Treatment options for metastatic castration-resistant prostate cancer (mCRPC) are expanding rapidly. However, two major challenges remain in clinical decision-making: how to adjust treatment following oligoprogression and how to optimize the sequencing of precision therapies.With androgen receptor pathway inhibitors (ARPIs) increasingly being used earlier in the disease course, treatment decisions in the mCRPC setting require comprehensive consideration of resistance patterns, prior treatments, molecular characteristics, tumor burden, and bone marrow reserve.
In this edition of Getting to the Bottom of the Debate, Professor Jianming Guo of Zhongshan Hospital, Fudan University, and Professor Qing Zou of Jiangsu Cancer Hospital engage in a debate on two key clinical questions:
- Can local treatment during oligoprogression extend the benefit of the existing systemic therapy regimen?
- In patients with both homologous recombination repair (HRR) gene alterations and positive prostate-specific membrane antigen (PSMA) expression, how should PARP inhibitors and ¹⁷⁷Lu-PSMA-617 radioligand therapy be sequenced?
Debate Topic 1
Managing Oligoprogression: Can Local Therapy Extend the Benefit of the Existing Systemic Treatment Regimen?
For patients with mCRPC whose disease remains generally controlled systemically but who develop progression in only one to three bone or lymph node lesions, should clinicians use stereotactic body radiotherapy (SBRT), surgery, or ablation to treat the progressing lesions while continuing the existing ARPI, PARP inhibitor, or other systemic therapy? Or should the systemic treatment regimen be changed immediately?
Opening Arguments
Maintain the Existing Regimen + Local Therapy
Professor Jianming Guo
Zhongshan Hospital, Fudan University
My position is that when the disease remains generally stable systemically, with progression limited to a small number of lesions, the existing systemic treatment can be maintained after a thorough assessment, while local treatment is added to the progressing lesions. Options include stereotactic body radiotherapy (SBRT), ablation, and, when necessary, surgery. Surgery is relatively more invasive, so the choice of treatment should be guided by the location of the lesions and the patient’s overall condition.
Oligoprogression more often indicates the emergence of locally resistant tumor clones rather than complete failure of systemic therapy. Existing studies and clinical practice suggest that local treatment of progressing lesions may delay further disease progression and the initiation of the next line of systemic therapy.
Therefore, I tend to favor maintaining the existing treatment regimen while actively assessing the feasibility of local therapy.
Partially Agree, but the Systemic Treatment Regimen Should Be Reassessed at the First Progression
Professor Qing Zou
Jiangsu Cancer Hospital
At present, the management of oligoprogressive metastatic castration-resistant prostate cancer (mCRPC) still lacks high-level evidence that can directly guide clinical practice. Therefore, I partially agree with Professor Guo’s position.
For patients confirmed to have oligoprogression through imaging reassessment, such as PSMA PET/CT, local treatment may be considered. In my own clinical practice, I have also attempted radiotherapy for a single progressing lesion while maintaining the existing systemic treatment regimen. However, only a small proportion of patients achieved sustained control of prostate-specific antigen (PSA) levels, while most experienced further progression within a relatively short period. This suggests that local treatment is not suitable for every patient.
In my view, local treatment is more appropriate in two situations. First, when patients have local symptoms, such as pain, treatment may help relieve symptoms and improve quality of life. Second, when the lesions are clearly defined and local control offers substantial clinical value, as may be the case with certain soft-tissue or lymph node lesions.
For patients with a small number of bone lesions, treatment decisions should also take into account symptoms, imaging characteristics, and other available therapeutic options.
At the same time, it is essential to distinguish between first and subsequent episodes of progression. At the first progression, clinicians should review the patient’s prior endocrine and other systemic treatments. If subsequent treatment options with different mechanisms of action and sufficient supporting evidence remain available, the need to switch systemic therapy should be assessed concurrently.
