PARP inhibitors (PARPi) have ushered in a new era of precision treatment for prostate cancer. Multiple studies have confirmed that patients with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair deficiency mutations (HRRm) can benefit from this therapeutic approach. At the recently held 2025 European Association of Urology(EAU25) conference , a single-arm Phase II PROact study conducted by Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School，Nanjing University, was reported. The study demonstrated promising preliminary efficacy and safety of the combination of olaparib, abiraterone, and prednisone in the treatment of metastatic hormone-sensitive prostate cancer (mHSPC). UroStream was honored to invite Prof. Junlong Zhuang from Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School,Nanjing University, and Prof. Samson Chan from Department of Surgery, Tuen Mun Hospital, HONG KONG, to engage in a dialogue and share the latest advancements and clinical experiences in precision therapy for prostate cancer.UroStream: Thank you both for joining our interview. It centers on prostate cancer. At this EAU conference, Prof. Zhuang’s team presented the phase II PROact study (abstract P191), the first to explore PARPi + ARPi in mHSPC. Could you share details?
Prof. Junlong Zhuang: Thank you for the interview. It’s a pleasure to be here with Oncology Frontier, and it’s a great honor to join Prof. Chan. The PROact clinical trial will be presented at tomorrow’s EAU conference. It was designed as a phase II, single-arm clinical trial. We enrolled 30 patients with de novo mHSPC who had homologous recombination repair (HRR) mutations,and were administered olaparib 3 plus abiraterone and prednisone.The most common HRR mutation was BRCA2, present in 40% of cases. The primary endpoint was the 1-year radiographic progression-free survival (rPFS) rate. At the time of abstract submission, the primary endpoint had not been reached. But now, we have data showing a 1-year rPFS of approximately 70%.
As for secondary endpoints, the overall response rate (ORR) was 84% among the 30 patients. With a median follow-up of 14 months, all patients achieved PSA50 response, and 29 out of 30 reached PSA90 response. in terms of safety, we observed no grade 5 adverse events. The most common adverse event of any grade was anemia, with an incidence rate of 43%. Overall, the safety profile is tolerable and acceptable.These results of this single-arm Phase II study indicate that the combination of olaparib, abiraterone, and prednisone has good anti-tumor activity and safety in the treatment of mHSPC. It is worth further validation through expanded sample studies in the future.
UroStream: Next, I’d like to ask Prof. Chan if there were any studies at this EAU conference that caught your interest, especially on PARPi precision therapy? Gene detection is currently needed for PARPi use, including tissue-based tests or ctDNA liquid biopsies. Were there any relevant studies (abstracts A0525, P009) discussed at the conference?
Prof. Samson Chan: There is indeed a very noteworthy study that will be reported by the research team from Beijing Friendship Hospital, Capital Medical University, tomorrow. This study focuses on the application of ctDNA liquid biopsy in patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after first-line treatment with abiraterone or enzalutamide.
This study is highly similar to the case analysis in the PROfound study. Researchers utilized next-generation sequencing (NGS) technology to analyze ctDNA and identified a broad spectrum of somatic and germline mutations. More importantly, patients who underwent ctDNA testing had a significant improvement in overall survival (30 months vs. 20 months, P=0.035). In fact, over 90% of patients received more targeted subsequent treatment plans after ctDNA testing. The detection rate of germline mutations was 54.55%, with the incidence of BRCA1/2 and ATM mutations as high as 23.3%. This indicates that these patients could benefit from precision treatments like olaparib and other PARP inhibitors. This result strongly supports the clinical application of liquid biopsy in mCRPC. As Professor Zhuang mentioned, this technology may also play a role in the earlier metastatic hormone-sensitive prostate cancer (mHSPC) stage.
UroStream: We know olaparib is now used in mCRPC first-line treatment based on the PROpel study. Could you both, drawing on your clinical experience, share your views on PARPi treatment value and your thoughts on the timing and methods of relevant gene testing?
Prof. Junlong Zhuang: I believe that PARP inhibitors have great potential in the treatment of metastatic prostate cancer. In the mCRPC stage, several key clinical trials, including PROfound, PROpel, MAGNITUDE, and TALAPRO-2, have shown that the combination of PARPi and ARPi in first-line treatment can improve rPFS and even OS in patients with both HRR mutations and non-mutations.
From a clinical perspective, I am inclined to initiate genetic testing and PARP-targeted therapy earlier, especially in patients with the following poor prognostic factors: family history of BRCA mutations, Gleason grade 5 histological type, younger age, and high tumor burden of metastatic lesions. Currently, several studies are also evaluating the potential application of PARPi in patients with HRR mutations in mHSPC, and I am very optimistic about this.
