Choosing AR-Targeted Therapy in CSPC
During a live virtual event, Roby A. Thomas, MD, discussed the choice of therapy for a patient with metastatic castration-sensitive prostate cancer.
A 73-year-old man presented with urinary retention, fatigue, and decreased appetite. He was physically active and had no family history of prostate cancer. Transrectal ultrasound and biopsy revealed adenocarcinoma of the prostate gland with Gleason score 8 [4+4] with disease in 10/12 cores. His prostate-specific antigen (PSA) level was 150 ng/mL; hemoglobin (Hb) was 9.7 g/dL; absolute neutrophil count (ANC) was 1.9. His liver function tests (LFTs) were abnormal.
In September 2018, he received a diagnosis of localized high-grade prostate cancer. He underwent robotic radical prostatectomy with subsequent PSA decrease (0.2 ng/mL), and CT and bone scans showed no residual disease.
In October 2019, the patient complained of right hip pain and abdominal pain. Imaging with CT and bone scan showed multiple metastatic bone lesions in the pelvis and diffuse liver lesions. His PSA was 90 ng/mL; Hb 9.4 g/dL; ANC 1.5. He received a diagnosis of metastatic prostate cancer; germline genetic testing was negative.
He wishes to receive oral treatment/avoid chemotherapy and minimizing adverse events (AEs) is very important to him.
What systemic treatment option are you most likely to recommend for this patient?
ANEEL CHOWDHARY, MD: Patients who have 4 bone lesions or more, 1 of which is outside the axial skeleton, or visceral metastases, would be high volume. Low volume would be 1 to 3 bone lesions.…I don’t know if there are any other definitions out there, but those [were used in] the CHAARTED [NCT00309985] and the TITAN [NCT02489318] trials.
KASRA KARAMLOU, MD: But, does high versus low volume matter [with the current treatment options]?
VIVEK ABHYANKAR, MD: When it comes to visceral metastases, that is where I make my differentiation of using chemotherapy versus oral therapy.
ZACHARY HORNE, MD: It also makes a difference if you’re thinking about radiation for treating low-volume versus high-volume or high-risk disease, since the high-risk patients don’t benefit.
KARAMLOU: As far as your upfront recommendation for therapy, I think nowadays if you feel a patient is a candidate for triplet therapy, you’ll treat them with triplets. If you feel that they’re not a candidate for chemotherapy, then you would just use androgen deprivation therapy [ADT] plus a novel androgen blockade.
CHOWDHARY: Yes, but in castration-sensitive disease like this patient, at least the TITAN trial showed that there was benefit with apalutamide and ADT at both low and high volume.1 So from that perspective, whether you have low volume or high volume, it may not matter.
KARAMLOU: CHAARTED was the only trial that, at least for the docetaxel, didn’t show a benefit [for love-volume disease].2
ROBY A. THOMAS: So, what I’m hearing is you do use a little bit of this high volume versus low volume in terms of your decision-making.
MICHAEL NEMUNAITIS, MD: I might also consider doing a biopsy, if he has diffuse liver metastases, just to make sure there are no small-cell components.
ABHYANKAR: But otherwise, he’s already stated that he wants oral therapy. So, I think in that sense, he’s already decided that he wants one of the novel androgen blockades. I have had problems getting apalutamide [Erleada] approved. I get boxed into putting patients on abiraterone [Zytiga] and prednisone; is anyone else experiencing that?
ELAINE BEED, MD: Yes, we have a hard time because patients had to pay for this out of pocket—we’re in a rural area and they don’t have a lot of money. I end up using abiraterone because its cost is lower. Enzalutamide [Xtandi] has a [patient assistance] program, but they never seem to qualify….It’s a big problem that the patient can’t pay for it.
THOMAS: Sometimes coverage is a major issue, and the out-of-pocket costs can be quite significant. Do [you think] abiraterone might be a little bit easier for our patients to get?
BEED: It’s [around] a tenth of the price of some of the others, or a fifth, depending on their insurance.
THOMAS: Has anybody tried to utilize 1 pill, a 250-mg dose of abiraterone, with a low-fat meal, [which showed noninferiority versus standard dosing]3 if they’re running into financial concerns or toxicity concerns?
KARAMLOU: I find that to be confusing for the patients, honestly.