Resistant tumor clones may already have a tendency toward systemic dissemination. Therefore, local treatment cannot replace a comprehensive reassessment and risk stratification of the systemic disease.
Exchange 1
How Should Oligoprogression Be Defined: By the Number of Lesions, Their Location, Imaging Findings, or the Rate of Progression?
Professor Jianming Guo
Zhongshan Hospital, Fudan University
The assessment of oligoprogression involves at least three dimensions: the number of lesions, the rate of progression, and whether the progression is the first or a subsequent episode. Among these, the number of lesions remains the most straightforward and fundamental indicator. However, it should not be assessed in isolation from imaging modalities, lesion location, and disease kinetics.
In addition to conventional imaging techniques such as CT, MRI, and bone scans, PSMA PET/CT can help identify smaller lesions that might otherwise go undetected.
For patients experiencing subsequent progression, an increasing number of lesions, or a markedly accelerated rate of progression, clinicians should be more alert to the possibility of systemic resistance and consider broadening the scope of treatment. For patients with PSMA-positive disease, ¹⁷⁷Lu-PSMA-617 radioligand therapy may also be evaluated.
Overall, the higher the metastatic burden and the faster the disease progresses, particularly in the presence of visceral metastases, the less likely local treatment alone is to be sufficient. Accordingly, the importance of modifying or intensifying systemic therapy increases.
Exchange 2
Which Patients Are Unsuitable for Continuing the Existing Regimen After Local Treatment?
Professor Qing Zou
Jiangsu Cancer Hospital
When patients develop rapid progression at multiple sites, systemic resistance should be suspected, and treating only a few lesions with localized “spot treatment” is not advisable.
In such cases, assessment can incorporate conventional imaging and PSMA PET/CT. If necessary, fluorodeoxyglucose (FDG) PET/CT can also be added to identify lesions with heterogeneous PSMA expression or more aggressive biological behavior.
If there are also indications of neuroendocrine differentiation, further pathological evaluation and relevant investigations are required, with systemic treatment adjusted accordingly.
For a single lesion with high PSMA expression, local treatment may improve local disease control. However, whether it can prolong progression-free survival (PFS) or overall survival (OS) remains to be validated in further studies.
Exchange 3
Which Efficacy Endpoint Should Be Prioritized: Delaying the Next Line of Treatment, PFS, or OS?
Professor Jianming Guo
Zhongshan Hospital, Fudan University
From a long-term perspective, overall survival (OS) benefit is the most important goal. Progression-free survival (PFS) and the time to the next line of systemic therapy are also clinically meaningful endpoints. However, whether improvements in these outcomes translate into an OS benefit still needs to be validated through prospective studies or high-quality real-world data.
Based on the available evidence, I continue to favor maintaining the existing treatment regimen and adding local therapy for carefully selected patients with oligoprogression.
When discussing treatment with patients, we should clearly explain the level of evidence currently available, the expected benefits and risks of local treatment, and the alternative options for switching systemic therapy. Patients should be fully informed and actively involved in shared decision-making.
Round Summary
Areas of Agreement
Both professors agreed that for patients with mCRPC and oligoprogression confirmed through comprehensive imaging assessment, local treatments such as stereotactic body radiotherapy (SBRT) may be considered as alternative options. In appropriately selected patients, SBRT offers advantages such as relatively low invasiveness and good feasibility.
Areas of Disagreement
Professor Jianming Guo advocated maintaining the existing treatment regimen and adding local therapy after careful patient selection.
Professor Qing Zou emphasized the need to distinguish between first and subsequent episodes of progression and to assess the necessity of switching systemic therapy at the time of first progression. His clinical experience suggests that local radiotherapy alone may provide limited PSA control, with substantial variability in the duration of benefit among individual patients.
Debate Topic 2
Treatment Sequencing in Patients with Dual Biomarkers: How Should PARP Inhibitors and ¹⁷⁷Lu-PSMA-617 Be Sequenced?
