Alexandra Sokolova, MD, assistant professor, medicine, Division of Hematology/Medical Oncology, School of Medicine, Oregon Health & Science University, discusses the importance of genetic testing in patients with prostate cancer, which patients may benefit most from genetic testing, and how cascade testing can identify additional people who are at risk for developing cancer.

 State of the Science Summit™ on genitourinary cancers, Sokolova emphasizes critical needs that remain for patients with prostate cancer and how increased genetic testing can help address these needs. Sokolova explained that germline testing is now recommended for all men with high-risk, localized disease, as well as all men with metastatic prostate cancer and those with a family history of prostate cancer that meets genetic testing criteria. Genetic testing should also be considered for those who have cribriform features in their disease pathology, Sokolova says.

It continues to be very important to not only identify these men early, but to test them early as well, sooncologists can provide them with the best available care, Sokolova emphasizes. Many prostate cancer therapies can only be given following germline testing, Sokolova expands. Moreover, it is important to recommend that these patients’ family members also be tested to identify any other cases of prostate cancer and determine the existence of inherited germline mutations, she explains. This cancer prevention strategy, known as cascade testing, can benefit both men and women, she adds.

Progress in the prostate cancer genetics field relies on identifying men with germline mutations who are at high risk of developing prostate cancer before this cancer develops, Sokolova continues. Cascade testing allows oncologists to determine which patients are at high risk of developing prostate cancer, so they can treat thosecancers earlier and more aggressively, with the goal of cure, she concludes.

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Alexandra Sokolova, MD, discusses the importance of genetic testing in patients with prostate cancer, which patients may benefit most from genetic testing, and how cascade testing can identify additional people who are at risk for developing cancer.

Dr Sokolova on the Importance of Genetic Testing in Prostate Cancer

Alexandra Sokolova, MD, assistant professor, medicine, Division of Hematology/Medical Oncology, School of Medicine, Oregon Health & Science University, discusses key findings from the phase 3 TALAPRO-2 trial (NCT03395197) in patients with metastatic castration-resistant prostate cancer (mCRPC) and unanswered questions regarding the use of PARP inhibitors plus androgen receptor (AR) inhibitors in patients with biomarker-negative disease.

The TALAPRO-2 trial randomized patients with previously untreated mCRPC to receive either talazoparib (Talzenna) plus enzalutamide (Xtandi) or placebo plus enzalutamide, with a primary end point of radiographic progression-free survival (rPFS). Patients in the TALAPRO-2 population were unselected for DNA damage repair (DDR) pathway genetic alterations either directly or indirectly involved with homologous recombination repair. Further subgroup analyses of TALAPRO-2 are necessary to determine the efficacy of talazoparib plus enzalutamide in different patient subgroups, Sokolova says. However, in findings presented at the 2023 Genitourinary Cancers Symposium, the median rPFS was improved in the portion of patients in the TALAPRO-2 population who had DDR-deficient disease vs those without DDR-deficient disease or with unknown DDR disease status, with respective hazard ratios (HRs) of 0.46 and 0.70. In the overall population, the median rPFS was not reached in the talazoparib arm vs 21.9 months in the placebo arm, with an HR of 0.63. Although the overall survival (OS) data are not yet mature, the OS HR was 0.89 in favor of talazoparib.

The significance of these findings for the population of patients with biomarker-negative mCRPC remains to be seen, Sokolova notes. There is a biological rationale for combining PARP inhibitors, such as talazoparib, with AR inhibitors, such as enzalutamide, Sokolova says. AR binds to DDR sites, so inhibiting the AR pathway likely inhibits DDR and causes a DNA DDR-deficient phenotype, Sokolova explains. However, the TALAPRO-2 data are still too immature to provide the rationale for the broad use of talazoparib plus enzalutamide in patients with mCRPC, Sokolova concludes.

Alexandra Sokolova, MD, discusses key findings from the phase 3 TALAPRO-2 trial in patients with metastatic castration-resistant prostate cancer and unanswered questions regarding the use of PARP inhibitors plus androgen receptor inhibitors in patients with biomarker-negative disease.

Dr Sokolova on Talazoparib Plus Enzalutamide in mCRPC

Alexandra Sokolova, MD, assistant professor of medicine, Division of Hematology/Medical Oncology, School of Medicine, Oregon Health & Science University, discusses the evaluation of rucaparib (Rubraca) vs physician’s choice standard of care therapy in patients with 

-positive metastatic castration-resistant prostate cancer (mCRPC).

The phase 3 TRITON3 trial (NCT02975934) enrolled chemotherapy-naïve men who were treated with 1 prior line featuring a second-generation androgen receptor pathway inhibitor (ARPI) for their mCRPC, Sokolova begins. Patients were randomly assigned to receive treatment with rucaparib or physician’s choice of therapy, including docetaxel or another second-generation ARPI with abiraterone acetate (Zytiga) or enzalutamide (Xtandi).

Data presented at the 2023 Genitourinary Cancers Symposium showed that the study met its primary end point of radiographic progression-free survival (rPFS). There was an improved rPFS both in those with 

-mutant mCRPC, as well as in the intention-to-treat (ITT) population, which included patients who harbored 

 mutations, Sokolova continues. In the ITT population, the rPFS was 10.2 months (95% CI, 8.3-11.2) with rucaparib compared with 6.4 months (95% CI, 5.6-8.2) in patients treated with physician's choice (HR, 0.61; 95% CI, 0.47-0.80; 

 < .001). Additionally, in patients with 

-mutant mCRPC, the median rPFS was 11.2 months (95% CI, 9.2-13.8) with rucaparib compared with 6.4 months (95% CI, 5.4-8.3) with physician’s choice of therapy.

