Editor's note: Precision treatment begins with testing. PARP inhibitors (PARPi) such as olaparib have become a precision treatment option for metastatic castration-resistant prostate cancer (mCRPC), offering therapeutic benefits to patients carrying BRCA1/2 and other DNA homologous recombination repair (HRR) gene mutations. Beyond guiding treatment decisions, genetic testing plays a crucial role in assessing the genetic risk of prostate cancer, and in evaluating treatment efficacy and prognosis. At the recently held 2024 ASCO-GU conference, numerous studies on PARPi precision treatment and genetic testing were reported, providing valuable insights for the clinical practice of precision treatment in prostate cancer. Dr. Shun Zhang from the Affiliated Drum Tower Hospital, Medical School of Nanjing University, shared his thoughts on these research advancements in an interview with Oncology Frontier.
Oncology Frontier: The research presented at this ASCO-GU prostate cancer session highlights the increasing importance of genetic testing in prostate cancer, guided by molecular typing for precision targeted therapy. Based on your experience, what role do you think genetic testing currently plays in the treatment of prostate cancer?
Dr. Shun Zhang: Genetic testing is of great significance for the precision treatment of prostate cancer. Summarizing the current domestic and international guidelines on the application of genetic testing, its importance can be categorized into three aspects: firstly, identifying gene mutations related to tumor genetic susceptibility; secondly, identifying gene mutations related to poor prognosis in cancer patients; and thirdly, guiding treatment decisions by detecting clinically significant mutations, such as using PARP inhibitors, which primarily target patients carrying BRAC1/2 and other DNA homologous recombination repair (HRR) gene mutations.
Firstly, in terms of guiding genetic risk assessment, specific genetic variants such as BRCA1/2, MSH2, MSH6, MLH1, and others, are closely associated with the incidence of prostate cancer and have familial genetic tendencies. Genetic testing can identify individuals carrying these high-risk genetic variants, allowing for early screening and preventive interventions in these high-risk populations, such as more frequent PSA testing and prostate biopsies in suspicious cases. Moreover, the genetic testing results of familial prostate cancer patients can guide genetic counseling and risk assessment for their direct relatives, helping family members take appropriate monitoring measures to detect and treat prostate cancer timely.
Secondly, genetic testing is used to predict poor prognosis, especially for late-stage prostate cancer patients who have reached the end stage of the disease. Choosing the right medication is crucial for extending patients’ survival. Genetic testing helps doctors determine the likelihood of disease progression in prostate cancer patients. Certain gene mutations, such as BRCA2, ATM, and other DNA repair-related gene mutations, have been proven to be associated with the aggressiveness and worsening tendencies of prostate cancer. These mutations can lead to increased resistance of cancer cells to radiotherapy and chemotherapy, affecting treatment outcomes. Genetic testing can help doctors identify these high-risk mutations, providing more accurate prognostic information for patients.
Lastly, and most importantly, genetic testing guides treatment decisions. From this ASCO-GU conference, we can see that many studies on prostate cancer targeted drugs have been released. Especially for the HRR pathway, PARPi offers effective targeted treatment options. Currently, olaparib, a prostate cancer targeted drug available in our country, has been applied in clinical practice. The previously reported PROfound study indicated that for mCRPC patients who had previously failed NHA treatment and carried BRCA mutations, olaparib provided a median overall survival (OS) of 20.1 months compared to the doctor’s choice of sequential NHA, with a radiographic progression-free survival (rPFS) of 9.8 months, more than three times that of the control group. The PROpel study, a phase III study of olaparib combined with abiraterone for first-line treatment of mCRPC patients without HRR selection, previously reported reaching its primary endpoint of rPFS (24.8 vs 16.6 months, HR 0.66), with a median OS extended to 42.1 months. This year’s ASCO-GU conference further reported survival data for patients carrying HRR mutation genes, showing a reduction in death risk for HRRm and BRCAm patients by 34% (HR 0.66) and 71% (HR 0.29), respectively, with common HRRm patients like BRCA2 (HR 0.20), ATM (HR 0.79), CDK12 (HR 0.57) experiencing varying degrees of reduced death risk. These results reconfirm that patients carrying BRCA1/2 and other HRR mutations benefit significantly from olaparib treatment. Identifying patients carrying these gene mutations through genetic testing and providing timely precision treatment can improve patient survival outcomes.
