Introduction

The CARE™ Prostate Cancer Faculty reviews important plenary session content and data presented from various conferences throughout the year. Recent clinical trial updates presented at the beginning of the 2022 are outlined within this report with additional context for how they are expected to impact the Canadian landscape.

Content focus

  • Overall survival with darolutamide versus placebo in combination with androgen-deprivation therapy and docetaxel for metastatic hormone-sensitive prostate cancer in the phase 3 ARASENS trial.
    • Related trial in progress – ARANOTE (NCT04736199)
  • 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.
  • PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
  • Phase 3 MAGNITUDE study: First results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations.

Content that continues to hold interest

  • Association between patient-reported outcomes (PROs) and changes in prostate-specific antigen (PSA) in patients (pts) with advanced prostate cancer treated with apalutamide (APA) in the SPARTAN and TITAN studies.
  • Patterns of progression of patients with high-volume metastatic castration-sensitive prostate cancer treated with early docetaxel chemotherapy: The LONGITUDE observational study.
  • Overall survival (OS) after progression on first novel hormonal therapy (NHT) in patients (pts) with metastatic castration-sensitive versus castration-resistant prostate cancer (mCSPC versus mCRPC)

This issue was developed with oversight and perspectives provided by CARE™ GU faculty.

Focused Content

Overall survival with darolutamide versus placebo in combination with androgen-deprivation therapy and docetaxel for metastatic hormone-sensitive prostate cancer in the phase 3 ARASENS trial.

NCT02799602. Matthew Raymond Smith et al.

Trial Highlights:
  • The primary endpoint was OS. Secondary efficacy endpoints included time to CRPC, time to pain progression, time to first symptomatic skeletal event (SSE), and time to initiation of subsequent systemic antineoplastic therapies
    • Safety was also assessed
  • 1306 pts were randomized (651 to DARO and 655 to PBO, in combination with ADT + docetaxel)
  • At the primary data cutoff (Oct 25, 2021), early treatment combining DARO with ADT + docetaxel significantly increased OS
    • DARO significantly decreased the risk of death by 32.5% vs PBO (HR 0.675, 95% CI 0.568–0.801; P< 0.0001)
    • Improvement in OS was observed even though substantially more pts received subsequent life-prolonging systemic antineoplastic therapy in the PBO arm (75.6%) vs the DARO arm (56.8%)
    • Benefit was consistent across prespecified subgroups
  • DARO also significantly improved:
    • Time to CRPC versus PBO (HR 0.357, 95% CI 0.302–0.421; P< 0.0001)
    • Time to pain progression (HR, 0.792, 95% CI 0.660–0.950; P= 0.0058)
    • Time to first SSE and time to initiation of subsequent systemic antineoplastic therapy
  • TEAEs were similar between treatment arms
    • Incidences of the most common TEAEs (≥10%) were highest during the overlapping docetaxel treatment period for both arms, with grade 3/4 TEAEs of 66.1% for DARO and 63.5% for PBO, mainly due to neutropenia (33.7% vs 34.2%, respectively)
CARE™ Canadian Perspective:

There is a great need to improve outcomes for patients with metastatic hormone-sensitive prostate cancer, which remains the most lethal state of PC when diagnosed. This study looked to answer the question as to whether using an aggressive triplet approach upfront is better than the current standard doublet (ADT and docetaxel).

Based on the significant OS advantage seen in the DARO arm for both high- and low- volume patients, the answer to this question is clearly yes. Of note, the patients in control arm of the study had a much more likely chance of receiving a crossover life prolonging therapy, and still the results clearly favour the DARO arm.

Proper implementation of this as a new standard of care will ensure that our patients are receiving the best treatment with proven survival benefit. In terms of implementing this as a new standard of care in Canada, a multidisciplinary team approach will be key for optimizing patient care. Communication and collaboration between members of the integrated cancer care team will be paramount.

Based on the significant OS advantage seen in the DARO arm for both high- and low- volume patients, using an aggressive triplet approach upfront is better than the current standard doublet (ADT and docetaxel).”
Related Trial in Progress to Watch For

A randomized, controlled, phase 3 study of darolutamide in addition to androgen deprivation therapy (ADT) versus ADT alone in metastatic hormone-sensitive prostate cancer (ARANOTE). NCT04736199

  • In total, 555 patients will be randomized 2:1 to darolutamide 600 mg twice daily or placebo, plus ADT
  • The primary endpoint is rPFS; secondary endpoints include overall survival, time to castration-resistant prostate cancer, time to prostate-specific antigen progression, and safety
  • Interim results are anticipated later this year
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. NCT02288247.