Because chemotherapy was an option in the standard-of-care arm, it allowed investigators to evaluate whether docetaxel or rucaparib provided more benefit in this setting, Sokolova says, adding that rucaparib elicited an improved rPFS compared with docetaxel in the 

In May 2020, the FDA granted accelerated approval to rucaparib for the treatment of adult patients with BRCA mutation (germline and/or somatic)—associated mCRPC who have been treated with AR-directed therapy and a taxane-based chemotherapy. TRITON3 helped confirm prior data that supported the accelerated approval for 

-mutated mCRPC and provided more insight on those with 

Alexandra Sokolova, MD,discusses the evaluation of rucaparib vs physician’s choice standard of care therapy in patients with BRCA-positive metastatic castration-resistant prostate cancer.

Dr Sokolova on Rucaparib vs Physician’s Choice Therapy in BRCA+ mCRPC

Alexandra Sokolova, MD, a hematology/oncology fellow of the University of Washington, discusses the rationale for ​systematic germline testing in patients with metastatic prostate cancer.

In 2017, the National Comprehensive Cancer Network (NCCN) guidelines recommended germline testing for all men with metastatic prostate cancer, says Sokolova. In 2019, the guidelines were updated to include all men with high-risk, localized prostate cancer or those with a family history ​of prostate cancer. 

Implementation of a better genetic testing model is an area of unmet need in prostate cancer as there is no streamlined infrastructure to deliver effective services to these men, explains Sokolova. To that end, a prospective, pilot study aimed to test the feasibility of systematic genetic testing in all men with metastatic disease receiving care at the VA Puget Sound Health Care System.

Alexandra Sokolova, MD, discusses the rationale for ​systematic germline testing in patients with metastatic prostate cancer.

  Dr. Sokolova on the Rationale for Systematic Germline Testing in Prostate Cancer

Alexandra Sokolova, MD, a hematology/oncology fellow of the University of Washington, discusses the challenges of germline testing in patients with metastatic prostate cancer. 

The lack of infrastructure to facilitate efficient germline testing is an unmet need, says Sokolova. Traditionally, ​when patients aresent to a genetic counselor, they must undergo pre-test counseling, germline testing, and post-test counseling.

This method can be time consuming, and there is a lack of available resources to provide this service to eligible patients. Providingan alternative model that could help them streamline the resources could lead to better care for their patients, Sokolova adds. 

In an IRB-approved prospective trial, genetic counseling was conducted through video meetings. This method appeared effective, especially when the patients were comfortable with the ​genetic provider, Sokolova concludes.

Alexandra Sokolova, MD, discusses the challenges of germline testing in patients with metastatic prostate cancer. 

Dr. Sokolova on Challenges of Germline Testing in Metastatic Prostate Cancer

Alexandra Sokolova, MD, a hematology/oncology fellow of the University of Washington, discusses the systematic implementation of a germline testing protocol for patients with metastatic prostate cancer.

In an IRB-approved, prospective trial, investigators evaluated the feasibility of implementing a systematic workflow to identify patients with metastatic prostate cancer receiving care at the Puget Sound VA Prostate Cancer Clinic. To this end, a research coordinator prescreened each clinic schedule to identify patients with metastatic prostate cancer who qualified for germline testing and subsequently notified oncologists caring for those patients.

Oncologists would then discuss germline testing with their patients during follow-up appointments, says Sokolova. In these discussions, oncologists would explain what the testing is, the potential benefits of these tests for both patient and their family members, and weigh the pros and cons of undergoing such testing. If patients were interested, after signing a consent form, they would provide a saliva test the same day of their appointment. This made the process simple and convenient for patients, as they would not need to make another appointment or visit another clinic to get the testing done, Sokolova adds.

Furthermore, genetic counseling was provided by the Color Genomics 30-gene cancer gene panel utilized for the testing. As such, patients had the opportunity to participate in post-test counseling with a genetic counselor. If interested, they would be referred to a local counselor, Sokolova concludes.

Alexandra Sokolova, MD, discusses the systematic implementation of a germline testing protocol for patients with metastatic prostate cancer.

Dr. Sokolova on Implementing a Germline Testing Protocol for Metastatic Prostate Cancer

Alexandra Sokolova, MD, a hematology/oncology fellow of the University of Washington, discusses the rationale for systematic implementation of germline testing for patients with metastatic prostate cancer.

In a prospective, IRB-approved trial, investigators sought to evaluate whether systematic identification of men with metastatic prostate cancer correlated with a high uptake of germline testing, says Sokolova. In the study, a research coordinator prescreened each clinic schedule to flag patients with metastatic prostate cancer. Then, these coordinators would notify the oncologist. Knowing which patients qualified for germline testing reminded oncologists to discuss germline testing with their patients, says Sokolova.

When speaking with patients with metastatic prostate cancer, there's a lot of information that must be covered in these important discussions, such as symptoms, quality of life, and treatment plans, among others, says Sokolova. As such, it’s easy for germline testing to escape an oncologist’s attention, especially with regard to patients whom they have been seeing for quite some time.

As such, alerting oncologists when a patient qualifies for this testing, and doing so in a systematic manner, could help to create an infrastructure that could help oncologists remember to discuss germling testing with their patients, concludes Sokolova.

Alexandra Sokolova, MD, discusses the rationale for systematic implementation of germline testing for patients with metastatic prostate cancer.

Alexandra Sokolova

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