The American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium for 2023 (ASCO-GU 2023) kicked off on February 16th in San Francisco, USA. Numerous innovative treatment studies have emerged in the fields of metastatic hormone-sensitive prostate cancer (mHSPC), metastatic castration-resistant prostate cancer (mCRPC), non-metastatic castration-resistant prostate cancer (nmCRPC), and early/localized prostate cancer. These studies encompass a wide range of therapies, including androgen deprivation therapy (ADT), novel hormonal therapy (NHT), PARP inhibitors (PARPi), immunotherapy, nuclear medicine therapy, and localized treatments.
Fudan University Shanghai Cancer Center
mHSPC
In the mHSPC field, the focus of this year’s conference continues to be on the three-drug combination therapy involving novel hormonal therapy (NHT).
Last year, ASCO-GU and NEJM simultaneously reported the first interim analysis results of the phase 3 ARASENS study. Compared to ADT + docetaxel, darolutamide + ADT + docetaxel significantly reduced the risk of death in mHSPC patients by 32.5% (HR 0.68, P < 0.0001). This year’s ASCO-GU conference presented subgroup analyses based on tumor burden (defined according to CHAARTED criteria as visceral metastases and/or ≥4 bone metastases, with ≥1 beyond the spine/pelvis) and disease risk (defined according to LATITUDE criteria as high risk with ≥2 risk factors: Gleason score ≥8, ≥3 bone metastases, and measurable visceral metastases). Regardless of whether it was a newly diagnosed (HR 0.71) or recurrent disease (HR 0.61), high tumor burden (HR 0.69) or low tumor burden (HR 0.68), or high risk (HR 0.71) or low risk (0.62) patients, the degree of overall survival (OS) benefit remained consistent.
Phase 3 PEACE-1 Study is another highly anticipated clinical trial for three-drug combination NHT. Previously, it was reported that adding abiraterone to the standard of care (SOC, ADT±docetaxel) significantly improved overall survival (OS) (HR 0.82; P=0.03). However, the primary beneficiaries were patients with a high tumor burden (OS HR=0.72, P=0.019), while those with a low tumor burden did not significantly benefit (OS HR=0.83, P=0.66). At this year’s ASCO-GU, further analysis stratified by age was presented: compared to younger patients (<70 years), elderly patients (≥70 years) had a higher prevalence of hypertension (56.5% vs 38.2%) and diabetes (15.5% vs 11%) and discontinued treatment earlier (30 vs 41.4 months). Overall, elderly patients had lower benefits in radiographic progression-free survival (rPFS) (HRs of 0.65 and 0.49) and OS (HRs of 0.80 and 0.71) compared to younger patients, and the rate of severe adverse events (grades 3-5) was slightly higher in elderly patients (69% vs 61%).
mCRPC
In the mCRPC field, there have been several results from phase 3 clinical trials on PARP inhibitors as monotherapy or in combination with NHT in first-line treatment. Additionally, there have been advancements in the use of PARP inhibitors, immunotherapy, and nuclear medicine therapy in the post-treatment setting for mCRPC.
1. First-Line Treatment
In first-line treatment, one of the major highlights was the presentation of overall survival (OS) results from the phase 3 PROpel study, which expanded the use of PARP inhibitors in first-line treatment to the entire population beyond HRR. Last year, ASCO-GU reported that the primary endpoint was met, and compared to abiraterone alone (Abi), abiraterone + olaparib (Abi + ola) significantly extended radiographic progression-free survival (rPFS) for patients (24.8 vs 16.6 months; HR=0.66, P<0.001). This year’s updated OS results showed a maturity of 47.9% in the intention-to-treat (ITT) population, with OS of 42.1 months for the Abi + ola group and 34.7 months for the Abi group (HR 0.81, 95% CI: 0.67~1.00, P=0.0544), which did not reach statistical significance (two-sided significance threshold was 0.0377). Subgroup analysis indicated more significant benefits for HRRm (HR 0.66) and BRCAm (HR 0.29) patients, while non-HRRm (HR 0.89) and non-BRCAm (HR 0.91) patients had smaller benefits.
