New Precision Medicine Approaches in Advanced Prostate Cancer
In this companion article, Neeraj Agarwal, MD, discusses the role of genomic testing and imaging in the initial diagnosis, staging, and treatment of prostate cancer.
Results from the VISION trial announced at the 2021 American Society of Clinical Oncology Annual Meeting signaled an exciting future for precision medicine in prostate cancer. The results showed that theranostic lutetium 177-PSMA-617 (LuPSMA) significantly improved radiographic progression-free survival and overall survival when compared with best standard of care alone in patients given a diagnosis of prostate-specific membrane antigen (PSMA) –positive, metastatic, castrate-resistant prostate cancer (mCRPC) who had progressed after chemotherapy and hormone therapy. Further, treatment with LuPSMA revealed no unexpected or concerning safety signals. Together, these findings heralded possibilities both for the target population and for other men given the diagnosis of advanced prostate cancer.
As with the 2 PSMA positron emission tomography–imaging agents currently approved for use in patients given a diagnosis of prostate cancer (ie, gallium 68-PSMA-11, fluorine 18-DCFPyL), LuPSMA builds upon the success of genomic tests to target tumor-specific biomarkers. However, unlike the widely-used, National Comprehensive Cancer Network (NCCN) –recommended genomic assessments of metastasis and mortality risk related to prostate cancer (ie, Decipher Prostate, Oncotype DX Genomic Prostate Score assay, Prolaris, and many comprehensive genomic profiling platforms such as CARIS, Foundation Medicine, Guardant-360, and Tempus), these PSMA-targeting agents exploit phenotypic expression, not genotypic mutation. In so doing, they highlight the usefulness of targeting PSMA specifically and, more broadly, phenotypically expressed biomarkers.
Thus, LuPSMA opens prostate cancer to theranostics, an exciting area of precision medicine.
In the New Precision Medicine Approaches in Advanced Prostate Cancer series, experts discuss the evolving spectrum of precision medicine in advanced prostate cancer. This series features a review of NCCN guidelines, genomic testing, nuclear imaging, PSMA, advanced disease, and the rapidly developing treatment landscape and emphasizes the potential impact of newer therapies on prostate cancer treatment.
In the first interview of the series, Neeraj Agarwal, MD, a genitourinary oncologist, director of the Genitourinary Oncology Program and the Center of Investigational Therapeutics, and professor of medicine and Presidential Endowed Chair of Cancer Research at the Huntsman Cancer Center of the University of Utah, Salt Lake City, discusses the role of genomic testing and imaging in the initial diagnosis, staging, and treatment of prostate cancer.
TARGETED ONCOLOGYTM: Could you discuss the current NCCN guidelines for initial prostate cancer screening and diagnosis?
AGARWAL: In the guidelines, the first step is to perform a digital rectal examination to confirm the clinical stage of prostate cancer. That’s followed by looking at the PSA [prostate-specific antigen] level, calculating the PSA density and PSA doubling time, and reviewing the diagnostic prostate biopsies or, if they have not been done, obtaining prostate cancer biopsies.
This is followed by a very important step: estimating the life expectancy of a given patient, using the validated tools on the NCCN guidelines website. This estimate is used to not overtreat those patients who are not likely to die because of prostate cancer. For instance, if somebody has major cardiovascular disease, heart failure, and a performance status of 3 and [is] diagnosed to have a prostate cancer, but his life expectancy turns out to be 1 or 2 years, is there any reason [for this patient] to undergo radiation therapy or surgery for his prostate cancer? This patient likely is going to die with prostate cancer and not because of prostate cancer. Hence, estimating the life expectancy is so important.
For the next step, we follow important changes in the recent NCCN guideline versions. These require us to obtain testing for high-risk germline mutations. If we come across a family history of high-risk germline mutations, such as BRCA1, BRCA2, or Lynch (MSH2) mutations; if the family history is suspicious for these mutations; or if there is intraductal and/or cribriform histology in an intermediate-risk patient, then the patient needs to be sent to a genetic counselor for pretest genetic counseling before undergoing germline testing. It should be noted that the intraductal and/or cribriform histology are known to be associated with increased risk of these mutations. Even if I don’t see a family history of these genetic mutations, I still consider germline testing in many patients if they have high-risk clinical features. And, of course, obtaining a thorough family history when the patient is diagnosed for the first time is also very important.
This is the initial approach to screen and diagnose a patient with newly diagnosed prostate cancer or who is suspected to have prostate cancer.
TARGETED ONCOLOGYTM: The NCCN guidelines place staging as the next step. After patients are staged, who should undergo genomic testing?
AGARWAL: The NCCN guidelines lay out very nicely how to stage newly diagnosed patients into very low-, low-, intermediate-, high-, or very high-risk categories. Once staged, [patients at] very low risk usually are not required to have tumor-based molecular assays or genomic tests such as Decipher, Oncotype Dx prostate, and Prolaris. They are required to have a confirmatory prostate biopsy or an MRI of the prostate and, mostly, are candidates for active surveillance, so we can put [patients at] very low risk on the side. On the other side of the spectrum, we have [patients given a diagnosis of] very high-risk prostate cancer who are likely to have metastatic disease. If distant or regional metastasis [has] been found in the bone scan or the CT scan, [patients] obviously require systemic therapy. If they do not have metastatic disease, [patients] still require some kind of surgery or radiation or definitive therapy. So, we usually don’t need these tumor-based molecular assays for patients who [have received a diagnosis of] very low- or very high-risk prostate cancer.
