Genotypic vs. Phenotypic Biomarkers in Prostate Cancer Precision Medicine

DANIEL E. SPRATT, MD is Vincent K. Smith Professor and Chair of Radiation Oncology for University Hospitals Seidman Cancer Center, Cleveland, Ohio. Dr. Spratt’s research has focused on developing ultra-prognostic and predictive biomarkers in prostate cancer. His work has been the basis of multiple Phase 2 and 3 national and international clinical trials. He currently leads NRG Oncology’s Intact Prostate Cancer Subcommittee and serves on the National Cancer Institute’s Genitourinary Steering Committee. Dr. Spratt runs an NIH-funded translational research team focused on improving outcomes for men with prostate cancer.

Precision vs personalized medicine

“Precision medicine” and “personalized medicine” have different meanings and should not be used interchangeably, Dr. Spratt stresses. Personalized medicine, the older expression, has been practiced “for decades” in prostate cancer, and involves tailoring medical treatment according to individual patients, based on disease stage, PSA level, and Gleason score, Dr. Spratt explains. Precision medicine “takes that to the next level,” with tissue-based molecular and genomic biomarkers and imaging tools to guide therapy and improve clinical risk stratification. Development of precision medicine for prostate cancer has been much slower than for other malignancies such as breast, lung, and colorectal cancers, where upfront genetic testing is already part of standard management. “It is only in the past couple of years that precision medicine tools have become available for prostate cancer, especially in advanced prostate cancer, so we’re entering a new era,” Dr. Spratt recalls.

Over the past two years, multiple biomarker-based therapies have emerged for prostate cancer, some of which have already been improved by the Food and Drug Administration (FDA). The first genomic targeted therapy class for prostate cancer, poly (ADP-ribose) polymerase (PARP) inhibitors, which are guided toward men with certain DNA repair alterations (homologous recombination deficiency; HRD), were approved in May 2020.2,3 An upcoming “new frontier” of phenotypic therapies is based on the expression of prostate-specific membrane antigen (PSMA), a transmembrane protein anchored in the cell membrane of prostate cancer epithelial cells that is highly overexpressed in prostate cancer cells compared with healthy tissues. PSMA can now be measured by imaging, as well as other tools. The first PSMA-targeted imaging drug for men with prostate cancer was approved by the FDA in 2020.4

Challenges of genotypic biomarkers in prostate cancer

There are several challenges associated with genotypic biomarkers in prostate cancer, Dr. Spratt points out.

Genotypic biomarkers are assessed most frequently through biopsy, which is invasive and associated with significant morbidity, whether the lesion biopsied is primary or metastatic. The most common metastatic site in prostate cancer is bone, and bone biopsies are technically challenging to obtain, with diagnostic yield of only about 70%, even in expert hands, Dr. Spratt points out. It may be difficult to obtain sufficient tissue for genomic and other molecular studies.

Another challenge with genotypic biomarkers is that patients with advanced prostate cancer often have dozens, sometimes hundreds of metastatic tumors in different organs, including the lung, liver, bone, and lymph nodes, some in the prostate itself, and although evidence has been presented for the monoclonal origin of different metastases within an individual patient, there is heterogeneity. “It is not feasible to sample all metastatic sites in the body to determine the composite genetic make-up of each cancer,” Dr. Spratt points out.

In addition, although the genotype is often regarded as a gold standard, i.e., the presence of a specific gene alteration means that a patient will benefit from a certain drug, Dr. Spratt cautions in reality, that is not the case, “even with the best precision medicine tool based on a genotype.” For example, although about one-quarter of patients’ mCRPC will have altered HRD genes, such as BRCA1 or BRCA2, the majority of patients will not respond or have improved outcomes with a PARP inhibitor, he notes. “We are still missing a component from which patients will benefit. I would say that although there are definitely strengths to phenotypic precision medicine, at present there are a lot of obstacles and limitations that we’re working on.”