Phase 3 TALAPRO-2 Study enrolled 805 mCRPC patients who were not selected based on HRR status. They were randomly assigned to receive talazoparib or placebo in combination with enzalutamide (TALA±ENZA) as first-line treatment. The primary endpoint was radiographic progression-free survival (rPFS) assessed by BICR according to RECIST 1.1 and PCWG3 criteria. The study results showed that compared to the placebo group, the TALA group had a significant improvement in rPFS (not reached vs 21.9 months; HR 0.69, 95% CI: 0.51~0.78, P<0.001). Significant benefits were observed in HRR+ (HR 0.46, P<0.001), HRR-/unknown (HR 0.70, P=0.004), and HRR- (HR 0.66, P=0.009) subgroups. Overall survival (OS) data were not yet mature (31% maturity) but showed a trend favoring the TALA group (HR 0.89; 95% CI: 0.69~1.14; P=0.35). Additionally, other secondary endpoints, such as PSA-PFS (HR 0.72, P=0.002), time to castration-resistant prostate cancer (TCC: HR 0.49, P<0.001), time to second progression (PFS2: HR 0.77, P=0.04), and objective response rate (ORR) (61.7% vs 43.9%, P=0.005), all showed significant benefits. The incidence of grade 3-4 treatment-emergent adverse events (TEAEs) in the TALA group and placebo group was 71.9% and 40.6%, respectively. The most common grade ≥3 TEAEs in the TALA group were anemia (46.5%), neutropenia (18.4%), and thrombocytopenia (7.3%). The median time to worsening of global health status/quality of life (GHS/QoL) also showed a significant extension in the TALA group (HR 0.78, P=0.04).
The phase 3 MAGNITUDE study, which investigates the first-line treatment with niraparib, has previously reported a significant improvement in radiographic progression-free survival (rPFS) for HRR+ and BRCA mutation-positive patients. This year’s ASCO-GU conference also presented the results of the second interim analysis of the study:
For all HRR+ patients, rPFS continued to show improvement (16.7 vs 13.7 months; HR 0.76, P=0.0280). Among BRCA mutation-positive patients, rPFS also remained improved (19.5 vs 10.9 months; HR 0.55, P=0.0007). However, the primary stratified analysis did not show significant overall survival (OS) benefits (HRs of 1.01 for HRR+ and 0.88 for BRCA mutation-positive patients). Still, there was a trend towards OS benefit in the multivariate analysis (HRs of 0.82 for HRR+ and 0.68 for BRCA mutation-positive patients).
Additionally, both HRR+ and BRCA mutation-positive patients experienced significant improvements in time to symptomatic progression (TSP) and time to castration-resistant prostate cancer (TCC).
In the context of PARP inhibitor (PARPi) treatment, the phase 3 TRITON3 study enrolled patients who had progressed after receiving second-generation AR inhibitors. They were randomly assigned (2:1) to receive Rucaparib (600mg BID) or physician’s choice of treatment (docetaxel [DTX], abiraterone or enzalutamide [ABI/ENZ]). The updated results of this study are as follows:
Rucaparib, compared to the physician’s choice regimen, significantly improved radiographic progression-free survival (rPFS) (10.2 vs 6.4 months, HR 0.61, P=0.0003). However, overall survival (OS) did not show a significant improvement with Rucaparib (23.6 vs 20.9 months, HR 0.94, P=0.6702). When comparing Rucaparib to DTX and ABI/ENZ, the rPFS and OS benefits were similar. In the population with BRCA mutations, the Rucaparib group showed a trend towards OS benefit (HRs of 0.81 compared to physician’s choice, 0.75 compared to DTX, and 0.81 compared to ABI/ENZ).
