The recent ASCO GU 2023 showcased insights and latest evidence on enzalutamide in PCa including combination strategies in mHSPC, new combinatorial regimens in mCRPC and real-world evidence on the optimal use of NHT in mCRPC patients with frailty syndrome.
Treatment combinations for mHSPC patients starting ADT: Building on recent victories
Prof Gerhardt Attard from University College London (UK) shared his insights of the treatment combination strategies for patients with mHSPC who are initiating ADT based on the latest clinical trial data. 1
1
ADT plus 2nd generation ARSi
Patients with high-risk localized disease per the STAMPEDE trial criteria (i.e. N1, or N0 either PSA ≥40ng/dl, ≥T3 or Gleason score ≥8) have improved survival benefit duration from the addition of ARSi to ADT and RT with longer follow-up.1 Next key questions are the duration of survival benefit and the potential advantage in unselected patients from Prof Attard.
He emphasized that ARSi is now considered as the backbone of mHSPC treatment with ADT. Key exclusion serving as SoC for all patients who are fit enough.1 Treatment de-intensification for a finite duration in selected M1 low-volume patients guided by PSA level was considered based on clinical trial outcomes (Table 1).1 Additional trials are needed to see whether this potential advantage can be repeated in patients with other disease criteria as well as devising better treatment combinations for patients with poor prognosis.
He emphasized that ARSi is now considered as the backbone of mHSPC treatment with ADT. Key exclusion serving as SoC for all patients who are fit enough.1 Treatment de-intensification for a finite duration in selected M1 low-volume patients guided by PSA level was considered based on clinical trial outcomes (Table 1).1 Additional trials are needed to see whether this potential advantage can be repeated in patients with other disease criteria as well as devising better treatment combinations for patients with poor prognosis.
Table 1. Survival benefits from ADT plus ARSi vs. ADT alone from clinical trials1
2
ADT plus RT to primary tumour
Survival benefit of RT in M1 low-volume patients was observed in the STAMPEDE trial but not for the high-volume group.1 Markers for selecting patients for RT intervention (e.g. number of bone metastasis) for improving survival benefits are limited; hence, PSMA PET has yet to replace CT or WBBS for disease spread evaluation.1
3
ADT plus docetaxel
Although the addition of docetaxel to ADT or ADT plus ARSi improved survival in mHSPC patients with high-volume metastatic disease, current data indicated that the treatment effect of docetaxel are uneven.1 Some studies showed that addition of docetaxel worsens patients’ global-QoL in comparison with ARSi combination; better prognostic and predictive tests are required to identify the patients who can benefit from docetaxel.1 Results from gene expression profiling hold promise for improving treatment selection according to disease subtypes.1
The treatment of mHSPC may be guided by the patient risk group, tumour presentation and metastatic volume (Table 2).1
Table 2. Treatment plans for mHSPC1
Potent NHT forms the backbone of mHSPC treatment for all risk groups1
TALAPRO-2: Talazoparib plus enzalutamide improves rPFS over placebo plus enzalutamide as first-line treatment in mCRPC
Prof Neeraj Agarwal from Huntsman Cancer Institute, University of Utah (USA) presented primary findings from TALAPRO-2, the first phase III, randomized, double-blind trial examining the outcomes of talazoparib plus enzalutamide vs. placebo plus enzalutamide as first-line treatment in patients with mCRPC.2
First-line mCRPC patients with ECOG PS 0 or 1 were randomized 1:1 to receive talazoparib 0.5mg QD + enzalutamide 160mg QD (treatment arm) or placebo plus enzalutamide 160mg QD (control arm). Stratification factors include prior treatment with abiraterone or docetaxel in castration-sensitive state (yes vs. no) and HRR gene alteration status (deficient vs. nondeficient/unknown).2
Total recruitment was 805 patients; 27% patients in both arms had received abiraterone or docetaxel for mHSPC.2 Samples were prospectively assessed for HRR gene status with tumour tissue making up 99.9% of the primary source for genetic biomarker testing (Table 3).2