Axel Merseburger et al.

Trial Highlights:
  • Patients received open-label ENZA (160 mg) + ADT in Period 1 (P1). Those with a prostate-specific antigen (PSA) response of ≥50% change from baseline to week 13 and later progression were eligible for Period 2 (P2)
  • The primary endpoint was PFS in P2 (from randomization to radiographic/clinical progression or death)
    • Secondary endpoints included time to PSA progression (≥25% increase; absolute increase ≥2 ng/mL) and PSA response in P2
  • 687 patients received ENZA in P1; 273 patients were randomized and 271 were treated in P2
  • Continued ENZA therapy in men with mCRPC who progressed on ENZA + ADT and received post-progression DOC + PDN significantly improved PFS compared to PBO
    • PFS was significantly improved with ENZA (HR 0.72; 95% confidence interval [CI] 0.53, 0.96; p = 0.027), with a higher median PFS with ENZA (9.53 months; 95% CI 8.25, 10.87) than with PBO (8.28 months; 95% CI 6.28, 8.71)
  • ENZA also significantly delayed TTPP (8.44 vs. 6.24 months with PBO; HR 0.58; 95% CI 0.41, 0.82; p = 0.002) and improved PSA response at any time (ENZA, n = 76 [55.9%]; PBO, n = 50 [37.0%])
  • Treatment was well tolerated and ENZA AEs were consistent with its known safety profile
CARE™ Canadian Perspective:

These results help to address an important and clinically relevant question as enzalutamide remains a commonly employed first-line treatment in mCRPC. However, most patients will progress. The data suggests that continuing ENZA while initiating docetaxel in second-line may provide an improvement in progression-free survival. 

Biomarker and subgroup analysis for this trial is currently underway and may provide insight on patient characteristics that may be more likely to benefit from this approach (i.e. initial good response to enzalutamide, ongoing clinical benefit with enza, and fitness for combination therapy). How this may impact current practice remains unclear.

While PFS does provide important information in this contest, OS remains the gold-standard endpoint. Other considerations such as tolerability, side effects, and cost will also be important in the evaluation of prolonged enzalutamide treatment.

PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). NCT03732820.

Fred Saad et al.

Trial Highlights:
  • The primary endpoint was investigator-assessed rPFS with multiple secondary endpoints, including OS
  • 796 pts were randomized to ola + abi (n=399) or pbo + abi (n=397)
  • In this interim analysis, first-line treatment with ola + abi significantly prolonged rPFS vs pbo + abi in patients with mCRPC irrespective of HRR status (24.8 vs 16.6 months; hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54–0.81; P<0.0001).
    • rPFS improved across all subgroups
  • An early trend in OS favoring ola + abi was observed (HR 0.86, 95% CI 0.66–1.12)
  • Secondary endpoints of time to first subsequent treatment (HR 0.74, 95% CI 0.61–0.90) and time to second progression-free survival or death (HR 0.69, 95% CI 0.51–0.94) were supportive of long-term benefits.
  • The safety and tolerability profile of ola + abi was consistent with the known safety profiles of the individual drugs
    • The most common grade ≥3 AE reported was anemia (15.1 vs 3.3%) for ola + abi vs pbo + abi
  • Follow-up is ongoing for the planned OS analysis.
CARE™ Canadian Perspective:

These results show the benefit of the use of combination PARP-inhibition with olaparib and abiraterone acetate to reduce the rPFS in mCRPC. The benefit of combination therapy was found irrespective of HRR status and was found across all subgroups.

Although too early to ascertain OS differences, these interim results show exciting results of therapies that may change the landscape of the management of mCRPC.

Phase 3 MAGNITUDE study: First results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations. NCT03748641.

Kim N. Chi et al.

Trial Highlights:
  • Approximately 20% of mCRPC has alterations in genes associated with HRR and is responsive to PARP inhibitors (PARPi)
  • The primary endpoint was radiographic progression-free survival (rPFS)
  • Secondary, and other endpoints, were time to initiation of cytotoxic chemotherapy (TTCC), time to symptomatic progression (TTSP), overall survival (OS), time to PSA progression (TTPP) and objective response rate (ORR).
  • 423 HRR BM+ patients were randomized to NIRA + AAP (n = 212) or PBO + AAP (n = 211).
  • Median follow-up was 18.6 months.
  • NIRA + AAP improves rPFS and other clinically relevant outcomes in patients with mCRPC and alterations in HRR associated genes.
    • Results are summarized in Table 1.
  • There was no evidence of benefit with the addition of NIRA to AAP in HRR BM- patients with mCRPC.
  • There were no clinically significant differences in overall quality of life (FACT-P).
Table 1.