In the realm of immunotherapy, the phase 3 KEYNOTE-921 study enrolled 1030 mCRPC patients who had progressed after receiving NHT treatment. They were randomized (1:1) to receive either Pembrolizumab or placebo in combination with docetaxel. Previously, this study did not meet its dual primary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS). The final analysis results presented at ASCO-GU are as follows: rPFS remained without significant benefit (8.6 vs 8.3 months; HR 0.85, P=0.0335). OS also did not show a significant benefit (19.6 vs 19.0 months; HR 0.92, P=0.1677). The incidence of any-grade treatment-related adverse events (TRAEs) was similar between the two groups (94.6% vs 94.9%), as was the incidence of ≥3 grade TRAEs (43.2% vs 36.6%).
Additionally, at the conference, a phase 2a study was reported, which enrolled 32 mCRPC patients with small cell neuroendocrine (SCNC) features. These patients received a combination of Pembrolizumab and oral innate immune activator BXCL701 on a Pembrolizumab basis. This treatment demonstrated good tolerability (with mainly low blood pressure, fever, and fatigue as the primary adverse events) and positive anti-tumor activity. Among the 25 evaluable patients, 5 achieved a partial response (4 confirmed, 1 unconfirmed), resulting in an overall response rate (ORR) of 20%.
In the field of non-metastatic castration-resistant prostate cancer (nmCRPC), PSMA (Prostate-Specific Membrane Antigen) is widely expressed in prostate cancer cells, and there are currently several targeted PSMA-based nuclear medicine therapies available. J591 is an anti-PSMA antibody labeled with either Lutetium-177 (177Lu, β radiation) or Indium-111 (111In, γ radiation). A verbal report at this year’s ASCO-GU conference presented a study that enrolled 55 high-risk nmCRPC patients.
These patients had a PSA doubling time (PSA DT) of less than 8 months and/or a PSA level greater than 20 ng/mL, as well as a serum testosterone level less than 50 ng/mL, with no evidence of metastatic disease on CT/MRI scans. After receiving 4 weeks of ketoconazole (keto) and hydrocortisone (HC) induction therapy, patients were randomized (2:1) to receive either 177Lu-J591 or 111In-J591 treatment until they experienced toxicity intolerance or developed metastases. The primary endpoint was 18-month metastasis-free survival (MFS).
The study results revealed the following: The 18-month MFS rates for the 177Lu-J591 group and the 111In-J591 group were 50% and 76%, respectively (P=0.066). The median time to biochemical progression-free survival (bPFS) was 18.67 months for the 177Lu-J591 group and 8.87 months for the 111In-J591 group. In the PP (per-protocol) population, the median MFS for both groups was 23.8 months and 20.8 months, respectively. PSA50 response rates were 82% for the 177Lu-J591 group and 71% for the 111In-J591 group, while PSA90 response rates were 50% and 35%, respectively.
Common grade ≥3 hematologic adverse events (AEs) included neutropenia (57% vs. 11%) and thrombocytopenia (77% vs. 11%). Common grade ≥3 non-hematologic AEs included abdominal pain (0 vs. 11%), elevated ALT (3.3% vs. 22%), and diarrhea (0 vs. 22%).
In the context of early or localized treatment for patients who have undergone radical prostatectomy (RP) with high-risk factors or biochemical recurrence, the standard treatment involves 6 months of GnRH agonist therapy combined with salvage radiotherapy (SBT). The FORMULA-509 study aimed to determine whether the addition of neoadjuvant hormone therapy (NHT) to this regimen could further improve patient outcomes. This study enrolled 345 patients who had undergone RP and had a post-surgery PSA level of ≥0.1 ng/ml, along with one or more high-risk factors (Gleason 8-10, PSA >0.5, pT3/T4, pN1 or radiographic N1, PSA doubling time <10 months, negative surgical margins, persistent PSA elevation, large local/regional disease, high Decipher score). Patients were randomized (1:1) to receive either SBT+GnRH agonist+bicalutamide or SBT+GnRH agonist+NHT (abiraterone or apalutamide). The primary endpoints were PSA progression-free survival (PSA-PFS).
The study results indicated that while overall NHT did not significantly improve PSA-PFS (HR 0.71; 90% CI: 0.49~1.03; P=0.06) and metastasis-free survival (MFS) (HR 0.57; 90% CI: 0.33~1.01; P=0.05), in patients with a PSA level >0.5 ng/ml, there were significant benefits in terms of PSA-PFS (HR 0.50; 90% CI: 0.30~0.86; P=0.03) and MFS (HR 0.32; 90% CI: 0.15~0.72; P=0.01).