The PROpel study previously reported the results of rPFS and OS for the ITT population (not selected for HRR).
The 2024 ASCO-GU conference reported the OS results for the HRRm subgroup patients in the PROpel study.
Oncology Frontier: Looking to the future, what new developments do you anticipate for genetic testing in the treatment of prostate cancer?
Dr. Shun Zhang: The era of precision treatment has arrived, and clinical treatment demands require us to explore richer, more precise, and convenient genetic testing methods. First is the multi-gene panel testing. Future genetic testing might not be limited to single gene mutations but will employ multi-gene panel testing to obtain more comprehensive genetic information, thereby providing more accurate treatment guidance. Currently, the most clinically significant mutation group in urology is the HRR homologous recombination repair pathway variations, but variations in other pathways such as the androgen receptor (AR) signaling pathway and the PI3K/AKT/mTOR pathway can also provide effective references for patient diagnosis and treatment. Therefore, future clinical testing may need to adopt the concept of extensive testing, guiding prostate cancer treatment better through large panel testing where economically feasible.
Second is the widespread adoption of liquid biopsies. For genetic testing sample selection, tissue is indeed the gold standard. However, prostate cancer patients have a long disease course, and long-stored tissue samples greatly affect the success rate of testing. It’s often difficult for end-stage disease patients to undergo another biopsy, necessitating the search for alternative testing methods. Currently, liquid biopsy technology allows for genetic testing through the analysis of circulating tumor DNA (ctDNA) in the blood. This non-invasive testing method will make monitoring genetic variations and treatment responses of tumors more convenient. Both domestic and international guidelines recommend using ctDNA as an effective alternative when tissue is not accessible.
Third, this ASCO-GU conference also presented research progress on the application of ctDNA in prostate cancer, offering us more to consider. An Australian study (abstract number: 196) assessed the value of adding ctDNA Tumor Fraction (TF) early changes on top of PSA to predict early progression in mCRPC patients. The results suggest that ctDNA can provide an independent, non-invasive strategy supplementary to PSA and can refine personalized diagnostic and treatment plans based on individual patient progression risk. Additionally, a Canadian study (abstract number: 205) aimed to assess the longitudinal molecular changes in ctDNA after systemic treatment, thereby providing information for sequential treatment strategies for mCRPC patients. The study results underscored the prognostic significance of ctDNA load in mCRPC, aiding in formulating personalized sequential treatment strategies for mCRPC patients. These latest research advancements highlight the significance of ctDNA in genetic testing and treatment decision-making in prostate cancer, and its application in clinical practice should be strengthened in the future.
Reference :
- de Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020;382(22):2091-2102.
- Saad F, Clarke NW, Oya M, et al. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24(10):1094-1108.
- Neal D. Shore,et al.Efficacy of olaparib (O) plus abiraterone (A) versus placebo (P) plus A in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with single homologous recombination repair gene mutations (HRRm) in the PROpel trial.ASCO-GU 2024,Abstract 165
- Christopher Sweeney, et al.Evaluating early changes in circulating tumor DNA (ctDNA) tumor fraction (TF) as a value add to PSA in predicting early progression in metastatic castrate resistant prostate cancer (mCRPC).ASCO-GU 2024,Abstract 196
- Eli Tran, et al.Characterizing longitudinal molecular changes in ctDNA in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).ASCO-GU 2024,Abstract 205
TAG: ASCO-GU Interview, Prostate Cancer, Genetic Testing