First-line mCRPC patients with ECOG PS 0 or 1 were randomized 1:1 to receive talazoparib 0.5mg QD + enzalutamide 160mg QD (treatment arm) or placebo plus enzalutamide 160mg QD (control arm). Stratification factors include prior treatment with abiraterone or docetaxel in castration-sensitive state (yes vs. no) and HRR gene alteration status (deficient vs. nondeficient/unknown).2
Total recruitment was 805 patients; 27% patients in both arms had received abiraterone or docetaxel for mHSPC.2 Samples were prospectively assessed for HRR gene status with tumour tissue making up 99.9% of the primary source for genetic biomarker testing (Table 3).2
Table 3. Baseline HRR gene status in TALAPRO-22
Talazoparib plus enzalutamide showed a 37% reduced risk of progression or death over the control arm after a median follow up of approximately 25 months (Figure 1).2
Figure 1. Primary endpoint of rPFS by BICR2
Consistent rPFS by BICR benefits were observed across various subgroups: i.e. age (≥70 vs. <70 years), ECOG PS, Gleason score (<8 vs. ≥8), stage at diagnosis (M0 vs. M1), and prior abiraterone or docetaxel (Yes vs. No) etc.2 A clinically meaningful reduction in risk of disease progression or death was demonstrated in the talazoparib plus enzalutamide arm regardless of HRR status – with 54% and 30% reduction for HRR-deficient patients and HRR-nondeficient/unknown patients respectively – in comparison with the control arm.2
Figure 2. rPFS by BICR according to HRR-deficiency status2
The key secondary endpoint of OS was still immature (HR 0.89; 95% CI, 0.69–1.14; p=0.35).2 Consistent benefits of talazoparib plus enzalutamide over the control arm were also seen in other secondary endpoints (Table 4).2
Table 4. TALAPRO-2 secondary endpoints2
The safety profile of talazoparib plus enzalutamide was consistent with individual profiles and generally managed through dose modifications and supportive measures; it was noted that 49.0% of the patients had grade 1 or 2 anaemia at baseline.2 The most common all-cause TRAEs (all grades) in the experimental arm were anaemia (65.8%), neutropenia (35.7%), and fatigue (33.7%).2 About 46.5% of patients in the experimental group developed grade 3 or 4 anaemia, of which 8.3% discontinued talazoparib.2 In the experimental group, 19.1% of patients discontinued treatment due to AEs in comparison with 12.2% in the placebo group. The median relative dose intensity of talazoparib remained at more than 80%.2
The combination of talazoparib and enzalutamide significantly prolonged median time to definitive clinically meaningful deterioration in global health status and QoL in comparison with the control arm (30.8 vs. 25.0 months; HR 0.78; 95% CI, 0.62–0.99; p=0.04).2
The combination of talazoparib and enzalutamide significantly prolonged median time to definitive clinically meaningful deterioration in global health status and QoL in comparison with the control arm (30.8 vs. 25.0 months; HR 0.78; 95% CI, 0.62–0.99; p=0.04).2
Primary analysis of TALAPRO-2 supports the use of talazoparib plus enzalutamide as a first-line treatment in mCRPC patients with consistent individual safety profiles2
Real-world evidence: Enzalutamide demonstrated better OS outcome over abiraterone in mCRPC population with frailty syndrome
Patients who progress to mCRPC are 75 years old by average, around 30% to 70% of whom have frailty syndrome.3,4 Frailty is an important consideration in mCRPC treatment and drug selection as patients with frailty are predisposed to toxicity events, have fewer treatment options, and suffer from poorer HRQoL.3,4
Dr Ekamjit Singh Deol from the Saint Louis University School of Medicine (USA) and his team conducted a real-world retrospective analysis to examine the association of frailty and OS in mCRPC patients treated with NHTs.3 Data of patients who received either abiraterone or enzalutamide from September 2014 to June 2017 in the United States Department of Veterans Affairs database were analysed.3
The patient population were categorized according to the Veterans Affairs Frailty Index (VA-FI-10) as non-frail (VA-FI-10 ≤0.2) and frail (VA-FI-10 >0.2).3 VA-FI-10 is an electronic frailty index integrated into the United States Department of Veterans Affairs database that measures health deficits and summative frailty, strongly associated with mortality.5
The study identified 5,822 patients with mCRPC, of which 57% and 43% were initially treated with abiraterone and enzalutamide respectively.3 Patients with frailty were older at 76.1 years old vs. 74.9 years old without frailty (p<0.001), and have poorer OS compared with non-frail patients (Figure 3). 3