Considering the results from last year’s ESMO-reported RADICALS-HD study and the findings from the FORMULA-509 study, it appears that for high-risk patients in the post-radical prostatectomy setting, extended and longer-term androgen deprivation therapy (ADT) provides benefits over shorter courses.
The RADICALS-HD study suggested that 24 months of ADT might be superior to 6 months of ADT for high-risk patients, supporting the recommendation for extended ADT. Although the FORMULA-509 study did not show an overall positive result, there was a trend of benefit in the combination of 6 months of ADT with neoadjuvant hormone therapy (NHT), especially in the subgroup of patients with a PSA level >0.5 ng/ml, where significant improvements in PSA progression-free survival (PFS) and metastasis-free survival (MFS) were observed. This suggests that a “short-term intensification” of hormonal therapy with 6 months of ADT plus NHT might be a feasible approach for these patients after salvage radiotherapy.
Ultimately, the choice of treatment duration should be based on individual patient characteristics, including risk factors and response to therapy, and should be discussed with a healthcare provider to determine the most appropriate course of treatment.
For localized high-risk prostate cancer patients receiving external beam radiation therapy (EBRT), extending androgen deprivation therapy (ADT) from 6 months to 30 months does not appear to provide further improvement in patient outcomes. The findings come from the phase 3 TRIP study conducted in Japan, which included 332 patients with T2c-3a stage, PSA >20 ng/ml, or Gleason score >7. These patients were randomized (1:1) to receive either short-term (6 months) or long-term (30 months) ADT. The primary endpoint was biochemical progression-free survival (bPFS).
The study results revealed that there was no significant difference in the 9-year cumulative biochemical progression rates between the short-term and long-term ADT groups (10.4% vs. 9.5%, P=0.647). Secondary endpoints, including overall survival, clinical progression, distant metastasis, disease-specific death, and others, also did not show significant differences. This suggests that extending ADT treatment did not improve patient outcomes in this population.
The PACE (Patient-Reported Outcomes After Clinical Treatment for Prostate Cancer) study is a phase 3 open-label, multi-cohort, randomized controlled trial that aims to compare local treatments for localized prostate cancer patients, including radiation therapy and surgical treatment. In the PACE-A cohort, patients with clinically localized prostate cancer (T1-T2, Gleason ≤3+4, PSA ≤20 ng/mL) who were eligible for surgical removal were randomly assigned (1:1) to receive either Stereotactic Body Radiation Therapy (SBRT) with a total dose of 36.25 Gy delivered in 5 fractions or surgical treatment (either laparoscopic or robot-assisted radical prostatectomy). None of the patients received androgen deprivation therapy (ADT). The primary endpoint was patient-reported outcomes (PROs) at 2 years, including urinary incontinence and bowel symptoms assessed using the Expanded Prostate Cancer Index Composite (EPIC-26) questionnaire.
A total of 123 patients were enrolled in the study, with a median age of 66 years, a median PSA level of 8 ng/mL, 52% of tumors at or above T2b stage, 79% with Gleason 3+4 scores, and 93% being white patients. Of these, 58 out of 63 patients in the SBRT group and 48 out of 60 patients in the surgical group received their respective treatments. With a median follow-up of 50 months, the SBRT group had a significantly lower rate of urinary incontinence (pad usage) compared to the surgical group, with rates of 4.5% (2/43) and 46.9% (15/32), respectively (P<0.001). However, the SBRT group reported worse bowel symptom scores compared to the surgical group (88.4 vs. 97.3, P<0.001). The SBRT group also had a significantly higher proportion of moderate/severe bowel symptoms (15.6% vs. 0%, P=0.04). Furthermore, the SBRT group had higher sexual function scores compared to the surgical group (58.0 vs. 29.3, P<0.001), while both groups had similar urinary symptom scores (85.5 vs. 80.5, P=0.29). At 2 years, there were no significant differences in the occurrence of ≥2 grade genitourinary adverse events (Common Terminology Criteria for Adverse Events, CTCAE) between the two groups (9.3% vs. 9.5%, P=0.97), and no ≥2 grade gastrointestinal adverse events occurred in either group. This study suggests that SBRT, compared to surgery, offers better urinary control and sexual function but results in worse bowel symptoms.
