Editor's Note
The 2022 American Society of Clinical Oncology Symposium on Genitourinary Oncology (2022 ASCO-GU) was held in San Francisco, USA, on February 17-19, 2022. This is a grand event in the field of urogenitals, which has received widespread attention from colleagues at home and abroad. Professor Hao Liu of Sun Yat-sen Memorial Hospital of Sun Yat-sen University shared with us the progress of new endocrine therapy for prostate cancer.
Professor Liu Hao
Deputy Chief Physician of Sun Yat-sen Memorial Hospital, Sun Yat-sen University, M.D., Master Supervisor
- International Youth Member of the American Society of Urology (AUA).
- International Youth Member of the European Urological Society (EAU).
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Proficient in endoscopic minimally invasive surgery for common diseases of urology such as kidney stones, ureteral stones, benign prostatic hyperplasia, etc., with a solid professional foundation. He specializes in the early diagnosis of urinary tract tumors (especially bladder, prostate and kidney cancers), personalized whole-course treatment and minimally invasive urological techniques.
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He was awarded the title of "Excellent Clinical Teacher of Sun Yat-sen University". He has presided over and participated in a number of national and provincial research projects, and won the first prize of the Guangdong Provincial Science and Technology Progress Award.
The benefits of the new option, enzaluamine, in the treatment of mHSPC were significant
Endocrine therapy is the cornerstone of systemic treatment of prostate cancer. As a new generation of androgen receptor antagonists, enzaluamine (ENZA) can strongly inhibit the signaling pathways of androgen receptors, so it has a potent inhibitory effect on prostate cancer. Recent evidence-based medical evidence, including the AFRIM study, the PREVAIL study, the PROSPER study, and the ARCHERS study, has confirmed that enzaluamine is effective at different stages of prostate cancer. According to the results of these studies, the use of enzaluamine can be advanced to achieve a longer therapeutic effectiveness time and prolong the overall survival time of patients. At the ASCO-GU conference, the results of the post-mortem analysis of the ARCHES study were announced.
Abs 115 丨ARCHES trial post-mortem analysis: mHSPC patients treated with ENZA+ADT, OS stratified based on high/low tumor burden and progression to mHSPC (M0 for initial diagnosis) or newly diagnosed as mHSPC (M1 for initial diagnosis).
In the ARCHES (NCT02677896) study, ENZA+ADT improved progression-free survival (rPFS), overall survival (OS), and other key secondary endpoints in patients with metastatic hormone-sensitive prostate cancer (mHSPC) compared with placebo plus androgen deprivation (ADT). Final OS results confirmed the long-term survival benefit of ENZA+ADT (HR 0.66; 95% CI: 0.53-0.81; p<0.0001). Os is analyzed post-hoc based on disease burden and stratification of mHSPC first diagnosed as localized prostate cancer (M0), progression to M1, or newly diagnosed.
The duration of treatment was 40.2 months in the ENZA group and 13.8 months in the placebo group. Including cross-treatment patients, 401 patients (69.6%) in the placebo group received life-prolonging treatment. In all disease burden and M0/M1 populations, os-benefit in the ENZA+ADT group was similar to that in the overall population. With the exception of patients with high tumor burden in the placebo group (45.9 months; 95% CI: 40.1-NE) or high tumor burden + M1 population (43.4 months; 95% CI: 36.4 to 49.7) and high tumor burden + M0 population in the ENZA+ADT group (54.2 months; 95% CI: 54.2-NE), the median OS was not achieved in most patients.
Figure 1 Results of post-mortem analysis of arches research
At present, there are also clinical studies abroad on whether the use of enzaluamine in high-risk patients in the perioperative period can reduce the risk of biochemical recurrence or clinical recurrence. However, as the indications for this type of study move forward further, longer follow-up times are needed to confirm their efficacy in delaying biochemical and clinical recurrence, and we will have to wait for high-level evidence-based medical evidence.
