Importance of Molecular Imaging in Patients With Prostate Cancer

Channing J. Paller, MD

Nearly one-third of men with prostate cancer develop biochemical recurrence following treatment with local therapy. However, numerous options exist which help oncologists to manage patients with this disease.

Despite definitive local treatment with radical prostatectomy or radiation, patients with prostate cancer still develop prostate-specific antigen (PSA) recurrence. With this, there is often no evidence of disease on conventional imaging. According to Channing J. Paller, MD, this disease state is called biochemical recurrence.

For patients who develop biochemically recurrent prostate cancer, options include surveillance, salvage radiation, androgen deprivation therapy (ADT), and enrollment on clinical trials.

In research published in the American Society of Clinical Oncology Educational Book, investigators, including Paller, evaluated these current approaches in this patient population.

“First, radiation therapy, including selection of field, dose, and use of concurrent anti-androgen therapy, is reviewed. Next, molecular imaging is addressed, including prostate-specific membrane antigen PET imaging and its increased sensitivity in identifying sites of disease,” stated Paller in an interview with Targeted Oncology^TM. “Then, the factors associated with starting ADT are explored, and the data supporting intermittent over continuous ADT are reviewed. Lastly, the use of prostate-specific membrane antigen PET imaging and its potential role influencing therapy are discussed.”

In the interview, Paller further discussed the current approaches to radiation therapy, ADT, and molecular imaging for men with prostate cancer who have biochemical recurrence.

Targeted Oncology: Can you provide an overview of your published research “Best Approaches and Updates for Prostate Cancer Biochemical Recurrence?”

Paller: Biochemical recurrence develops in almost one-third of men with prostate cancer after treatment with local therapy. There are numerous options for management, including surveillance, salvage radiation, androgen deprivation therapy, and clinical trials. The research reviews the current approaches to radiation therapy, ADT, and molecular imaging in men with biochemically recurrent prostate cancer.

First, radiation therapy, including selection of field, dose, and use of concurrent anti-androgen therapy, is reviewed. Next, molecular imaging is addressed, including prostate-specific membrane antigen PET imaging and its increased sensitivity in identifying sites of disease. Then, the factors associated with starting ADT are explored, and the data supporting intermittent over continuous ADT are reviewed. Lastly, the use of prostate-specific membrane antigen PET imaging and its potential role influencing therapy are discussed.

What are the current treatment options or ways to manage patients with biochemically recurrent prostate cancer?

[There is] salvage radiation to the prostate bed and pelvic lymph nodes is the standard approach to treating biochemical recurrence. Then, concurrent use of antiandrogen therapy with radiation therapy has also demonstrated improved overall survival. Prostate-specific membrane antigen PET scans can detect recurrent disease at lower PSA levels and improve progression-free survival when these lesions are covered in the radiation treatment plan.

[Also,] the decision to initiate androgen deprivation factors depends on multiple factors, including Gleason score, initial PSA, PSA doubling time, and patient preference. If androgen deprivation therapy is initiated, intermittent therapy is preferable to continuous therapy.

Can you explain biochemical recurrence and why it develops in nearly one-third of men with prostate cancer?

Despite undergoing definitive local therapy with radical prostatectomy [RP] or radiation for prostate cancer, many men will go on to develop prostate-specific antigen [PSA] recurrence with no evidence of disease on conventional imaging. This disease state is called biochemical recurrence [BCR].

The Phoenix criteria are used to define BCR post radiation therapy, which requires an increase in PSA of at least 2 ng/mL above the post radiation PSA nadir, whereas BCR post-RP is defined as at least 2 PSA values that are 0.2 ng/mL or higher. The PSA rise means that some cancer cells have survived and are producing PSA. These patients exhibit no signs of prostate cancer clinically or by standard bone or cat scan imaging. When BCR is documented in post prostatectomy patients, the critical first patient evaluation step is to determine whether the recurrence is due to local recurrence or disseminated disease.

Can you discuss molecular imaging in this patient population?

Molecular imaging has been used to stage patients with prostate cancer, starting with bone scans, 18F-NaF PET, 18F-fluorodeoxyglucose PET, and, more recently, 18F-fluciclovine PET. These imaging studies are used to determine the presence of local recurrence, regional nodal involvement, and distant metastases. Most patients being considered for salvage radiation therapy have no evidence of disease on these imaging modalities, and radiation therapy planning depends on previously defined consensus tumor volumes.