Reference:
1. Efficacy and safety of darolutamide(DARO)in combination with androgen-deprivation therapy(ADT)and docetaxel(DOC)by disease volume and disease risk in the phase 3 ARASENS study.（abstract:15）https://meetings.asco.org/abstracts-presentations/217337
2. Efficacy and safety of abiraterone acetate plus prednisone and androgen deprivation therapy+/-docetaxel in older patients(≥70 years),with de novo metastatic-castration sensitive prostate cancer,compared to younger patients(<70 years):The PEACE-1 trial.（abstract:20）https://meetings.asco.org/abstracts-presentations/216889
3. Final overall survival(OS)in PROpel:abiraterone(abi)and olaparib(ola)versus abiraterone and placebo(pbo)as first-line(1L)therapy for metastatic castration-resistant prostate cancer(mCRPC).（abstract:LBA16）https://meetings.asco.org/abstracts-presentations/217650
4. TALAPRO-2:Phase 3 study of talazoparib(TALA)+enzalutamide(ENZA)versus placebo(PBO)+ENZA as first-line(1L)treatment in patients(pts)with metastatic castration-resistant prostate cancer(mCRPC)（abstract:LBA17）https://meetings.asco.org/abstracts-presentations/216877
5. Rucaparib for metastatic castration-resistant prostate cancer(mCRPC):TRITON3 interim overall survival and efficacy of rucaparib vs docetaxel or second-generation androgen pathway inhibitor therapy.（abstract:303）https://meetings.asco.org/abstracts-presentations/216883
6. Niraparib(NIRA)with abiraterone acetate and prednisone(AAP)in patients(pts)with metastatic castration-resistant prostate cancer(mCRPC)and homologous recombination repair(HRR)gene alterations:Second interim analysis(IA2)of MAGNITUDE.（abstract:170）https://meetings.asco.org/abstracts-presentations/217051
7. Pembrolizumab plus docetaxel for patients with metastatic castration-resistant prostate cancer(mCRPC):Randomized,double-blind,phase 3 KEYNOTE-921 study.（abstract:19）https://meetings.asco.org/abstracts-presentations/216884
8. First-in-class oral innate immune activator BXCL701 combined with pembrolizumab in patients with metastatic,castration-resistant prostate cancer(mCRPC)of small cell neuroendocrine(SCNC)phenotype:Phase 2a final results.（abstract:176）https://meetings.asco.org/abstracts-presentations/217076
9. Randomized,double-blinded phase II study of ketoconazole(keto),hydrocortisone(HC),and anti-PSMA antibody J591 labeled with 177Lu or 111In in patients(pts)with high-risk non-metastatic(met)castration-resistant prostate cancer(M0 CRPC).（abstract:LBA21）https://meetings.asco.org/abstracts-presentations/216890
10. FORMULA-509:A multicenter randomized trial of post-operative salvage radiotherapy(SRT)and 6 months of GnRH agonist with or without abiraterone acetate/prednisone(AAP)and apalutamide(Apa)post-radical prostatectomy(RP).（abstract:33）https://meetings.asco.org/abstracts-presentations/217586
11. Results of a multicenter,randomized,phase 3 trial of trimodality therapy with I-125 brachytherapy,external beam radiation therapy,and long-versus short-term androgen deprivation therapy for localized high-risk prostate cancer(TRIP/TRIGU0907).（abstract:305）https://meetings.asco.org/abstracts-presentations/217321
12. PACE-A:An international phase 3 randomised controlled trial(RCT)comparing stereotactic body radiotherapy(SBRT)to surgery for localised prostate cancer(LPCa)—Primary endpoint analysis（abstract:298）https://meetings.asco.oro/abstracts-presentations/217340