For patients with mCRPC who harbor BRCA1/2 or other homologous recombination repair (HRR) gene alterations and have positive PSMA PET imaging, how should PARP inhibitors (PARPi) and ¹⁷⁷Lu-PSMA-617 radioligand therapy (RLT) be sequenced?
Should treatment decisions be based primarily on the specific gene alteration, prior exposure to androgen receptor pathway inhibitors (ARPIs) or taxane chemotherapy, bone marrow reserve, or the rate of disease progression?
Opening Arguments
Affirmative | Consider Prioritizing ¹⁷⁷Lu-PSMA-617 When Clinically Feasible
Professor Qing Zou
Jiangsu Cancer Hospital
At present, high-quality head-to-head studies directly comparing the optimal sequencing of PARP inhibitors (PARPi) and ¹⁷⁷Lu-PSMA-617 are lacking.
In clinical practice, PARPi became available earlier, and many patients with HRR gene alterations received PARPi first, followed by ¹⁷⁷Lu-PSMA-617 after disease progression. Some of these patients still achieved responses, and the overall safety profile was manageable.
Recent real-world studies have also suggested that some patients may continue to benefit from subsequent systemic therapy after receiving ¹⁷⁷Lu-PSMA-617. However, these findings are not yet sufficient to establish the optimal treatment sequence.
As the indication for ¹⁷⁷Lu-PSMA-617 gradually moves into earlier treatment settings, further support is emerging for its use at earlier disease stages.
In light of these trends, I would consider prioritizing ¹⁷⁷Lu-PSMA-617 in patients with high PSMA expression and substantial disease burden, provided that treatment is clinically feasible.
Negative Position | Prioritize Genotype-Driven Treatment: PARP Inhibitors First for Patients with BRCA1/2 Mutations
Professor Jianming Guo
Zhongshan Hospital, Fudan University
My view is that treatment selection should prioritize actionable molecular biomarkers.
For patients with HRR gene alterations, particularly BRCA1/2 mutations, targeted therapies and relatively well-established supporting evidence are available, including data from studies such as PROfound. Therefore, PARP inhibitors (PARPi) should be prioritized for these patients.
For patients with non-BRCA HRR gene alterations, such as ATM, the benefits of PARPi are generally less consistent than those observed in patients with BRCA1/2 mutations. In these cases, treatment should be individualized based on PSMA expression, prior therapies, disease burden, and the rate of progression, with a choice between PARPi and ¹⁷⁷Lu-PSMA-617.
For patients without actionable HRR gene alterations who have a high metastatic burden, rapidly progressing disease, and PSMA-positive imaging, ¹⁷⁷Lu-PSMA-617 should be evaluated more proactively.
Exchange 1
Should Patients with BRCA and Non-BRCA HRR Alterations Follow the Same Treatment Sequence? How Should Discordant Test Results Be Managed?
Professor Qing Zou
Jiangsu Cancer Hospital
After listening to Professor Guo’s analysis, I am willing to further revise my initial position.
BRCA mutations, particularly BRCA2 mutations, are generally associated with more aggressive disease biology and represent a patient population with relatively well-established benefits from PARP inhibitor (PARPi) therapy in existing studies. If effective targeted therapy can be administered early, while the patient’s general condition and bone marrow reserve remain relatively good, it may be more beneficial for prolonging disease control.
I believe combination therapy is worth exploring, but at present, it should remain within the framework of clinical trials or rigorously designed research and should not yet be regarded as a routine treatment option.
The benefits of PARPi in patients with non-BRCA HRR gene alterations are more heterogeneous, making individualized treatment sequencing particularly important.
Regarding testing strategies, tissue-based testing remains an important foundation. However, many patients have a prolonged disease course, and previously collected tissue samples may be insufficient, of poor quality, or unavailable for repeat sampling.
