Editor’s Note:
Prostate cancer is the leading male urological tumor in China and has become one of the fastest-growing male malignancies in the past decade. The recent ESMO conference unveiled several advancements in prostate cancer research, extending the survival prospects for patients. Although there were some negative results, the research still holds positive significance. “Oncology Frontier” has specially invited Professor Yao Zhu from Fudan University’s affiliated Cancer Hospital to provide an in-depth interpretation of these research developments.
The recent ESMO meeting announced numerous latest advancements in prostate cancer research. Based on the conference reports and related papers that have been published, the current progress in prostate cancer research can be categorized into three aspects: first, the risk stratification after localized prostate cancer treatment and the choice of treatment methods and timing of radiotherapy after recurrence; second, clinical research on innovative therapies related to PSMA; and third, phase III clinical data on prostate cancer immunotherapy.
Act After Planning: Risk Stratification and Treatment Strategies for Localized Prostate Cancer
High-Risk Factors for Localized Prostate Cancer: For localized prostate cancer, the ICECaP working group conducted a long-term analysis of existing clinical trials [1] to identify the true high-risk factors for localized prostate cancer. This study screened 31 relevant radiotherapy studies, ultimately including 3604 patients. It compared common risk factors such as the Gleason score, tumor grading, PSA levels, and lymph node metastasis status to identify significant prognostic factors. Large-scale data analysis revealed that patients with lymph node metastases have significantly worse prognoses. For patients without apparent lymph node metastasis, if two or more of the three risk factors (Gleason score ≥8, PSA ≥20, cT3/T4) are present, they are at higher risk and have a significantly worse prognosis. If only one high-risk factor is present, the relative risk is lower. The study results indicate that patients with localized prostate cancer having two or more high-risk factors or lymph node metastasis have a poorer prognosis.
Timing of Radiotherapy after Radical Prostatectomy: Regarding patients with relapse after acute prostate treatment, the RADICALS RT study compared the differences between adjuvant and salvage radiotherapy post-surgery [2]. The inclusion criteria for the study were a postoperative PSA ≤0.2 ng/ml and more than one risk factor (including T3/T4, Gleason score ≥7, preoperative PSA >10 ng/ml, or positive surgical margins). The study found no significant difference in the occurrence and risk of distant metastases between the adjuvant and salvage radiotherapy groups. The 10-year survival rate was 88% in the adjuvant radiotherapy group and 87% in the salvage radiotherapy group. The results suggest that for patients whose postoperative PSA drops to within 0.2 ng/ml and who have one of the four high-risk factors (instead of multiple high-risk factors mentioned above), there may not be much difference in the effectiveness of adjuvant versus salvage radiotherapy. Moreover, nearly 60% of patients undergoing salvage radiotherapy did not need radiotherapy, making it very important for such patients to reduce the probability of overtreatment by treating according to the high-risk factors.
Intensified Treatment for Patients with High-Risk BCR nmHSPC: In the EMBARK study, patients who experienced postoperative recurrence, including recurrence after radiotherapy, with PSA >1 ng/ml and a prostate-specific antigen doubling time (PSADT) ≤9 months, and who had not previously received endocrine treatment, were given intensified treatment with enzalutamide combined with leuprolide. The study results showed that the intensified treatment regimen could significantly reduce the risk of distant metastases. Furthermore, this intensified treatment is not for lifelong use, but rather involves stopping medication approximately 9 months after achieving the target PSA level. If the PSA rises again, medication is resumed, which is akin to an intermittent treatment mode, more acceptable for patients [3]. Therefore, for patients after local treatment, the timing and combination of treatments can be decided based on high-risk factors. For extremely high-risk patients, such as those with rapid progression and PSA >1 ng/ml, intensified intermittent therapy may also be beneficial. It is important to note that the patients in the study were those with good postoperative outcomes, not those with oligometastatic or metastatic prostate cancer who still require medication after surgery.
A Promising Future: Research on Innovative Therapy with ^177Lu-PSMA-617
The second part of the research focuses on PSMA-related studies. One study compares enzalutamide combined with PSMA to enzalutamide monotherapy. Another study explores the use of ^177Lu-PSMA-617 or switching to other novel endocrine drugs for patients who have not undergone chemotherapy.
ANZUP 1901 Study: This study included mCRPC patients who had not received chemotherapy and androgen receptor pathway inhibitors and showed early progression with enzalutamide treatment, such as visceral metastases or rapid PSADT progression. Patients were randomly assigned to either the enzalutamide group or the enzalutamide combined with ^177Lu-PSMA-617 group. The study found that enzalutamide combined with ^177Lu-PSMA-617 significantly delayed the progression of prostate cancer, improving imaging progression compared to enzalutamide alone [4]. The study confirmed that most patients with mCRPC are sensitive to enzalutamide, and those who are not can use intensified therapy to improve efficacy.