A new era - advanced prostate cancer has entered the era of triple therapy
At this year's ASCO-GU conference, a Phase III clinical study of different modes of combined therapy for multiple prostate cancers presented the results. Among them, the ARASENS study showed that the disease control effect of ADT + novel endocrine therapy + docetaxel (DOC) chemotherapy triple therapy in patients with mHSPC was better than that of dual therapy using ADT + docetaxel chemotherapy, which can further prolong rPFS and overall survival time. In addition, the PRESIDE study further showed that continued use of nzaluamine in second-line docetaxel chemotherapy after failure of enzaluamine therapy in patients with metastatic castration resistance prostate cancer (mCRPC) can further improve rPFS with docetaxel alone.
Abs 15丨PRESIDE Study: A randomized, double-blind, placebo-controlled, phase IIIb trial evaluating the efficacy and safety of DOC + prednisolone (PDN) + ENZA in patients with mCRPC who have not received chemotherapy and progressed with ENZA treatment
The PRESIDE study (December 2014 to April 2020) enrolled patients with mCRPC who had not previously received chemotherapy and who experienced disease progression during treatment with luteinizing hormone-releasing hormone (LHRH) agonists/antagonists (ADTs) or after bilateral orchiectomy. Patients receive an open ENZA (160 mg) + ADT in stage 1 (P1). Subjects who had a PSA response ≥ 50% from baseline to week 13 and progressed subsequently were eligible for Phase 2 (P2). Patients with P2 received DOC (75 mg/m2), PDN (10 mg), and ADT, and were randomized to receive ENZA (160 mg) or placebo. The primary endpoint was progression-free survival (PFS) of P2 (from randomization to radiographic/clinical progression or death). Secondary endpoints included time to PSA progression (TTPP) [increase of ≥25%; absolute increase of ≥2 ng/mL] and PSA response to P2.
The results suggested that the median PFS in the ENZA group was higher than that in the placebo group (9.53 months vs 8.28 months), and that the ENZA group significantly delayed TTPP (8.44 vs. 6.24 months, HR 0.58; 95% CI: 0.41-0.82; p=0.002) and improved PSA remission at any time (55.9% vs 37.0%). There were 46 deaths (6.7%) in the P1 group and 20 in the P2 group (ENZA: 9.6% vs placebo: 5.2%). Treatment-related adverse events (TEAE) occurred in 264 (97.4%) patients in the P2 group [ENZA: n=133 (97.8%); placebo: n=131 (97.0%)].
Triple therapy was used at the mHSPC stage, and a 2x2 factorial analysis of the 2021 PEACE-1 study confirmed similar results. However, it is worth noting that the control group of the PEACE-1 study and the ASCENSI study was both ADT + docetaxel chemotherapy. According to the CHAARTED study, the main beneficiaries of docetaxel chemotherapy are those with high tumor burden, so whether docetaxel chemotherapy is suitable for all patients with mHSPC is still controversial.
The PEACE-1 study showed that while triple therapy reduced the risk of progression in both patients with high and low tumor burden and could prolong overall survival in patients with high tumor burden, it did not prolong overall survival in patients with low tumor burden. The network meta-analysis published at this meeting also showed that the adverse effects of triple therapy were also relatively high, which also reminded clinicians to measure the benefits and risks of treatment.
First-line treatment options for Abs 132丨mCSPC: A systematic review and network meta-analysis (NMA)
The NMA contains 9 trials (23 literature) involving 9 different treatments. When combined with Abitolone prednisone-ADT (AAP-ADT; HR 0.58, 95% CI: 0.44-0.76; ranked 5), apatamide (APA)-ADT (HR 0.63, 95% CI: 0.46-0.87; ranked 4), TAK-ADT (HR 0.55; 95% CI: 0.36-0.84; ranked 6) and enzaluamine (E)-AAP-ADT (HR 0.70, 95% CI: 0.51-0.97; ranked 3) Significantly improved rPFS in AAP-D-ADT (rank 1) compared to treatment regimens, but no significant difference was observed with E+ADT (rank 2).