JASON BIERENBAUM, MD: I’ve used it as a last resort with GoodRx; it [is inexpensive] for 1 pill a day, but it’s only if they can’t get the drug any other way.
THOMAS: This patient is pretty set on getting some sort of oral therapy and avoiding chemotherapy. How do you counsel or discuss this with your patients?
BEED: No one wants to come in and get IV [intravenous] therapy; that’s the bottom line. You have to guide them into what might be the best decision, and of course they can then decide for themselves what they want.
KARAMLOU: I think the picture has become a little more confusing after the ARASENS trial [NCT02799602], and one of the other trials that was recently presented where [an aggressive approach] seems like the way to go. But for chemotherapies, if somebody can get docetaxel, [I] certainly would offer it; [unless] a patient doesn’t want to get IV therapy, or they have any contraindication such as performance status issues, or you just don’t think they’re going to handle it.
ABHYANKAR: This patient is 73 years old and it sounds like he is in pretty good shape. I think maintaining his quality of life is likely best accomplished with one of the novel androgen suppressants. But, at the same time, I think he is also young enough that he is probably going to see chemotherapy at some point in time, and at what point in time do you use that?
THOMAS: That’s a very good point. As far as the novel hormonal agents, do you have any preferences? For abiraterone, I heard some of the rationale as far as concern for costs. What about the toxicity profiles? Is that something you think about when you’re prescribing these medications?
ABHYANKAR: Patients don’t like being on prednisone [with abiraterone].
KARAMLOU: I think with this patient, the LFTs being normal or abnormal might sway you one way or another. In a perfect world, I’d probably like using darolutamide [Nubeqa] because I think that’s the best tolerated out of all of them, but I’ve had a hard time getting that approved in the castrate-sensitive setting.
THOMAS: Darolutamide has the same mechanism of action, different molecular structure, and doesn’t cross the blood-brain barrier. Certainly, the AE profile is favorable. Hopefully, with the ARASENS data, we may have some easier time getting that authorized now.
Why [might] we use ADT alone? Is it simply [because] we couldn’t get the other drugs authorized?
ABHYANKAR: There are some men that just don’t tolerate the degree of androgen suppression. I’ve had a patient who [was lethargic and less functional], but…when pulled off ADT, he was very functional, very smart, no longer lethargic; and I was giving him testosterone, watching his PSA levels for years. So, that might be somebody that I would only have on ADT.
BEED: I use it to see how they’re getting better or worse, if it’s going up or down. There is always a rare case where the PSA isn’t elevated. It’s very positive feedback for the patient, because usually it works quickly.
JOSE SILVA, MD: [It generally does not] affect my treatment selection. The highest PSA [I ever saw] was 8000 ng/ml; that patient lived 7 years with metastatic disease.
KARAMLOU: Is there any rationale for [favoring one therapy over another due to PSA]?
THOMAS: If the PSA is low, and you’re seeing patients presenting with symptomatic lesions, then you would consider that this could be a high-grade neuroendocrine or small-cell differentiated tumor. Then I would think about doing a biopsy to verify that, and the treatment paradigm’s a little different.
I think the absolute value of the PSA really doesn’t play a huge role. [As Dr Silva] mentioned, [a patient had] PSA of greater than 7000 ng/ml to 8000 ng/ml, and lived for many years. Some of these prostate adenocarcinomas, especially with the lower Gleason scores, may be higher producers of PSA; whereas, in the spectrum of a higher-grade prostate adenocarcinoma, Gleason grade of 8, 9, or 10, you might not see a very high PSA. Sometimes the PSA kinetics are not predictive of how much metastatic disease you might see.
It’s a question physicians may consider, depending on their comfort level with treating prostate cancer. I have spoken with other physicians at different sites who said that the PSA was so high, they felt compelled to use chemotherapy in the first-line setting. But again, it’s something a little bit more complicated when you think about the biology of the tumor.
1. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021;39(20):2294-2303. doi:10.1200/JCO.20.03488
2. Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED Trial. J Clin Oncol. 2018;36(11):1080-1087. doi:10.1200/JCO.2017.75.3657
3. Szmulewitz RZ, Peer CJ, Ibraheem A, et al. Prospective international randomized phase II study of low-dose abiraterone with food versus standard dose abiraterone in castration-resistant prostate cancer. J Clin Oncol. 2018;36(14):1389-1395. doi:10.1200/JCO.2017.76.4381