Androgen Receptor Inhibition in CRPC

Part 1: Deciding Whether Next-Generation Scans Are Needed for nmCRPC

During a live event, Evan Yu, MD, discussed how to monitor a patient being treated with androgen deprivation therapy and hormonal agents for nonmetastatic castration-resistant prostate cancer using prostate-specific antigen levels and next-generation imaging.

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 QUESTIONS:

  • What is the role of molecular imaging in this situation?
  • Would you restage this patient based on the results of next-generation imaging?​

EVAN YU, MD: When would you image this patient? And what would you image this patient with?

AMANDA SUN, MD: The PSA doubling time of 8 months is borderline [indication] to do imaging.1 However…his lowest PSA level was following the prostatectomy. So I think he can be considered for advanced prostate imaging.

I ordered these scans for 1 of my patients. Not exactly in the same situation but a rising PSA with a doubling time of around 8 months or so. It is very difficult to get an insurance approval to get any imaging at that time. I think they can be considered around like 8 months or so.

The total PSA is also taken into consideration. If it is very low, I would not do imaging because the disease volume is too low to be detected.

RISA WONG, MD: I think that you could image, but if you image with the idea of doing metastasis-directed therapy, it [is] less likely to be of a significant benefit given that he is already castration resistant.

YU: Would you do PSMA [prostate-specific membrane antigen]-PET, or fluciclovine F18 [Axumin] PET, or 18F choline PET?

WONG: Unless they were pushing for it that, I think I would just stick with standard imaging.

YU: OK, why?

WONG: Maybe this patient would change their mind, but they declined adjuvant and salvage radiation [several] times. If their standard imaging is negative and they have already accepted systemic therapy with ADT, then I would probably just treat them as nonmetastatic castrate-resistant prostate cancer [nmCRPC] with darolutamide [Nubeqa] or [another hormonal agent].

YU: If someone else did a fluciclovine F18 PET scan, and the patient had 1 metastasis, would you still consider this patient to have nmCRPC?

WONG: If their standard imaging was negative, but they had next generation imaging that was positive?

YU: Yes, that is exactly what I'm asking. Would you up-stage them or not?

WONG: I think that I would not.

YU: So, you would still consider him available for all the nmCRPC treatments then. Does anyone think that [even though] the patient had conventional imaging, they want to do more? There are more sensitive imaging modalities.

ZHAO: I would want to do more. First of all, it is available. The fluciclovine PET CT scan is available in Seattle at Swedish Medical Center. We do it a lot. And there are some things we can do if we find oligometastatic disease. He could have abiraterone [Zytiga] or enzalutamide [Xtandi]. He has a seizure history so [I wouldn’t use] apalutamide [Erleada]. So, abiraterone would be an option.

He could get benefit from stereotactic ablative radiotherapy if he had oligometastatic disease based on the ORIOLE trial [NCT02680587] data and the SABR-COMET trial [NCT01446744].2,3

Depending on the insurance, he could get sipuleucel-T [Provenge] for mCRPC. But the data we have [that justify use of] sipuleucel T and abiraterone is for [metastases that were identified] using the conventional CT and a bone scan. So we do not know if we can extrapolate these data to next-generation imaging.

YU: You summarized it well. You are right, fluciclovine F18 is better. A PSMA-PET scan is probably even better. In 3 to 5 years, we will probably be doing PSMA-PET on everyone.

The challenge is, if you do next-generation PET imaging and their conventional imaging is negative, where do you place them? [It seems] you can place them where you want to place them because there are no set guidelines on that yet.

XINGWEI SUI, MD: I would definitely do next-generation imaging, if available, but I do not have a lot of confidence in regular bone scans. I have never done a next-generation PSA scan. Do you have any issues with insurance?

YU: PSMA-PET is newly FDA-approved 18F-DCFPyL [Pylarify] for staging of biochemical recurrence4 and gallium-68 gozetotide was [previously] FDA approved, with the University of California Los Angeles and University of California San Francisco having unlimited approval.5 Here in Seattle, we have a PSMA-PET imaging protocol, but you have to meet certain eligibility criteria. So, we have not been able to bill insurance companies for our PET imaging with PSMA-PET.

We have not had [insurance] problems with fluciclovine F18 PET. I would say that more often than not, it goes through without issues for fluciclovine F18.

But I generally counsel the patient in advance, and [find out] if they are interested in oligometastatic-directed therapy. [Are they willing] to irradiate if you find 1 metastasis? Then I will do [a next-generation scan]. If they say no, then I am not as interested in doing that. I will tell them that there are good systemic therapy options for nmCRPC. I probably would not do it in this instance.

ZHAO: Let’s say they did want to get the next-generation imaging, and there was a lesion that showed up there but did not show up on standard imaging, but they also refused oligometastatic therapy. Would you treat them as nmCRPC, or would you up-stage them?

YU: You can do what you want to do there. So, if you like giving sipuleucel-T early, you could do it. If you like giving apalutamide or darolutamide, you can't do that for mCRPC, but you can argue that by conventional imaging, that they have nmCRPC. So, you could do that, too. I think that you have freedom to do what you want to in that situation.

But again, my preference would be to counsel the patient and discuss it in advance. If the patient is not interested in site-directed therapy and they are interested in systemic therapy, I would make the argument that I have systemic therapies available too.

References:

1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 3.2022. Accessed February 16, 2022. https://bit.ly/3GU39tI

2. Phillips R, Shi WY, Deek M, et al. Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: the ORIOLE phase 2 randomized clinical trial. JAMA Oncol. 2020;6(5):650–659. doi:10.1001/jamaoncol.2020.0147

3. 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

4. FDA approves second PSMA-targeted PET imaging drug for men with prostate cancer. FDA. Published May 27, 2021. Accessed February 16, 2022. https://bit.ly/3oSOdpF

5. FDA Approves first PSMA-targeted PET imaging drug for men with prostate cancer. Published December 01, 2020. Accessed February 16, 2022. https://bit.ly/3oOAIqX