Editor's Note: In recent years, with the continued advancement of precision medicine, PARP inhibitors have assumed an increasingly important role in prostate cancer treatment, particularly among patients harboring homologous recombination repair (HRR) gene alterations, in whom they have demonstrated clear clinical benefits. At the same time, a range of combination strategies involving PARP inhibitors and androgen receptor pathway inhibitors (ARPIs), immunotherapy, chemotherapy, and other treatment modalities have emerged, ushering advanced prostate cancer into an era of combination therapy. However, despite the rapid accumulation of clinical evidence, questions remain regarding the optimal treatment sequence, differences in benefit across specific HRR mutation subtypes, and strategies for managing resistance in the setting of combination therapy. Further evidence is needed to clarify these issues.Against this background, Oncology Frontier – UroStream invited Professor Edmund Chiong of National University Hospital, Singapore, to provide an in-depth interpretation of recent advances in PARP inhibitor combination therapy and strategies for overcoming treatment resistance.
PARP Inhibitor Plus ARPI Therapy Moves into Earlier Treatment Lines, Reshaping the Prostate Cancer Treatment Landscape
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Oncology Frontier – UroStream: Prostate cancer has entered the era of combination therapy, and PARP inhibitor-based combinations have become a major focus of interest. How do you view the latest developments in this field?
Professor Edmund Chiong: We are currently witnessing rapid development in PARP inhibitor combination therapy. There is now mature clinical evidence supporting the combination of PARP inhibitors with androgen receptor pathway inhibitors (ARPIs), while early data on combinations of PARP inhibitors with immunotherapy have also been reported, with numerous additional clinical trials ongoing. Among these approaches, PARP inhibitor plus ARPI therapy has the most immediate impact on current clinical practice.
In the first-line treatment setting for metastatic castration-resistant prostate cancer (mCRPC), three pivotal phase III studies—PROpel, MAGNITUDE, and TALAPRO-2—have collectively demonstrated that combining a PARP inhibitor with an ARPI can provide significant progression-free survival benefits. The clinical value of this combination strategy has therefore been well established.
More importantly, research is now moving toward earlier treatment lines. Data from the AMPLITUDE study presented at the 2026 ASCO Annual Meeting showed that niraparib plus abiraterone provided a clear progression-free survival benefit compared with abiraterone alone in patients with metastatic castration-sensitive prostate cancer (mCSPC). This means that PARP inhibitor combination therapy is formally moving from the mCRPC setting into earlier stages of treatment, which could have a profound impact on the prostate cancer treatment landscape. Further studies, including TALAPRO-3, are expected to provide additional evidence in this area, and their results are highly anticipated.
In addition, combinations of PARP inhibitors with immunotherapy have also demonstrated potential. For example, the C3-NIRA study showed promising efficacy in patients with aggressive variant prostate cancer. Other studies have explored triplet regimens combining ARPIs, immunotherapy, and chemotherapy. However, these studies remain at an early stage, with relatively small sample sizes, and further breakthrough data are expected in the future.
HRR Mutation Profiles in Asian Populations Are Broadly Similar to Those in Western Populations
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Oncology Frontier – UroStream: Your team has previously conducted a systematic assessment of prostate cancer diagnosis and treatment in Southeast Asia. Compared with Western populations, what are the characteristics of HRR gene mutation profiles among prostate cancer patients in Southeast Asia and across Asia?
Professor Edmund Chiong: Genetic testing is a core component of precision diagnosis and treatment in prostate cancer. As early as a decade ago, studies by the Pritchard and Robinson teams demonstrated that the prevalence of HRR gene mutations in patients with metastatic hormone-sensitive prostate cancer (mHSPC) was approximately 11.8%, increasing to around 23% after disease progression to the mCRPC stage.
Based on currently available real-world data, the prevalence of HRR mutations in Southeast Asian populations is broadly similar to that observed in Western populations. However, large-scale, high-quality studies specifically focusing on local populations in this region remain limited.
In my view, compared with subtle differences in mutation profiles, promoting the clinical implementation of genetic testing is a more important issue. Although requiring genetic testing for every prostate cancer patient presents various practical challenges, at a minimum, patients with mCRPC should undergo genetic testing. In addition, patients with high-volume metastatic disease, a family history of cancer, or young patients with extremely high-risk disease—groups who are more likely to require PARP inhibitors later in their treatment course—should undergo testing as early as possible, so that subsequent treatment options can be preserved.
Impact of HRR Mutation Profiles on Clinical Benefit from PARP Inhibitors
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Oncology Frontier – UroStream: How do these mutation profile characteristics affect the clinical benefit of PARP inhibitors and the choice of treatment?
Professor Edmund Chiong: The vast majority of clinical studies have demonstrated that mutations in BRCA1 and BRCA2, particularly BRCA2 mutations, are key predictive biomarkers for response to PARP inhibitors. This predictive value of BRCA2 mutations also holds true in Southeast Asian and broader Asian populations. Patients harboring BRCA2 mutations can clearly derive clinical benefit from PARP inhibitor-based combination therapy.
Patients with other types of HRR gene mutations may also derive treatment benefits. For example, in the monotherapy setting, patients with certain HRR mutation subtypes can still benefit from PARP inhibitor treatment.
Key Strategies for Managing PARP Inhibitor Resistance
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Oncology Frontier – UroStream: PARP inhibitor resistance remains a major clinical challenge. Based on your research and clinical experience, what are the main strategies for addressing resistance?
Professor Edmund Chiong: At present, there is still a lack of high-level evidence regarding how to reverse or overcome PARP inhibitor resistance. However, available research suggests that combining PARP inhibitors with other treatment modalities, such as ARPIs, may produce synergistic effects and prolong the duration of PARP inhibitor efficacy, which could represent a key mechanism for delaying the development of resistance.
For example, the BRCAway study presented at the 2026 ASCO Genitourinary Cancers Symposium included patients harboring HRR gene mutations such as BRCA1, BRCA2, and ATM. Patients were assigned to three treatment strategies: the first group received abiraterone initially, followed by olaparib after disease progression; the second group received olaparib first, followed by abiraterone after progression; and the third group received the two drugs in combination from the outset. Based on the early results currently available, the upfront combination group demonstrated better objective response rates and progression-free survival.
Therefore, I believe that a key strategy for overcoming PARP inhibitor resistance is to initiate combination therapy with a PARP inhibitor and an ARPI as early as possible in patients who are clearly expected to benefit—namely, those harboring HRR gene mutations, particularly BRCA1/2 mutations.