OS improvements in AAP-D-ADT (HR 0.75, 95% CI: 0.59-0.95; ranked 2), E-AAP-ADT (HR 0.68, 95% CI: 0.48-0.97; ranked 1) and AAP-ADT (HR 0.82, 95% CI: 0.70-0.96; ranked 3) compared to D+ADT (ranked 6). However, most combination therapy comparisons were not statistically significant in terms of OS.
Similarly, in patients with high tumor burden, AAP+D+ADT (ranked 1) significantly improved rPFS compared to AAP-ADT, APA-ADT, E-ADT, and D-ADT. However, there were no significant differences between the different therapies in terms of OS improvement. Compared with other therapies, E-ADT (ranked 1) improved rPFS in patients with low tumor burden, but there was no difference in OS. When compared between pre-specified subgroups, no significant differences were observed between different treatment regimens. In addition, AAP+D+ADT is classified as the least safe compared to other treatment regimens, with a significantly increased risk of Grade 3 AEs.
Current NMA suggests that triple therapy is most likely to improve rPFS and OS, but with increased toxicity. For older patients with low tumor burden, a diptychal combination may still be the best option.
The results of the ARCHES study show that patients can benefit from ADT combined with enzaluamine therapy regardless of tumor load. Therefore, randomized controlled studies using ADT+ novel endocrine therapy as a control group may bring us more treatment ideas. Combined with the current acceptance of different treatment methods by doctors and patients in mainland China, whether triple therapy is suitable for full application to mHSPC patients needs to be further explored.
mCRPC is a highly heterogeneous disease with limited benefit from a single treatment. Therefore, the efficacy of combination therapy has been explored in many studies in recent years, and we have mainly obtained evidence of benefit of combination therapy in rPFS, but there is no evidence of benefit in overall survival. Therefore, whether to use different drugs sequentially or in combination at the mCRPC stage is still controversial, and clinicians are mainly concerned that the simultaneous use of different drugs may affect the choice and tolerability of subsequent treatment. PRESIDE study in the mCRPC first-line use of enzaluamine treatment after the emergence of disease progression, the second line of docetaxel chemotherapy while continuing to use enzaluamine, compared to docetaxel chemotherapy alone, can prolong rPFS, which suggests that the continuous strong inhibition of androgen signaling pathways for mCRPC disease control is still of great significance, may not affect the subsequent treatment choices and efficacy, and the expectation of the final overall survival results can bring us more treatment options.
As new therapeutic drugs continue to enter the clinical application of prostate cancer, combination therapy has gradually entered our clinical practice, which may be an important way to overcome the heterogeneity of prostate cancer, but the benefits and adverse reactions of multiple combination therapy still need more clinical evidence to confirm.
bibliography:
1. Axel S. Merseburger, Gerhardt Attard, Gunther Boysen,et al. A randomized, double-blind, placebo (PBO)-controlled, phase 3b study of the efficacy and safety of continuing enzalutamide (ENZA) in chemotherapy-naïve,metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with docetaxel (DOC) plus prednisolone (PDN) who have progressed on ENZA: PRESIDE[J].2022 ASCO-GU,abstract 15.
2. Andrew J. Armstrong, Taro Iguchi, Arun Azad,et al. Overall survival (OS) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) treated with enzalutamide (ENZA) + androgen deprivation therapy (ADT) by high or low disease volume and progression to mHSPC (M0 at diagnosis) or de novo mHSPC (M1 at diagnosis): Post hoc analysis of the phase 3 ARCHES trial[J]. 2022 ASCO-GU,abstract 115.
3. Irbaz Bin Riaz, Syed Arsalan Ahmed Naqvi, Waleed Ikram,et al. First-line treatment options in metastatic castration-sensitive prostate cancer: A systematic review and network meta-analysis[J]. 2022 ASCO-GU,abstract 132.