Editor's note: At the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO-GU 2024) held recently, data on patients with homologous recombination repair mutations (HRRm) from the PROpel study were reported. Additionally, researchers conducted a meta-analysis of several Phase III studies on the combination of PARP inhibitors (PARPi) and novel hormonal agents (NHA) for first-line treatment of metastatic castration-resistant prostate cancer (mCRPC). What significant insights do these studies to the precision treatment of prostate cancer with PARPi? How can genetic testing be improved in clinical practice to benefit more patients with mCRPC with PARPi precision treatment? Dr. Fupu Zheng from the First Affiliated Hospital, Sun Yat-sen University, shared his insights at the ASCO-GU conference.
Oncology Frontier: Numerous studies targeting the HRR pathway in prostate cancer emerged at this conference. For instance, the PROpel study on olaparib combined with NHA revealed data for the HRRm population. Could you elaborate on the progress of PARPi in the first-line treatment of mCRPC based on reports from ASCO-GU?
Dr. Fufu Zheng: Olaparib has heralded a new era of precision treatment with PARPi for prostate cancer. The previously reported PROfound study has confirmed that for mCRPC patients who have failed NHA and carry BRCA mutations, olaparib significantly improves both PFS (9.8 vs 3.0 months, HR 0.22) and OS (20.1 vs 14.4 months, HR 0.63), reducing the risks of disease progression and death by 78% and 37%, respectively.
The PROpel study further explores the efficacy and safety of using olaparib plus abiraterone plus ADT or abiraterone plus ADT in first-line treatment for mCRPC. Last year’s ASCO-GU report showed that, in the ITT population (without HRRm differentiation), the olaparib group significantly improved rPFS (25.0 vs 16.5 months, HR 0.68) and extended mOS to 42.1 months, an increase of 7.4 months (42.1 vs 34.7 months, HR=0.81), which is clinically significant, extending OS to over 3.5 years, especially in patients with HRRm (HR 0.66) and BRCAm (HR 0.29), where the risks of death were reduced by 34% and 71%, respectively. The detailed data for the HRRm population reported at this ASCO-GU conference show that overall, 28.4% of patients carried HRRm, with common HRR mutation types (BRCA2, ATM, CDK12) all demonstrating survival benefits favoring olaparib. Patients with BRCA2 mutations had an 80% reduction in both disease progression and risk of death (rPFS and OS HR both at 0.20); ATM mutation patients had reductions of 45% and 21% (rPFS and OS HR at 0.55 and 0.79, respectively); CDK12 mutation patients had reductions of 49% and 43% (rPFS and OS HR at 0.51 and 0.57, respectively). This underscores the importance of determining molecular subtype through genetic testing before choosing a treatment plan for advanced prostate cancer patients, to better predict the treatment outcome of targeted drugs for different populations and maximize treatment benefits for patients.
The PROpel study previously reported results for rPFS and OS in the ITT population (without HRR selection).
The PROpel study reported rPFS and OS for the overall population, non-HRRm patients, and HRRm patients (including those with various HRR gene mutations).
PARPi combined with NHA has accumulated extensive evidence-based medical evidence. This year’s ASCO-GU also presented a study that conducted a meta-analysis of results from key Phase III studies, including PROpel, TALAPRO-2, and MAGNITUDE, showing that patients with HRRm who used the PARPi combination approach had better trends in rPFS and OS benefits (with PFS and OS HRs of 0.55 and 0.79, respectively), especially for BRCAm patients (with PFS and OS HRs of 0.28 and 0.55, respectively).
Considering the studies mentioned above, olaparib plus abiraterone for first-line treatment in patients with mCRPC can improve PFS and OS, especially showing a more pronounced benefit trend in patients with HRRm (including classic mutations such as BRCA, ATM, and CDK12). For patients carrying HRR mutation genes, olaparib plus NHA can be considered a standard first-line treatment. Also, in clinical practice, genetic testing should be provided as much as possible for patients with advanced prostate cancer, as those carrying HRR-related mutations could achieve better survival benefits from treatments like olaparib and other PARPi.
Oncology Frontier: The studies related to PARPi treatment indicate that molecular typing based on genetic testing and guiding targeted drug treatment is the future trend of diagnosis and treatment. Based on your personal experience, how do you think genetic testing should be better used to guide treatment so that patients with advanced prostate cancer can survive longer?
Dr. Fufu Zheng: Current research shows that molecular typing based on genetic testing and targeted drug treatment has become the future trend in treating advanced prostate cancer. In advanced prostate cancer, about 90% of mCRPC cases have clinically significant genetic mutations, with approximately 27.9% of tumors having homologous recombination repair mutations (HRRm); among these, BRCA1/2 mutations are the most common types, accounting for about 9.7%. Tumors in patients carrying such mutations are more malignant and have a worse prognosis, making it essential to screen this specific group to provide more precise treatment plans. In my clinical experience, the key to effectively using genetic testing lies in two aspects: “test as broadly as possible” and “pay attention to the timing and samples of genetic testing.”
First, the principle of “test as broadly as possible” should be emphasized, aiming to offer genetic testing opportunities to all patients with advanced prostate cancer. Only through testing can we accurately identify those patients who may benefit from specific targeted treatments, such as those carrying BRCA1/2 or other related homologous recombination repair (HRR) gene mutations, who may respond better to targeted drugs like PARPi. Therefore, widespread genetic testing is fundamental to ensuring all patients carrying therapeutic targets can receive the best treatment plans.
Second, we need to learn and master the appropriate population, timing, and samples for genetic testing scientifically and rationally. The ideal timing for genetic testing is at critical decision-making points in treatment, such as at initial diagnosis, disease progression, or after treatment failure. This ensures the information obtained is most relevant and timely, guiding subsequent treatment choices.
Currently, genetic testing for advanced prostate cancer is primarily recommended for the following groups: (1) all patients with metastatic castration-resistant prostate cancer (mCRPC) for BRCAm testing to guide subsequent treatment plans; (2) to assess genetic risk, recommendations include individuals from families with pathogenic/likely pathogenic mutations in BRCA1/2; patients with tumors showing pathogenic/likely pathogenic mutations in BRCA1/2 but where it is unclear if the mutation is germline; patients with high risk, N1, and M1 prostate cancer, intraductal carcinoma of the prostate; patients meeting certain family history criteria; and those with one or more first-degree or second-degree relatives.
In clinical practice, it is crucial to seize the right moment for testing. For high-risk and very high-risk groups, as well as those with a family history, we advocate for early testing to assess genetic risks. For patients with metastatic prostate cancer, we recommend undergoing genetic testing upon diagnosis of metastasis to capture the optimal window for guiding treatment plan formulation.
Lastly, choosing the appropriate testing sample is also vital. Testing for BRCA mutations includes both germline and somatic mutations. Although tissue testing remains the gold standard, obtaining tissue from some advanced-stage patients can be challenging due to various complications that preclude biopsy, or because archived samples are too old or there isn’t enough tissue, leading to failed tests. In such cases, non-invasive tests like circulating tumor DNA (ctDNA) in the blood can be considered. This “liquid biopsy” can provide information about the genetic characteristics of the tumor and help monitor the disease’s dynamic changes. Authoritative guidelines from CSCO and CUA note that the consistency between tumor tissue and plasma ctDNA samples in mCRPC patients reaches over 80%, hence recommending ctDNA and other blood biopsies as alternative options when tissue biopsy is not feasible or fails.