PSMAfore Study: The second study also targeted mCRPC patients, treating them with ^177Lu-PSMA-617 or switching to other novel endocrine drugs. This study confirmed that, compared to switching to other novel endocrine drugs, ^177Lu-PSMA-617 significantly prolonged the imaging progression of patients [5]. However, it is important to note that the enrolled patients had already used novel endocrine drugs, and the effect of this drug interchange was not significant. Theoretically, a chemotherapy regimen should be used. Therefore, this study can only confirm that ^177Lu-PSMA-617 is superior to the interchange of endocrine drugs but cannot prove that ^177Lu-PSMA-617 is more promising than chemotherapy or other strategies. Additionally, overall survival differences in this study have not yet been published.
Both studies indicate that the treatment sequence of ^177Lu-PSMA-617 is gradually moving forward, but more evidence is needed to confirm its superiority over other treatment strategies. With many types of new endocrine drugs for prostate cancer, such as abiraterone, enzalutamide, darolutamide, apalutamide, and relugolix, the efficacy of interchanging these drugs is not high. More analysis and data are needed to prove whether ^177Lu is stronger and more effective than other strategies, such as chemotherapy or precision treatment for patients with mutations.
Not Judging by Success or Failure: Immunotherapy for Prostate Cancer
Two clinical studies of immunotherapy in prostate cancer, namely KEYNOTE-641 and KEYNOTE-991, were once highly anticipated, hoping to see an effect greater than the sum of their parts (1+1>2). Unfortunately, it was discovered that both studies did not achieve positive results in terms of imaging progression and survival, and significantly increased side effects: KEYNOTE-641 is a phase III study evaluating the benefits of combining pembrolizumab with enzalutamide as a second-line sequential treatment for mCRPC, where the combination therapy group experienced grade 3 or higher toxic reactions at a rate of 77.9%, compared to only 31.2% in the enzalutamide-only group [6]. KEYNOTE-991, on the other hand, studied the use of enzalutamide combined with pembrolizumab for mHSPC, but the results showed that the serious adverse event (AE) rate in the immunotherapy combination group was 40.3%, compared to only 23.2% in the control group.
It can be seen that if prostate cancer patients are not selected appropriately or if the treatment modalities are not optimized, the strategy of combining immunotherapy with novel endocrine treatments is essentially at a standstill. The above studies and others also confirm that the efficacy of combined treatment does not significantly increase, but the risk of side effects significantly rises. Therefore, clinical use of immunotherapy strategies needs optimization. KEYNOTE-641 also conducted a PD-L1 analysis, but did not find significant improvement in immunotherapy for PD-L1 positive patients. The data from KEYNOTE-991 is still awaiting further analysis. Currently, there is no strong and effective clinical evidence for immunotherapy in prostate cancer, and further exploration and analysis are still needed.
References:
- Ravi P, Xie W, Buyse M E, et al. 1770O Refining risk stratification in patients undergoing radiotherapy (RT) and long-term (lt) ADT for high-risk/locally advanced prostate cancer (HR/LA-PC): An individual patient data (IPD) analysis of randomized controlled trials (RCTs) from the ICECaP consortium[J]. Annals of Oncology, 2023, 34: S954.
- Parker C, Clarke N, Cook A, et al. 1764O Timing of radiotherapy (RT) after radical prostatectomy (RP): Final results of RADICALS RT randomized controlled trial[J]. Annals of Oncology, 2023, 34: S953.
- Freedland S J, Gleave M E, Rannikko A, et al. 1766MO Health-related quality of life (HRQoL) in nonmetastatic hormone-sensitive prostate cancer (nmHSPC) patients (pts) with high-risk biochemical recurrence (BCR) from the EMBARK study[J]. Annals of Oncology, 2023, 34: S955.
- Cho B C, Felip E, Spira A I, et al. LBA14 Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results from MARIPOSA, a phase III, global, randomized, controlled trial[J]. Annals of Oncology, 2023, 34: S1306.
- Sartor O, Gauna D E C, Herrmann K, et al. LBA13 Phase III trial of [^177Lu] Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (PSMAfore)[J]. Annals of Oncology, 2023, 34: S1324-S1325.
- Graff J N, Burotto M, Fong P C, et al. 1771MO Pembrolizumab (pembro) plus enzalutamide (enza) for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Randomized double-blind phase III KEYNOTE-641 study[J]. Annals of Oncology, 2023, 34: S957.
- Gratzke C J, Ozguroglu M, Peer A, et al. 1772MO Pembrolizumab (pembro) plus enzalutamide (enza) and androgen deprivation therapy (ADT) for patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC): Randomized double-blind phase III KEYNOTE-991 study[J]. Annals of Oncology, 2023, 34: S957-S958.