Biomarker analyses from the PROfound study have shown that circulating tumor DNA (ctDNA) can serve as an important complement to tissue-based testing, particularly for patients whose tissue samples are inaccessible or inadequate. However, its detection capability may be affected by factors such as ctDNA abundance and the type of genetic alteration.
When tissue-based testing and ctDNA results are discordant, clinicians should consider the timing of sample collection, sample quality, tumor burden, and prior treatments. Repeat testing may be necessary, and multidisciplinary discussion can help establish an appropriate basis for treatment decisions.
PSMA PET reflects target expression, whereas genomic testing addresses a different question. The two approaches should complement each other rather than be compared simply in terms of whether their results are concordant or discordant.
Exchange 2
How Should Prior Chemotherapy, Bone Metastatic Burden, and Bone Marrow Reserve Influence Treatment Sequencing?
Professor Jianming Guo
Zhongshan Hospital, Fudan University
Combination therapy is theoretically appealing, but bone marrow safety is a key issue that must be addressed. Both PARP inhibitors (PARPi) and ¹⁷⁷Lu-PSMA-617 can cause myelosuppression and other hematologic toxicities.
For patients who have previously received chemotherapy, have extensive bone metastases, or have limited bone marrow reserve, a thorough pretreatment assessment is essential. This should include blood counts, transfusion requirements, recovery from prior toxicities, and the extent of disease involvement. Close monitoring throughout treatment is also necessary.
The risks associated with the two treatment modalities should not be treated as identical or generalized across all patients.
For patients with BRCA1/2 mutations whose hematologic parameters permit treatment, I still favor using a PARP inhibitor first. If efficacy is inadequate, treatment is not tolerated, or disease progression occurs, ¹⁷⁷Lu-PSMA-617 can then be evaluated.
Exchange 3
Does Prior PARP Inhibitor Treatment Affect Tolerability of Subsequent Radioligand Therapy? What Unknown Risks Are Associated with the Reverse Sequence?
Professor Qing Zou
Jiangsu Cancer Hospital
Both treatment modalities can cause myelosuppression. Most patients with prostate cancer are elderly, and after prolonged treatment across multiple lines, their bone marrow reserve is often already compromised. Therefore, regardless of which treatment is administered first, it may affect the feasibility of subsequent therapies.
Clinical decisions must be individualized. For example, in patients with a high BRCA mutation allele frequency, a PARP inhibitor may be administered first, with dynamic assessment based on PSA levels, imaging findings, and hematologic tolerability. If the response becomes inadequate or disease progression occurs, ¹⁷⁷Lu-PSMA-617 can then be discussed. A rigid, predetermined sequence of alternating treatments should be avoided.
I have administered ¹⁷⁷Lu-PSMA-617 to a small number of patients. One patient had a PSA level exceeding 900 ng/mL, poor general condition, extensive bone metastases, a “superscan” pattern on bone scintigraphy, and severe anemia. This patient would not typically meet the eligibility criteria for clinical trials.
Following a thorough assessment and discussion, the patient received one treatment cycle. PSA levels declined markedly in the short term, and hemoglobin levels did not deteriorate further.
This case illustrates that responses among patients in real-world practice can vary considerably. However, individual case experiences cannot replace evidence-based data or be generalized into routine treatment recommendations.
At present, prospective head-to-head studies directly comparing the two treatment sequences are still lacking. This is precisely the question that future research needs to address.
Round Summary
Areas of Agreement
Both professors agreed that patients with BRCA and non-BRCA HRR gene alterations should not necessarily follow the same treatment sequencing strategy.
For patients without clearly actionable HRR alterations who have a high tumor burden, rapidly progressing disease, and PSMA-positive imaging, ¹⁷⁷Lu-PSMA-617 may be evaluated more proactively.
Both PARP inhibitors (PARPi) and ¹⁷⁷Lu-PSMA-617 can cause hematologic toxicity. Treatment sequencing must therefore be highly individualized, taking prior treatments and bone marrow reserve into account.