Dr Ekamjit Singh Deol from the Saint Louis University School of Medicine (USA) and his team conducted a real-world retrospective analysis to examine the association of frailty and OS in mCRPC patients treated with NHTs.3 Data of patients who received either abiraterone or enzalutamide from September 2014 to June 2017 in the United States Department of Veterans Affairs database were analysed.3
The patient population were categorized according to the Veterans Affairs Frailty Index (VA-FI-10) as non-frail (VA-FI-10 ≤0.2) and frail (VA-FI-10 >0.2).3 VA-FI-10 is an electronic frailty index integrated into the United States Department of Veterans Affairs database that measures health deficits and summative frailty, strongly associated with mortality.5
The study identified 5,822 patients with mCRPC, of which 57% and 43% were initially treated with abiraterone and enzalutamide respectively.3 Patients with frailty were older at 76.1 years old vs. 74.9 years old without frailty (p<0.001), and have poorer OS compared with non-frail patients (Figure 3). 3
Figure 3. OS of patients with mCRPC according to frailty level and treatment categories3
Data parsed by NHTs showed that patients with frailty who were treated with enzalutamide had an OS advantage of 3.5 months over those who received abiraterone (20.7 vs. 17.2 months, p=0.0003).3 Furthermore, enzalutamide reduced the risk of death by 15% (aHR 0.85; 95% CI, 0.78–0.94) for mCRPC patients with frailty syndrome; propensity-matched cohort analysis demonstrated that the enzalutamide group had 3.2 months greater median OS in comparison with those in the abiraterone group.3
mCRPC patients with frailty syndrome live longer when treated with enzalutamide compared to abiraterone3
Abbreviations: ADT, androgen deprivation therapy; AE, adverse events; aHR, adjusted hazard ratio; ARSi, androgen receptor signalling inhibitors; ASCO GU23; American Society of Clinical Oncology Genitourinary Cancers Symposium 2023; BICR; blinded independent central review; CI, confidence interval; CT, computed tomography; ECOG PS, Eastern Cooperative Oncology Group performance status scale; ENZA, enzalutamide; HR, hazard ratio; HRQoL, health-related quality of life; HRR, homologous recombinant repair; M0, cancer has not metastasized; M1, cancer has metastasized; mCRPC, metastatic castration-resistant prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer; N0, no lymph node infiltration detected; N1, cancer has infiltrated one regional lymph node; NA, not achieved; NHT, novel hormonal therapy; NR, not reached; NRLN, non-regional lymph node; ORR, overall response rate; OS, overall survival; PCa, prostate cancer; PFS2, time to second disease progression or death; PBO, placebo; PSA, prostate-specific antigen; PSMA PET, prostate-specific membrane antigen positron emission tomography; QD, once a day; QoL, quality of life; rPFS, radiographic progression-free survival; RT, radiotherapy; SBRT, stereotactic body radiotherapy; SoC, standard of care; TALA, talazoparib; T3, tumour stage 3; TRAEs, treatment-related adverse events; UK, United Kingdom; USA, United States of America; VA-FI-10, Veterans Affairs Frailty Index; vs., versus; WBBS, whole body bone scintigraphy.
References:
References:
- Attard G. Treatment combinations for patients starting androgen-deprivation therapy: Building on recent victories. Presented at: American Society of Clinical Oncology Genitourinary Symposium 2023; 16–18 February 2023; San Francisco, CA, USA.
- Agarwal N, et al. TALAPRO-2: Phase 3 study of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line treatment in patients with metastatic castration-resistant prostate cancer. Presented at: American Society of Clinical Oncology Genitourinary Symposium 2023; 16–18 February 2023; San Francisco, CA, USA.
- Deol ES, et al. Frailty and overall survival in metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide. Presented at: American Society of Clinical Oncology Genitourinary Symposium 2023; 16–18 February 2023; San Francisco, CA, USA.
- Mafla-España MA, et al. Analysis of frailty syndrome in men with metastatic prostate cancer: A scoping review. J Pers Med 2023;13,319.
- Cheng D, et al. Updating and validating the US Veterans Affairs Frailty Index: Transitioning from ICD-9 to ICD-10. J Gerontol A Biol Sci Med Sci 2021;76:1318–1325.
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