A phenotypic biomarker in advanced prostate cancer

Phenotypic biomarkers, observable characteristics produced through the interaction of a genotype and environment, are emerging as a new approach in precision medicine that is becoming increasingly popular. The foremost example is prostate-specific membrane antigen (PSMA). PSMA expression can be measured in many ways, by genotyping and measuring the level of protein expression, and now by new technology, recently FDA approved, based on positron emission tomography-computed tomography (PET-CT), by which the burden of prostate cancer can be assessed in the whole body. “It overcomes many of the limitations of having to biopsy one tumor in that it is possible to noninvasively assess a patient’s entire body relatively quickly and painlessly, and all the tumors in the body that express PSMA can be assessed,” Dr. Spratt explains. “You can really start to understand the differences in the phenotype and its interplay with biology across the whole patient’s burden of disease. I think it is a potential game-changer.”

With the approval of PSMA PET-CT imaging in prostate cancer, “I think it’s going to become the standard of care imaging for patients with localized through advanced prostate cancer,” Dr Spratt predicts. “It’s a more sensitive imaging tool, meaning that it can detect more areas of cancer, allowing better risk stratification, or providing prognosis.” Since around 80% of patients with prostate cancer are likely to have PSMA expression, he expects it to be far more widely used than genomic biomarkers, which are relevant for only 5-20% of patients.

PSMA PET-CT more than just an imaging tool

Dr. Spratt stresses that it is important to understand that PSMA PET-CT is “so much more than just as another imaging tool.” Very importantly, unlike other tools, it also provides therapeutic options; not only is it possible to view the cancer cells, but they can also be targeted with, for example, stereotactic external radiation therapy, and numerous types of PSMA-directed therapies are in development. One such is 177Lu-PSMA-617, which the US Food and Drug Administration (FDA) recently designated as Breakthrough Therapy based on the results of a Phase 3 study (VISION) that showed improved survival in patients with metastatic castration-resistant prostate cancer.6 Numerous studies have shown that PSMA expression (number of metastases) is prognostic, so it provides valuable information and is predictive. Patients with PSMA overexpression are more likely to benefit from PSMA-targeted therapies.

“Finally, we have a diagnostic tool, total body imaging, which is very easy to perform. There are therapies that can be directed at it, and we can assess the response with the imaging,” Dr. Spratt acknowledges. He predicts that over the next 12 months, there will be a radical change in the way prostate cancer patients are staged and imaged, prognoses provided, and in the therapies that are going to be FDA-approved, as well as the therapies being designed and developed, like antibody-drug conjugates, chimeric antigen receptor–engineered T cells, and radiotherapeutics. “We really need to start interpreting this tool as a true game-changer rather than just a fancy imaging agent, and our patients are going to reap the rewards from it,” he urges.

References

  1. Dilllard R. Dr. Daniel Spratt discusses phenotypic precision medicine in advanced prostate cancer. GU Oncology Now. July 28, 2021. https://www.docwirenews.com/condition- center/precision-medicine-in-prostate-cancer/precision-medicine-in-prostate-cancer- videos/dr-daniel-spratt-discusses-phenotypic-precision-medicine-in-advanced-prostate- cancer/
  2. US Food and Drug Administration (FDA). FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer. FDA news release. May 15, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants- accelerated-approval-rucaparib-brca-mutated-metastatic-castration-resistant-prostate
  3. US Food and Drug Administration. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. FDA news release. May 19, 2021. https:// www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-hrr- gene-mutated-metastatic-castration-resistant-prostate-cancer
  4. US Food and Drug Administration. FDA approves first PSMA-targeted PET imaging drug for men with prostate cancer. FDA news release, December 1, 2020. https://www.fda.gov/ news-events/press-announcements/fda-approves-first-psma-targeted-pet-imaging-drug- men-prostate-cancer
  5. Novartis receives FDA Breakthrough Therapy designation for investigational 177Lu- PSMA-617 in patients with metastatic castration-resistant prostate cancer (mCRPC). Novartis; News release, June 16, 2021. https://www.novartis.com/news/novartis- receives-fda-breakthrough-therapy-designation-investigational-177lu-psma-617-patients- metastatic-castration-resistant-prostate-cancer-mcrpc
  6. Sartor O, de Bono J, Chi KN, et al; VISION Investigators. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. Published online June 23, 2021. DOI: 10.1016/S1470-2045(18)30198-0