Anyone in between—which includes low-, intermediate-, and high-risk patients—requires one of these molecular assays, according to the NCCN guidelines, as long as they have a life expectancy of 10 years or more. And, again, we don’t need any of this testing or definitive therapy if patients have a low life expectancy. Those patients are unlikely to die because of prostate cancer; they’re likely to die with prostate cancer.
TARGETED ONCOLOGYTM: You mention MRI, bone scan, and CT scan. What is the role of imaging in prostate cancer therapy?
AGARWAL: After the initial diagnosis of prostate cancer, depending upon the risk of the prostate cancer—but especially in those who belong to intermediate- or high-risk localized prostate cancer—according to the NCCN guidelines, we obtain a bone scan [and/or] a CT scan of the pelvis, plus or minus the abdomen … Basically, we want to rule out regional or distant metastasis. For low-risk prostate cancer, the NCCN guidelines ask that we consider confirmatory prostate biopsy with or without a prostate MRI to establish candidacy for active surveillance. The NCCN guidelines have very specific indications on when to get imaging studies. But if you look at intermediate- and high-risk prostate cancer, when the risk of metastasis is higher, clearly there is a definite role of bone scan and CT scan, so the first step is to rule out metastasis.
TARGETED ONCOLOGYTM: For these low-, intermediate-, and high-risk patients who have long life expectancy and who don’t have metastases, what’s the role of genomic testing? Why is it done?
AGARWAL: Once you have ruled out [metastasis], and as long as these patients are well—have a life expectancy of more than ten years—there are 3 genomic tests or tumor-based molecular assays which can be performed. The tests that are currently approved and widely utilized in the clinic are Decipher [Prostate], Oncotype DX [Genomic Prostate Score assay], and Prolaris. All of these are not done in 1 patient; 1 test can be offered to a patient. Patients who have [been given a diagnosis of] low-risk, intermediate-risk, [or] high-risk localized prostate cancer with a life expectancy of 10 years or more can be offered one of these tests.
What are these tests supposed to do? They are supposed to tell us, in those patients who do not have obvious evidence of metastasis on the scan, what is the likelihood of these patients [dying] of prostate cancer? What is the likelihood of these patients developing metastasis? What is the likelihood of these patients having non-organ-confined disease? Also, in [the] case of Decipher, the test can also be used after surgery; so, most of these tests are used after the biopsy, not after the surgery. But in the case of Decipher, we can use this test after the surgery if there are high-risk features present, especially to look for the role of radiation therapy in those patients.
Overall, what these tests … are doing is that they are helping us in determining the likelihood of metastasis and death because of prostate cancer in our patients who are considered to have localized prostate cancer today. When you are doing this testing—genomic testing—they’re actually helping us in determining whether we should treat these patients with definitive therapy or [if] it [is] safe for these patients to undergo active surveillance … That is one of the reasons we are doing this testing.
So, questions may be asked in this context. If you already [have] NCCN risk stratification in place, you have CAPRA [Cancer of the Prostate Risk Assessment] scores in place, why do you need these tests? Studies have shown that Decipher [Prostate], Oncotype DX [Genomic Prostate Score assay], and Prolaris testing can independently predict or correlate with metastasis and prostate cancer–specific mortality versus traditional NCCN risk stratification or CAPRA risk.
So, I think because of the independent nature of being able to predict prostate cancer–specific mortality, onset of metastasis, [and] onset of biochemical recurrence, there is a value of doing those tests.
TARGETED ONCOLOGYTM: Could you describe these tests in greater detail?
AGARWAL: These tests are done on biopsy specimens and are RNA-based. All of these independently predict risk of recurrence and metastasis, and risk of death because of prostate cancer.
In the case of Decipher, this is a whole-transcriptome assay [that] is looking at 1.4 million RNA covering more than 46,000 genes and noncoding parts of the genes. This is an oligonucleotide microarray, which is optimized for FFPE [(formalin-fixed paraffin-embedded) tissue specimen] addition. It’s pretty easy to do the test. You can send out the tissue for tests to be performed in an external laboratory without having to worry about the degradation of the quality or quantity of tissue.
Oncotype DX [Genomic Prostate Score assay] is also used on the biopsy tissue. Oncotype DX is a quantitative RT–PCR [(reverse transcription–polymerase chain reaction) test] for 12 prostate cancer–related genes.
The third approved, widely utilized genomic test is Prolaris. This uses a quantitative RT–PCR platform for 31 cell cycle–related genes and 15 housekeeping genes.
TARGETED ONCOLOGYTM: How helpful are these NCCN-recommended genomic tests—is genomic testing—for treating prostate cancer?
AGARWAL: These tests—Prolaris, Decipher [Prostate], and Oncotype DX [Genomic Prostate Score assay]—are for patients who have local, organ-confined disease; who have [been given a diagnosis of] low-, intermediate-, or high-risk prostate cancer; and who have an estimated life expectancy of 10 years or more. They can help independently of the NCCN risk stratification or CAPRA risk stratification. These genomic tests can independently help our patients in deciding whether they want to pursue active surveillance or definitive therapy with surgery or radiation by telling them their risk of recurrence—either biochemical recurrence or metastatic disease—or their risk of dying because of prostate cancer.