Prof. Samson Chan : In Hong Kong, we currently mainly conduct HRR gene testing in the mCRPC stage, especially after failure of first-line ARPi treatment. At this stage, patients have elevated PSA levels, which is conducive to the detection rate of mutations in ctDNA testing. Our local consensus guidelines—jointly formulated by the Hong Kong Urological Society and the Hong Kong Society of Clinical Oncology—recommend ctDNA testing after failure of first-line treatment, which is also consistent with the EAU and NCCN guidelines. However, with the increasing influence of studies like PROpel, we believe that more and more patients will undergo HRR gene testing at the initial treatment of mCRPC and even mHSPC.
In addition, the concordance rate between ctDNA testing results and tissue biopsy results is over 80%. CtDNA can also help us identify germline mutations, which is of great significance for the formulation of individualized treatment plans for patients and for genetic counseling related to BRCA mutations in families.
UroStream: Besides PARPi, new prostate cancer treatment strategies are being explored, such as PSMA radiotherapy, immune checkpoint inhibitors (ICIs), and antibody-drug conjugates (ADCs). What do you think is the most promising direction for future prostate cancer treatment?
Prof. Junlong Zhuang: To be honest, I am not optimistic about the application of immune checkpoint inhibitors in prostate cancer. Currently, most Phase III clinical trials, whether monotherapy or combination regimens, have not shown significant efficacy. Personally, I am more optimistic about antibody–drug conjugates (ADCs). These drugs are essentially targeted chemotherapy and are still in the developmental stage in the field of prostate cancer, but they hold promise. However, I believe the most promising treatment remains radioligand therapy targeting PSMA. Studies such as VISION and PSMAfore have demonstrated that Lu-177 PSMA therapy shows efficacy in improving survival in patients with mCRPC. Several new drugs and studies in this area are currently in progress, and I am very confident in this therapeutic pathway.
Prof. Samson Chan: I agree with Professor Zhuang’s view. Regrettably, the overall efficacy of ICIs in prostate cancer is rather poor. Currently, only in patients with high microsatellite instability (MSI-H), has pembrolizumab shown some efficacy in the mCRPC stage. Beyond that, the results of most clinical trials have been less than satisfactory. However, PSMA radioligand therapy is indeed very noteworthy. Our center has also attempted Lu-177 PSMA radiotherapy for PSMA-positive patients, with significant therapeutic effects. Although some patients have experienced severe bone marrow suppression, requiring regular blood transfusion support, the therapeutic response is promising and warrants further exploration. In the future, perhaps we could consider combining ICIs with PSMA-targeted therapy, which might lead to better outcomes.
Reference
1 Guo X., Zhang F. The role of plasma ctDNA detection for CRPC patients with failure of first-line abiraterone/enzalutamide treatment.EAU25; Abstract P009
2 Zhuang J., et al.Update efficacy results of PROact: A prospective phase II study to evaluate olaparib plus abiraterone and prednisone combination therapy in metastatic hormone sensitive prostate cancer patients with HRR gene mutation.EAU25; Abstract P191
Professor Junlong Zhuang
Associate Chief Physician
Department Assistant of Urology, Nanjing Drum Tower Hospital
Associate Professor and Master’s Thesis Supervisor at Nanjing University and Nanjing Medical University
Group Leader of Prostate Cancer Subspecialty in the Department of Urology, Nanjing Drum Tower Hospital
Member of the Youth Committee of the Jiangsu Provincial Urological Surgery Branch
Member of the Jiangsu Provincial Urology Physicians Branch of the Jiangsu Provincial Medical Association
Candidate of the Jiangsu Provincial “333 High-Level Talent Training Project”
Jiangsu Provincial Natural Science Fund Outstanding Youth
Hosted a total of 15 scientific research projects, including 3 national-level projects.
Published 20 SCI papers as the first or corresponding author.
Focuses on the precise diagnosis and treatment of urological tumors, especially prostate cancer.
SAMSON CHAN
- Tuen Mun Hospital (HK) Consultant (Urology)
- NTWC (HK) Consultant (Urology)
- S.H. Ho Urology Centre （CUHK）Clinical associate professor
- HKUA Young Urologists Section – Chairperson
- HKUA Co-opt member
- NTWC Drug and Therapeutics Committee – Department representative
- NTWC Clinical Research Governance Committee – Committee member
- HK SOMIP Steering Committee – Urologist Representative
- Asian Urological Surgery Training & Education Group – Faculty member
- 2018 CH LEONG Medal & Scholarship Awardee
- Specialized in uro-oncological service, invasive surgery & complex urologic reconstruction