Prospective studies directly comparing the optimal treatment sequence are still lacking.
Areas of Disagreement
Professor Jianming Guo emphasized genotype-driven treatment selection and advocated prioritizing PARP inhibitors for patients with BRCA1/2 mutations.
Professor Qing Zou initially favored prioritizing ¹⁷⁷Lu-PSMA-617 when clinically feasible, reflecting the trend toward its use earlier in the treatment course. He subsequently agreed that patients with BRCA mutations should receive PARP inhibitors early and proposed that combination strategies warrant further investigation in clinical trials.
Expert Summary and Outlook
Professor Qing Zou
Jiangsu Cancer Hospital
Reflecting on today’s two rounds of debate, I would first like to reiterate my position on the management of oligoprogression. I partially agree with Professor Guo’s approach of maintaining the existing treatment regimen and adding local therapy, but I place greater emphasis on individualized disease assessment. For patients whose oligoprogression is confirmed through imaging reassessment, including PSMA PET/CT, local therapy may be considered, particularly for those with local symptoms such as pain or lesions in soft tissues and lymph nodes where local control may offer substantial clinical value.
Based on my clinical experience, PSA control with local radiotherapy alone may be limited. Therefore, it is essential to distinguish between first and subsequent episodes of progression. At the first progression, previous endocrine and other systemic therapies should be reviewed. If subsequent treatment options with different mechanisms of action and sufficient supporting evidence remain available, the need to switch systemic therapy should also be assessed. Resistant clones may already have a propensity for systemic dissemination, and local therapy cannot replace a reassessment of the disease at the systemic level.
Regarding the sequencing of PARP inhibitors and ¹⁷⁷Lu-PSMA-617, I initially leaned toward prioritizing ¹⁷⁷Lu-PSMA-617 when feasible, based on the trend toward its use at earlier stages of treatment. However, after hearing Professor Guo’s argument centered on molecular profiling, I am willing to revise my initial position. For patients with BRCA mutations, particularly BRCA2 mutations, the evidence of benefit is relatively clear. Administering a PARP inhibitor earlier, while the patient’s general condition and bone marrow reserve remain favorable, may help prolong disease control. Combination therapy is worth exploring, but for now, it should remain within the context of clinical trials or rigorously designed research and should not be regarded as a routine treatment option.
Overall, sequencing decisions must be highly individualized, taking into account molecular profiling, tumor burden, prior treatments, and bone marrow reserve, rather than following a predetermined, rigid sequence.
Looking ahead, I am particularly interested in moving treatment to earlier stages of the disease. First, neoadjuvant therapy: if we can better control locally advanced disease in the early stages, there may be an opportunity to reduce or delay progression to the castration-resistant stage. Second, earlier risk stratification at initial diagnosis: even in patients who already have metastatic disease, comprehensive assessment should be performed as early as possible, integrating PET imaging, genetic testing such as BRCA testing, and pathological and molecular profiling. Once an actionable abnormality is identified, intervention should begin promptly.
With the continued development of new drugs and treatment approaches, I remain optimistic about improving long-term survival for patients.
Professor Jianming Guo
Zhongshan Hospital, Fudan University
Reflecting on today’s two rounds of debate, I would like to reiterate my core positions.
Regarding oligoprogression, I maintain that when the overall systemic disease remains stable and only a limited number of lesions progress, the existing treatment regimen should be maintained, with local therapy added to the progressing lesions. Oligoprogression more often indicates the emergence of locally resistant clones rather than complete failure of systemic treatment. The number of lesions remains the most straightforward fundamental criterion for defining oligoprogression. As metastatic burden increases and disease progresses more rapidly, particularly in the presence of visceral metastases, the importance of adjusting or intensifying systemic therapy also increases.