This has changed with the introduction of radiopharmaceuticals that target PSMA, a transmembrane protein that is overexpressed on prostate cancer cells and represents a relevant target for PCa imaging and therapy. PSMA PET can detect disease recurrence outside of the consensus tumor volumes. Two PSMA PET radiopharmaceuticals are currently approved by the FDA: 18F-DCFPyL [18F-piflufolostat] and 68Ga-PSMA-11 [68Ga-gozetotide].
 

What is the importance of PSMA PET imaging for these patients?

PSMA PET using small, radiolabeled ligands is highly sensitive, even at low PSA levels, and may offer early localization of PCa BCR. It has major impact on salvage radiation therapy planning by revealing lesions not covered by the standard radiation fields, including both the prostate bed and pelvic lymph nodes.

The ORIOLE trial [NCT02680587] demonstrated that patients who had PSMA-positive disease that was not included in the treatment plan experienced disease recurrence faster than did those whose disease was covered. The impact of the additional sites of disease detected by PSMA PET is also being evaluated in several prospective trials, including a multi-center RCT, the PSMA-SRT trial [NCT03582774], in which postoperative patients were randomly selected to receive conventional imaging and PSMA PET. The end points are salvage radiation therapy success rate at 5 years, measured by 5-year biochemical PFS and MFS.

What are the factors associated with starting ADT for these patients? Why?

The decision to initiate androgen deprivation depends on multiple factors, including Gleason score, initial PSA, PSA doubling time, and patient preference. Based on the latest 2 randomized controlled trials, TOAD and ELAAT [NCT00110162 and NCT00439751], immediate ADT resulted in longer time to local progression and distant progression. However, the long-term OS benefit is uncertain. This uncertainty about the OS benefit of immediate ADT initiation combined with serious AEs and quality of life issues that may accompany ADT treatment has led many patients to defer ADT initiation and to opt instead for observation. At Johns Hopkins University School of Medicine, given the lack of a clear overall survival advantage with the use of immediate ADT, it is generally recommended to defer ADT in patients at low-risk of metastatic progression, while early initiation of ADT remains a reasonable choice for those at high risk of developing metastatic disease.

Can you discuss the use of prostate-specific membrane antigen PET imaging and its potential role influencing therapy?

PSMA PET helps determine if a patient has a locally recurrent, oligometastatic, or metastatic disease, which then helps us determine the next step of treatment. If the patient only has a locally recurrent or oligometastatic disease, then targeted therapy with radiation is still an option. If the patient has metastatic disease, systemic treatments are appropriate.

What research is currently being performed in this space? What compounds or agents are being explored?

The AbiCure study [NCT01751451] looked at abiraterone acetate [Zytiga] and found no benefit when adding it to ADT.Similarly, the EMBARK trial [NCT02319837] is ongoing and will ask if adding enzalutamide [Xtandi] to leuprolide [Lupron Depot] provides benefit.Although the AbiCure trial is negative, we have some exciting results from the 2022 American Society of Clinical Oncology meeting of another trial, SALV-ENZA [NCT02203695] that tested adding enzalutamide to salvage radiation therapy in men with BCR after radical prostatectomy. The trial found that salvage radiation plus enzalutamide monotherapy for men with PSA recurrent high-risk prostate cancer following radical prostatectomy is safe and delays PSA progression relative to salvage radiation alone.

What unmet needs still must be filled in this patient population?

In the salvage population, [we need to determine] the interval of ADT, whether it should be 6 months or 24 months of ADT, and determine whether we should use targeted radiation or whole pelvic radiation.

A second important unmet need is to understand how to integrate PET scans into treatment decision-making. We [also] have an ongoing trial testing the benefit of adding metastasis-directed radiation to standard of care in patients with BCR who show prostate cancer spreading outside of the pelvis by PET [NCT04423211].

With improvements in imaging and targeted therapy, this area is being redefined. It would be exciting to watch the progress for the next few years as we are able to better identify and precisely target prostate cancer.

REFERENCE:

Simon NI, Parker C, Hope TA, Paller CJ. Best Approaches and Updates for Prostate Cancer Biochemical Recurrence. Am Soc Clin Oncol Educ Book. 2022;42:1-8. doi:10.1200/EDBK_351033