Editor's Note: In the field of metastatic castration-resistant prostate cancer (mCRPC), the PROfound study marked the beginning of the era of precision targeted therapy for prostate cancer, while the PROpel study extended the use of PARP inhibitors (PARPi) to first-line treatment for mCRPC. At the ASCO-GU conference in 2024, the BRCAAway study reported the optimal first-line treatment for mCRPC, questioning whether it should be new hormonal agents (NHA), PARP inhibitors as monotherapy, or a combination of both. At the same time, genetic testing for DNA homologous recombination repair (HRR) genes like BRCA1/2 is a critical prerequisite for guiding PARP inhibitor therapy, yet real-world genetic testing still faces several challenges. Dr. Junlong Zhuang shared his insights on these topics in an interview with Oncology Frontier.
Oncology Frontier: BRCA mutations are the most clinically significant type of mutation in prostate cancer. At this ASCO-GU, we saw the presentation of treatment efficacy results from the BRCAAway study, which examines mCRPC patients with BRCA mutations receiving different first-line treatments. Could you introduce the BRCAAway study to us?
Dr. Junlong Zhuang: The BRCAAway study is a multi-cohort Phase II study exploring different first-line treatment of PARPi or NHA for patients with newly treated mCRPC (those who have not received anti-androgen therapy at the mHSPC stage). Patients were randomized into four cohorts, with cohorts 1-3 targeting patients with BRCA1/2 and/or ATM mutations: cohort 1 was treated with abiraterone (allowing for crossover to olaparib upon progression); cohort 2 received olaparib (with crossover to abiraterone upon progression); and cohort 3 used a combination of olaparib and abiraterone. Cohort 4 targeted patients with other non-classical DNA repair defects, using olaparib plus abiraterone. The results reported at the ASCO-GU conference for cohorts 1-3 showed median PFS (Progression-Free Survival) of 8.4 months, 14 months, and 39 months, respectively, with PSA response rates (PSA RR) of 61%, 67%, and 95%.
△Design of the BRCAAway Study
△Summary of the Efficacy of the BRCAAway Study
Considering the BRCAAway study and other researches, for mCRPC patients carrying BRCA mutations, targeted therapy drugs like olaparib may be better compared to traditional chemotherapy or hormone therapy. Overall, compared to olaparib monotherapy, the combination of olaparib and NHA demonstrates more efficacy; likewise, results from cohorts 1 and 2 indicate that olaparib monotherapy’s PFS and PSA RR are also comparable to monotherapy NHA for BRCA mutation patients. Therefore, early use of olaparib, either as monotherapy or in combination, can bring substantial survival to patients. We hope to see more data from olaparib-related studies in the future, providing guidance for precision treatment of prostate cancer.
Oncology Frontier: From research reports, it can be seen that the use of PARP inhibitors has significant benefits for people with specific target mutations, such as BRCA mutations. This also puts forward the clinical requirement to use molecular typing as a guide and genetic testing to guide precise targeted treatment. At this ASCO-GU conference, were there any research advancements regarding the application of genetic testing to guide PARPi treatment?
Dr. Junlong Zhuang: Testing for HRRm genes such as BRCA1/2 is a crucial prerequisite for guiding treatments with PARP inhibitors like olaparib. So, is genetic testing in the real world sufficient? This ASCO-GU conference presented some real-world studies that offer insights into genetic testing. A real-world study from the United States (Abstract No: 332) emphasized the necessity of early HRRm testing in mCRPC patients to ensure timely access to optimal treatment. The study showed that most patients underwent HRRm-related testing several months after being diagnosed with mCRPC, by which time they had high burdens of bone and distant metastases. Conducting HRR testing before or at the onset of mCRPC could facilitate earlier treatment with olaparib during the disease course. Another real-world study from the United States (Abstract No: 91) revealed that less than half of the mCRPC patients underwent HRRm testing, indicating that the real-world application of PARPi in mCRPC still needs addressing.
△Real-World Study in the United States (ASCO-GU 2024, Abstract No: 332): The overall population had a median time of 16.9 months to a positive HRRm test following the diagnosis of mCRPC.
△Real-World Study in the United States (ASCO-GU 2024, Abstract No: 332): Only 49% of mCRPC patients underwent HRR genetic testing.
These two studies highlight two current issues in genetic testing for advanced prostate cancer: first, the timing of genetic testing is often late, and second, the rate of genetic testing is low. Clinicians need to consider how to better utilize genetic testing to provide greater assistance to prostate cancer patients.
Oncology Frontier: Facing the issues you mentioned about the late timing of genetic testing and the low rate of genetic testing, what do you think are the solutions?
Dr. Junlong Zhuang: Firstly, there’s a need to raise awareness among doctors about testing. Although the real-world studies show that the rate of HRR genetic testing in the US is still not adequate, reaching nearly 50%, the overall level of genetic testing in China is currently around 20%, less than half of that in developed countries. This indicates a need for further academic learning and a change in mindset for Chinese prostate cancer specialists and the advanced prostate cancer patient community. Clinicians should participate more in domestic and international studies on precise diagnosis and treatment of prostate cancer to enhance their understanding of precision medicine. They need to guide patients to undergo genetic testing at the appropriate time, thereby directing subsequent treatment decisions.
Secondly, interdisciplinary collaboration must be strengthened. The diagnosis and treatment of prostate cancer should emphasize the development of a multidisciplinary team (MDT), as studies have shown that regular MDT discussions can significantly improve patient OS (Overall Survival) (39.7 vs 27.0 months, HR 0.549). Therefore, the CSCO guidelines for prostate cancer recommend the disciplines, members, discussion content, and daily activities of MDT diagnosis and treatment. Taking precision targeted therapy for prostate cancer as an example, in the individualized diagnostic and treatment decisions for patients with advanced prostate cancer, urologists need to provide sufficient clinical specimens for patients as much as possible, and the pathology department must have adequate tissue archives; in cases where tissue is not accessible, ctDNA testing can guide precision treatment, requiring communication and collaboration among urology, oncology, and pathology departments. Hospitals need to improve their genetic testing platforms and related processes, including informed consent before testing, specimen collection, testing, and interpretation of results.
Thirdly, public health awareness needs to be enhanced. Patients can increase their understanding of prostate cancer genetic testing through media, social platforms, and public lectures. Educating patients about the benefits of genetic testing, including early detection, personalized treatment, and family genetic risk assessment, is crucial.
By implementing these measures, we can increase the rate of genetic testing among prostate cancer patients and encourage genetic testing at early stages of the disease or at appropriate clinical junctures. This can provide patients with more optimized treatment options and improve their prognosis.
Reference :
- Maha H. A. Hussain, et al.BRCAAway: A randomized phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) bearing homologous recombination-repair mutations (HRRm).ASCO-GU 2024.Abstract 19
- Daniel J. George,et al.Real-world homologous recombination repair mutation (HRRm) testing patterns in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with olaparib in the United States.ASCO-GU 2024.Abstract 332
- Anupama Vasudevan,et al.HRR testing and PARPi utilization among patients with metastatic castration resistant prostate cancer treated in the real-world setting.ASCO-GU 2024.Abstract 91
- Zhu S, Chen J, Ni Y, et al. Dynamic multidisciplinary team discussions can improve the prognosis of metastatic castration-resistant prostate cancer patients. Prostate. 2021;81(11):721-727.
TAG: ASCO-GU Interview, Advanced Prostate Cancer, Genetic Testing