From a long-term perspective, overall survival (OS) benefit is the most important endpoint. Whether improvements in progression-free survival (PFS) and delays in the initiation of the next line of systemic therapy can translate into an OS benefit still requires validation through prospective studies or high-quality real-world data. When communicating with patients, we should be transparent about the level of available evidence, the expected benefits and risks of local therapy, and alternative options for switching systemic treatment. Patients should be fully informed and actively involved in shared decision-making.
Regarding treatment sequencing, I maintain that molecular profiling should be the central consideration. For patients with BRCA1/2 mutations, targeted therapies and relatively clear evidence-based support are available, as demonstrated by the PROfound trial. PARP inhibitors should therefore be prioritized. For alterations in non-BRCA HRR genes, such as ATM, the benefits are generally less consistent than those observed in patients with BRCA1/2 mutations. Treatment should be individualized based on PSMA expression, prior therapies, disease burden, and the rate of progression. For patients without clearly actionable HRR alterations who have a high metastatic burden, rapid disease progression, and PSMA-positive disease, ¹⁷⁷Lu-PSMA-617 should be evaluated more proactively.
Bone marrow safety is a key issue that must be addressed. Both PARP inhibitors and ¹⁷⁷Lu-PSMA-617 can cause myelosuppression. For patients with prior chemotherapy exposure, extensive bone metastases, or poor bone marrow reserve, blood counts and other relevant parameters should be thoroughly assessed before treatment, with close monitoring throughout therapy.
In the overall clinical population, the proportion of patients with prostate cancer harboring HRR gene alterations is relatively limited, whereas PSMA-positive patients are more numerous. Therefore, I believe that radioligand therapy for PSMA-positive patients has considerable potential for further development.
Of course, ¹⁷⁷Lu-PSMA-617 still faces challenges, including high costs and limited accessibility. Although existing studies have demonstrated an improvement in OS, there remains a gap between these findings and the needs of real-world clinical practice. Further research is needed to identify more appropriate treatment timing and combinations to improve long-term patient outcomes.
This article was prepared based on the audio recording of the academic debate “Getting to the Bottom of the Debate 2.0” and is intended for medical professionals only. The views expressed by the experts are their own academic opinions and do not constitute clinical treatment recommendations.
Professor Jianming Guo
Director of the Department of Urology, Zhongshan Hospital, Fudan University
- Professor (Second-Tier), Doctoral Supervisor, and Chief Physician
- Standing Committee Member, Urology Branch of the Chinese Medical Doctor Association
- Vice Chair, Urology Branch of the Shanghai Medical Association
- Vice Chair, Urological Oncology Committee of the Shanghai Anti-Cancer Association
- Standing Committee Member, CSCO Prostate Cancer and Urothelial Carcinoma Committees
- Standing Committee Member, Urological and Male Reproductive System Oncology Committee of the Chinese Anti-Cancer Association (CACA)
- Vice Chair, Urology Branch of the Cross-Straits Medicine Exchange Association
- Vice Chair, Urology and Andrology Committee of the China Association of Gerontology and Geriatrics
- Editorial Board Member, Chinese Journal of Urology
Professor Qing Zou
Chief Physician, Master’s Supervisor
Jiangsu Cancer Hospital
- Standing Committee Member, Urological and Male Reproductive System Oncology Committee of the Chinese Anti-Cancer Association (CACA)
- Deputy Head, Minimally Invasive Surgery Group, Urological and Male Reproductive System Oncology Committee of the Chinese Anti-Cancer Association (CACA)
- Standing Committee Member, CSCO Prostate Cancer Committee
- Chair, Urological and Male Reproductive System Oncology Committee of the Jiangsu Anti-Cancer Association
- Standing Committee Member, Urology Committee of the Jiangsu Medical Doctor Association
- Standing Committee Member, Urology Committee of the Jiangsu Medical Association
- Editorial Board Member, CSCO Prostate Cancer Guidelines
- Editorial Board Member, CUA Prostate Cancer Guidelines
