to palpation; slight limp and decreased weight bearing on right leg
• PSA level, 50.2 ng/mL; PSA DT, 4 months
• Core needle biopsy with transrectal ultrasound showed adenocarcinoma of prostate.
• Gleason score: 8 (4 + 4)
• Bone scan: 2 bone metastases, 1 in the right femur and 1 in the right pelvis
• CT chest/abdomen/pelvis scan: positive for 3 pelvic lymph nodes
• Diagnosis is stage IV metastatic hormone-sensitive prostate cancer.
• ECOG performance score: 1

Dreicer: How would you treat this patient?

George: I would be more aggressive with this patient. He’s 70 years old and is presenting 4 years after radical prostatectomy with disease on radiographic images, and the bone scan shows 2 lesions. The patient also has some lymph node [involvement], meaning at least 4 metastases, and…anemia as well.

If you consider bone marrow as an organ, technically he has organ
dysfunction from this. We consider red cell involvement as a high-risk feature. I would present ADT plus docetaxel and/or one of the newer agents based on the data. Given the fact that the patient has pain, I’d be very careful how I initiate the ADT. We tend to initiate ADT at the same visit using LHRH antagonists like degarelix. That way they can be medically castrated within 3 days, [and] symptoms are relieved within a week or so. Then I tend to initiate docetaxel, which has been in the practice since 2015 based on the ECOG 3805 trial [CHAARTED; NCT00309985].1 Now we have data from [the phase 3] PEACE1 trial [NCT01957436] and ARASENS trial [NCT02799602] showing that addition for abiraterone acetate [Zytiga] or darolutamide can prolong survival significantly in these patients.^2,3

Dreicer: PEACE1 was in a de novo group of patients. In ARASENS, 86% had de novo disease. Are you ready to apply [the results of] both those studies?

George: Patients with de novo metastatic disease at the outset are slightly different from a patient who recurred after primary treatment, like radiation or radical prostatectomy. For a practical reason, this patient has symptomatic bone metastases, anemia, and significant burden of disease.

Dreicer: You believe that triplet intensification needs to be applied a little bit more broadly, perhaps?

George: I would push for that in this patient. In an older patient, we must be very careful because [of frailty]. Adding triplet therapy may be too much in terms of toxicity and safety management. That has to be considered, and we need to have a long discussion about what oral [treatment] means. If that patient is in line with that and [the ECOG] performance status is 1, the patient may be able to get away with it.

Scholz: I concur with Dr George in terms of the reapplication of the PEACE1 and ARASENS data to patients such as this. Whether or not someone had local therapy previously [does not] change the general character of someone who has metastatic disease. Sometimes I’ll talk to patients about trying 1 treatment, see how they feel and how well they tolerate that initial cycle of docetaxel, and if it is well tolerated, we’ll proceed accordingly.

[Going back to] the PSMA PET scans, because I think we’re all going to be hearing about this, PSA is a marker for response and survival. PSA levels are powerful for determining what’s going on with these treatments. Now that we have better systemic scans, such as PSMA PET, we’re going to want to get a baseline PSMA head scan prior to starting treatment. Then, as we would with a patient that didn’t have elevated PSA, we would get a scan after 3 and 6 months. When we get into these more advanced stages, there is a subgroup of patients with cancer who don’t [have elevated PSA levels] and it is possible to get mixed responses. If you treat someone with widespread metastatic diseases, the patient probably has many metastases. When you get the PSMA PET scan, there may be 15 sites of metastasis or more. But after treating to a complete response, if they [achieve] undetectable PSA, they may also have complete disappearance of disease on PSMA PET. If so, should those few oligometastatic lesions be treated with spot radiation?

Dreicer: It’s certainly a proactive approach.

When you’re talking about a patient [for whom you] use intensification, what’s your general approach for helping the patient decide [between docetaxel and AR inhibitors]?

Scholz: I work backwards from what the patient’s quality of life is going to be like. There’s no comparison between the toxicity of darolutamide and docetaxel, it’s a no-brainer.

The darolutamide is dramatically less toxic than chemotherapy. They’re not within 2 orders of magnitude of each other. My assumption is this patient would immediately go on the darolutamide in combination maybe with leuprolide or degarelix.

Dreicer: Genomic testing obviously in prostate cancer has become a very
important consideration for lots of reasons. What’s your standard approach?

George: I turn to tumor somatic testing rather late in the game because I do believe that the vast majority of prostate cancer cells are modifiable or can be blocked using AR-targeting agents. We discussed earlier that LHRH or testosterone suppression is the mainstay of treatment. When this breaks through or progresses, despite suppression of testosterone, that usually signals the emergence of resistant clones. There are different kinds of cells, some of which may be responding to hormones and some may not. If that happens, that’s when I tend to get a biopsy and a test for somatic mutations. We also concurrently do the germline testing to see if there’s any BRCA [mutations] associated with those data that can be applied later as additional treatment options, like olaparib [Lynparza].

Scholz: We’ll usually get a baseline cell-free DNA test in our metastatic patients when we first meet them. We probably wouldn’t use the olaparib as a first-line treatment, but it’d be nice to know if they have BRCA2 or ATM [mutations]. The rare cases of microsatellite instability-high cancers that I’ve [had can be treated with] with Keytruda [pembrolizumab]. I find those very rare cases with a simple blood test to get cell-free DNA and make sure that I’m not missing something there.

Dreicer: The ARASENS data that were presented at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] and are now published in the New England Journal of Medicine, also suggest a very [significant] impact on overall survival. We talked about how it’s going to impact your practice. We all believe that the label will be expanded and we will be able to use this. What do those data mean to you in terms of how you think about patient management?

Scholz: It makes it easier for me to advocate for something I’ve been doing for over 10 years. With the data behind the recommendation now, the whole concept is that there’s a value to effective early treatment and lower volume of disease that has almost always been borne out.

In a situation where you have a life-threatening disease, I’ve always been attracted to treatment intensification in patients who can manage the potential toxicity. To me, it streamlines the whole educational process with patients. What we’re seeing now with the power of PSA and PSMA PET scans is that what would’ve been nonmetastatic disease in the past [is being recognized as] early metastasis. It’s the same low-volume disease that, in theory, would benefit from adjuvant therapy.

Dreicer: For patients who are fit to receive triplet therapy in your judgment, irrespective of age and physiological fitness, is this now becoming your standard of care in terms of management?

George: You bet. I want to be aggressive when I can. We know that ADT alone prolongs survival. Adding docetaxel prolongs survival further, and we’ve seen that PEACE1 and ARASENS [data] are demonstrating that adding abiraterone and darolutamide to the ADT-docetaxel backbone prolongs survival significantly beyond the previously established standard. When I have the opportunity to apply the triplet [regimen], I carefully select patients. As you mentioned, if somebody is 60 years old, but physiologically they are 75 or 80, then I’d be very cautious. But if it’s an 80-year-old who plays tennis 4 times a week and acts like a 55- or 60-year-old and is presenting with advanced prostate cancer, I would be aggressive in the second patient opposed to the first one.

References

1. Sweeney CJ, Chen YH, 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. 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. Published Online April 8, 2022. doi:10.1016/S0140-6736(22)00367-1
3. Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142. doi:10.1056/NEJMoa2119115