Androgen Receptor Inhibition in CRPC

Part 3: Combining Therapies to Treat a Patient With CRPC

During a live virtual event, Alicia Morgans, MD, MPH, discussed when to combine novel hormonal agents with androgen-deprivation therapy in nonmetastatic castrate-resistant prostate cancer and how novel imaging techniques could influence treatment.

CASE SUMMARY

In October 2016, a 57-year-old black man was referred to the urology department with a PSA (prostate-specific antigen) of 6.8 ng/mL. His medical history included seizures that were controlled with oxcarbazepine. His mother and sister had a history of breast cancer, and his brother had a history of pancreatic cancer. A multiparametric MRI scan showed a 58 cc index lesion to his left prostate zone, and prostate imaging reporting and data system showed it to be 4/5, 1.8 cm. 3 months later, he had a robotically assisted radical prostatectomy and extended lymph node dissection. 6 weeks post operation, the patient had a PSA of 0.15 ng/mL and baseline serum testosterone of 420 ng/mL.

Androgen deprivation therapy (ADT) was initiated with leuprolide depot at 45 mg. The patient returned in August 2019. His PSA doubling time (PSA-DT) was 8.6 months with a PSA of 1.2 ng/mL. In October 2019 he was restaged, and bone scans showed he was negative for metastatic disease with an ECOG performance score of 0. In October 2020, the patient’s PSA was 3.81 ng/mL.

DISCUSSION QUESTION

  • What are the practical implications of having both overall survival (OS) and metastasis-free survival (MFS) data for androgen receptor (AR)-targeted therapy in nonmetastatic castrate-resistant prostate cancer (nmCRPC)? Does this influence your use of these agents?

ALICIA MORGANS, MD, MPH: What do you think about the OS benefit and the MFS benefit of darolutamide [Nubeqa], apalutamide [Erleada], and enzalutamide [Xtandi]? Does that influence what your answer might be in terms of thinking through whether you would add something to ADT in this patient with nmCRPC?

MOHAMAD KHASAWNEH, MD: I’ve been using apalutamide since the approval in 2018. Those are really impressive. We know once patients fail definitive therapy for prostate cancer, more likely than not, they will progress and die from their disease or complications. Having such options available is great. We do not make our patients do these things; it’s always that we act like a counsel for the patient. We mention the adverse events [AEs], the benefits, quality of life [QOL] is really important thing for hormone therapy in general, but then you targeted a novel therapy, also.

For example, the seizure [risk] with enzalutamide is something that we always discuss with our patients. Not that it happens; in my opinion, I think the seizure was something that was probably an over-read AE, and it’s overprotective on the part of the FDA for the approval. So, I personally have been on the bandwagon for the use of apalutamide in patients with biochemical failure [based on the trial data for this agent].

EDWARD KAPLAN, MD: I would also use apalutamide, but I was wondering, in this young person with progressive cancer…I don’t use it, but is there a role for a pseudo-adjuvant taxane in this setting? Were there data to suggest that taxanes did have OS, or at least disease-free survival benefit. This patient case just bothered me because of the fact that he didn’t have the local radiation; he had a PSA-DT that seemed fast, and his young age. He’s also African American, [and prostate cancers in these patients] tend to be more aggressive, whatever the other histology shows. So, I wondered about that, and I don’t know if that’s what I would have done in real life, but I did suggest that as a possibility for this person. Normally, I would go to one of the novel hormonal agents.

MORGANS: I think it’s an interesting question. I practice in Chicago, too, and I can say that our radiation oncologists would potentially use PET imaging, see if they could find something, and then they would sometimes ask me, “Can you give a little bit of docetaxel to chemosensitize while I radiate this or that?” This is the kind of person that they might ask about that in.

Now, just to be clear, there are no data for that. I think the data from STAMPEDE [NCT00268476] included some patients with nonmetastatic disease in the hormone-sensitive assessment of docetaxel plus ADT vs ADT alone.1 But, when we look at the subgroup analyses in STAMPEDE, it’s not clear that the patients who don’t have metastatic disease on conventional imaging will benefit from taxane. Just 1 study, and it’s not powered for that end point, and so I am always a little bit hesitant, especially since I know what taxanes do to QOL. So, it’s an interesting question, and I appreciate you raising it. I have radiation oncology colleagues who would ask that same question and would probably use it.

BRIAN CHANG, MD: We have the randomized SABR-COMET trial [NCT01446744], which shows OS benefit with stereotactic body radiation therapy [SBRT] and oligometastatic prostate cancer.2 PSMA [prostate-specific membrane antigen] scanning is going to move the goal posts, it’s going to probably increase the number of patients. By the way, I believe [piflufolastat] F18 PSMA scanning is FDA approved in high-risk patients now.3 It’s just not available in the Midwest yet; it’s available on the East Coast, and the Southeast, apparently. But, later this year, it should be available.

DISCUSSION QUESTION

  • How will novel imaging impact your approach? Do patients with PSMA-only metastases fit into this group or do they have low-volume metastatic disease?

CHANG: To answer that second question about how PSMA scanning is going to affect systemic therapy, I think you can consider these patients who have oligometastatic disease as having low-volume metastatic disease, because they’re going to be receiving SBRT or ablative therapy to their gross disease. So all you’re dealing with would be subclinical microscopic disease. But I think things are going to change. You’re going to have a lot of arguments as to how to interpret PSMA data. If you don’t see things on conventional imaging, you wouldn’t have treated them in an aggressive fashion, with SBRT and systemic therapy. I think most of the physicians, at least in our neck of the woods, are going to adopt that aggressive strategy, citing not just the SABR-COMET trial, but I think we’ll also be treating the primary in some of these patients, because there was an arm in the STAMPEDE trial that did show benefit to treating the primary with radiation.1

MORGANS: I would agree with that, but I would point that this is a patient with castration-resistant disease.

CHANG: I’m just talking about in general, but for this particular patient, yes. If PSMA scanning showed disease, we would treat that gross disease if we thought it was feasible.

MORGANS: I think that’s exactly what we’re seeing happen. I do that in many cases, but what I also do is add that AR antagonist because I know I can get an OS advantage using phase 3, level 1 evidence data. Often, we’re doing stereotactic ablative radiotherapy [SABR], as well, to areas that we can see on a PSMA PET. But we are definitely in a gray area when we’re doing that, because we have to do the trials, and SABR-COMET was in a hormone-sensitive population, as well.

So many questions here, and there are ongoing trials that are trying to answer them. I think it’s interesting, the way that we all extrapolate a lot of data, and we do the same thing you do, Dr Chang. But I wouldn’t add a taxane, I would intensify my AR antagonist, plus my ADT, and I would probably do a little SBRT on a trial for this patient, as well.

CHANG: When they ask you to use a taxane as a sensitizer, are they giving conventional radiation to these metastatic sites?

MORGANS: I don’t know, but I usually say no.

CHANG: Yes, that shouldn’t be done. I’m not really sure where they’re getting that data from.

AJAY KANDRA, MD: I think the data are from patients with high-volume disease. Multiple, I think more than 4 or more than 5 bone metastases, or visceral metastases. So normally, we are not doing docetaxel up front unless somebody has very high-volume disease.

References:

  1. James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017;377(4):338-351. doi:10.1056/NEJMoa1702900
  2. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet. 2019;393(10185):2051-2058. doi:10.1016/S0140-6736(18)32487-5
  3. FDA approves second PSMA-targeted PET imaging drug for men with prostate cancer. News release. May 27, 2021. Accessed October 29, 2021. https://bit.ly/2TU7vhY