[Click on the Image to Enlarge]

CARE™ Canadian Perspective:

MAGNITUDE was tested the benefit of niraparib + abiraterone acetate/prednisone for mCRPC in patients prospectively identified with and without alterations in genes associated with HRR (using both tissue and blood-based approaches).

While there was no benefit observed in HRR biomarker negative patients, niraparib + abiraterone acetate/prednisone significantly improved the primary clinical outcome in HRR biomarker positive patients. This highlights the important role that testing for HRR gene alterations in patients with mCRPC will have in determining whether patients would benefit from this combination.

“This highlights the important role that testing for HRR gene alterations in patients with mCRPC will have in determining whether patients would benefit from this combination.”

Content that Continues to Hold Interest

Association between patient-reported outcomes (PROs) and changes in prostate-specific antigen (PSA) in patients (pts) with advanced prostate cancer treated with apalutamide (APA) in the SPARTAN and TITAN studies.

Eric Jay Small et al.

Trial Highlights:
  • Patients on ADT were randomized to APA (240 mg QD) or PBO: SPARTAN 2:1 (N = 1,207; APA n = 806), TITAN 1:1 (N = 1,052; APA n = 525). Each cycle was 28 days.
  • A landmark analysis at Month 3 evaluated association between deep PSA decline (≤ 0.2 ng/mL) and time to subsequent deterioration in PROs (defined as decrease ≥ 10 points FACT-P total, ≥ 3 points Physical Wellbeing, ≥ 30% baseline for BPI-SF worst pain, or ≥ 2 points for BFI worst fatigue).
    • Deep and rapid PSA responses with APA were associated with prolonged time to deterioration in HRQoL, FACT-P Physical Wellbeing, BPI-SF worst pain intensity, and BFI worst fatigue intensity in patients with advanced PC.
    • Patients in either study who achieved PSA ≤ 0.2 ng/mL at Month 3 had a lower risk of deterioration in FACT-P total or Physical Wellbeing.
  • Patients in TITAN with PSA ≤ 0.2 ng/mL at Month 3 had a lower risk of BPI-SF worst pain intensity or BFI worst fatigue intensity progression.
Patterns of progression of patients with high-volume metastatic castration-sensitive prostate cancer treated with early docetaxel chemotherapy: The LONGITUDE observational study.

Serena Macrini et al.

Trial Highlights:
  • 166 de novo mCSPC patients were identified, with a median age of 64 years (range 38-84)
  • Most patients (81%) completed six cycles of TXT.
  • The median time to PSA nadir was 10.2 months, PSA response > 50% was achieved in 96% of patients and the most common best response reported was partial response (58%)
  • At the time of this analysis, 122 patients (67%) had biochemical or radiographic progressive disease (PD) to TXT and 67 of these (60%) developing new metastatic sites (NMS).
  • In NMS group we found a higher rate of nodal PD (52% vs 22%, p = 0.001) and higher rate of bone PD (73% vs 47%, p = 0.005) compared to nonNMS.
  • With a median follow-up of 27.9 months, the median TCR was 14.3 months (95%CI 12.8-16.7), without significant differences between NMS and nonNMS groups.
  • About 90% of progressed patients received first-line treatment for mCRPC disease with similar outcomes.
  • The median OS was 41.8 months for the overall population, with not significant differences between NMS and nonNMS groups (22 months and 25 months).
  • Overall, median OS from mCRPC diagnosis was 19.6 mo, similar in NMS and no-NMS patients (10 mo and 12 mo).
  • In progressive mCSPC patients receiving early TXT, we observed more frequently the development of NMS with an elevated GG and a trophism for bone and lymph nodes.
  • NMS progression does not seem to have a prognostic role.
Overall survival (OS) after progression on first novel hormonal therapy (NHT) in patients (pts) with metastatic castration-sensitive versus castration-resistant prostate cancer (mCSPC versus mCRPC).

Nicolas Sayegh et al.

Trial Highlights:
  • OS of patients after progression on first-line NHT for mCSPC is not well characterized.
  • In this IRB-approved study, patient-level data were collected retrospectively, only those treated with NHT as first-line therapy for mCSPC or mCRPC were included.
  • A total of 173 pts (45 mCSPC and 128 mCRPC) were eligible and included in the analysis.
  • Median OS is similar after progression on one NHT whether given in first-line mCSPC or mCRPC
  • Median OS in the mCSPC versus mCRPC were similar: 23 vs. 17 months, hazard ratio: 0.9855, (95% CI: 0.6225 – 1.560, P=0.951).