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FAQs: Emerging Prostate Cancer Therapies
Emerging Therapies and the Near Future Evolution in Prostate Cancer: Expert Discussion of Frequently Asked Questions

Released: April 01, 2023

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Key Takeaways
  • False positives can occur with PSMA PET scans, and results should be interpreted with caution.
  • PARP inhibitors are required to be given in combination with androgen-deprivation therapy.

In this commentary, Neeraj Agarwal, MD, FASCO; Tanya B. Dorff, MD; and Rana R. McKay, MD, answer questions submitted by an audience of healthcare professionals at a live Clinical Care Options symposium during the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium.

Is it necessary to test for prostate-specific membrane antigen (PSMA) expression in tissue before starting PSMA-targeted therapy?

Tanya B. Dorff, MD:
I do not think it is necessary because we have a wonderful theranostic with the PET scan. I hope that some of the clinical trials testing PSMA-targeted therapy are performing immunohistochemistry (IHC) or detecting circulating tumor cell expression—just different ways of using a biomarker to predict who will have the best response. This also would allow us to better understand whether antigen escape is one of the mechanisms of resistance. As of now, it is not necessary to test for PSMA expression by IHC, but we may learn more in the future.

Why did the VISION trial of 177lutetium-PSMA-617 exclude patients with large PSMA-negative lesions?

Tanya B. Dorff, MD:
The randomized, open-label phase III VISION trial looked at 177lutetium-PSMA-617 in patients with metastatic castration-resistant prostate cancer with PSMA-avid metastatic disease based on Ga68-PSMA PET scans. The theranostic concept is that the PET scan tracer needs to find the cancer for the payload to affect it, so it makes sense that you do not want to treat someone for whom only part of the disease will respond because the tracer only goes to some of it. This is similar to how we use radium-223, which works only in the bone; you do not want to have a large soft tissue metastasis that will not be treated with your therapeutic. However, I think we have a lot more to learn about how to use PSMA PET scans to better select patients for 177lutetium-PSMA-617 treatment.

The UCLA compassionate access experience allowed patients who did not meet the VISION PET eligibility criteria to receive 177lutetium-PSMA-617. Although it was a small number of patients (n = 29), those who did not meet the VISION PSMA PET criteria did not derive as much benefit compared with those who did, with a lower response rate (reduction of ≥50% in prostate-specific antigen [PSA] in 20.7% vs 50.3%; P = .005) and median progression-free survival (2.1 months vs 4.1 months; P = .0023).

Neeraj Agarwal, MD, FASCO:
In the case of a PSMA PET scan that shows a PSMA negative lesion in the liver along with PSMA-positive lesions in the bone, would you perform a biopsy? You cannot use 177lutetium-PSMA-617 in this circumstance, but would you perform a biopsy to look for anything special?

Rana R. McKay, MD:
I would absolutely do a biopsy. We are seeing treatment emergent neuroendocrine tumors at a prevalence rate of 15% to 20%. The behavior of these tumors can change over time, and if I have a patient with a neuroendocrine tumor, I consider the addition of a platinum—perhaps even carboplatin/etoposide, depending on the histology and prior treatment status.

For patients with local prostate cancer who are found to have metastatic disease upon PSMA PET scan, what is your thought process for treatment consideration?

Rana R. McKay, MD:
I think the advent of PSMA imaging has created a lot of gray area. When a patient is negative by conventional imaging but positive by PSMA PET scan, we do not have level 1 evidence of how to best treat that patient. In my practice, those patients are seen in a multidisciplinary clinic. We already know from the multiarm, multistage STAMPEDE trial (NCT00268476) that patients who have untreated disease in the prostate with low-volume metastases derive benefit from prostate directed radiation therapy. There are many questions about escalating by adding novel hormonal therapy (NHT) in these patients. We have some data from STAMPEDE showing that patients with localized, high-risk disease as defined by Gleason score (8-10), PSA ≥40 ng/mL, or disease stage ≥T3 derived benefit from abiraterone.

Extrapolating from localized STAMPEDE and STAMPEDE low-volume, I treat patients with localized prostate cancer who are found to have metastatic disease upon PSMA PET with a multimodal approach of NHT, radiation therapy to the prostate, and, in certain circumstances, metastasis-directed therapy.

Is it possible for PSMA PET scans to have false positives?

Rana R. McKay, MD:
There can be false positives, and we biopsy when it is feasible. However, what we often see are small things on the ribs with nothing elsewhere, and in talking to our nuclear medicine colleagues, the likelihood that isolated rib metastases are positive in the context of localized disease is quite low. The trouble is that in those scenarios, it is very difficult to get conclusive data back from a rib biopsy. I think the big struggle is not whether to treat patients locally or give them NHT; rather, it is whether to provide stereotactic body radiation therapy to the rib.

Tanya B. Dorff, MD:
There are absolutely false positives, and you have to be very careful. I would caution people from relying solely on a PSMA PET scan without scrutiny. I recently had a patient who had received a cortisone injection in their shoulder, and the PSMA PET tracer lit up there. The radiologist explained that you can get leakage of the PSMA tracer into areas of inflammation. I do not think people appreciate enough how challenging it can be to interpret these PSMA PET scans; we discuss these scan results at length in our tumor board to scrutinize the results and determine if a biopsy is needed. We try to give patients the benefit of the doubt given that conventional imaging still forms the basis of most of our treatment paradigms.

Rana R. McKay, MD
Also, PSMA is expressed on endothelial cells, and we actually see it in the neovascular areas of tumors. If there is an area that is healing and there is blood vessel formation, you may see PSMA uptake.

What are your thoughts regarding initiating PARP inhibitors in earlier settings (eg, high risk castration sensitive disease)?

Neeraj Agarwal, MD, FASCO:
This question is being actively investigated in 2 ongoing clinical trials in patients with metastatic castration sensitive prostate cancer. The randomized phase III TALAPRO 3 trial (NCT04821622) is comparing enzalutamide/talazoparib vs enzalutamide/placebo in patients with DDR mutations. The randomized phase III AMPLITUDE trial (NCT04497844) is testing abiraterone/prednisone with or without niraparib in patients with HRR mutations. I hope this question will be answered by the results of these trials in the near future.

Do PARP inhibitors need to be given with androgen-deprivation therapy, either surgical or medical?

Neeraj Agarwal, MD, FASCO:
Yes, PARP inhibitors are required to be given in conjunction with ongoing castration therapy, either surgical or medical, as part of their regulatory approval. They are not approved as single agents without castration therapy.

With so many emerging therapies, targets, and combinations, how do you think through sequencing of agents?

Rana R. McKay, MD:
My hope is that we will become more selective in our strategies instead of administering these therapies to broad patient populations. Many of the ongoing trials in the metastatic hormone sensitive setting are being designed for biomarker-selected populations. The phase III CAPItello-281 study (NCT04493853) is looking at capivasertib plus abiraterone vs abiraterone alone in patients with PTEN deficiency, whereas the AMPLITUDE study, for example, is designed for patients with HRR mutations. It would be a good thing if these studies were positive, because it would add different combinations with medications with novel mechanisms of action into the clinic. However, it also will become increasingly challenging to answer the question of how we sequence these different agents.

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