Antiandrogens Progress In New Settings, Combinations in Prostate Cancer

Publication
Article
Targeted Therapies in OncologyApril 1, 2022
Volume 11
Issue 5

Data presented at the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium highlight the inhibitors’ use in combination regimens, other settings, and next-generation agents.

Alicia Morgans, MD, MPH

Alicia Morgans, MD, MPH

Second-generation androgen receptor (AR) signaling inhibitors have become the standard of care for treating patients with castration-resistant prostate cancer (CRPC). Data presented at the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium highlight the inhibitors’ use in combination regimens, other settings, and next-generation agents.

Background

For patients with CRPC, the AR is the primary pharmacological target given its importance in driving prostate cancer, despite biochemical recurrence in patients treated with androgen deprivation therapy (ADT).1 The success of newer-generation AR inhibitors has led to guidelines from the National Comprehensive Cancer Network (NCCN), the European Society for Medical Oncology (ESMO), and the European Association of Urology (EAU) recommending enzalutamide (Xtandi), apalutamide (Erleada), or darolutamide (Nubeqa) in addition to ADT to delay metastasis and prolong overall survival (OS) for patients with nmCRPC who are at increased risk of disease progression.1-4 Recently, research has shifted to evaluating these second-generation AR inhibitors in expanded settings (eg, metastatic, castration-sensitive, neoadjuvant, etc) as well as in combination regimens.

“These AR-signaling inhibitors are incredibly useful across the entire spectrum of prostate cancer,” said Alicia Morgans, MD, MPH, medical director of the Survivorship Program at Dana-Farber Cancer Institute, and member of the faculty of medicine at Harvard Medical School. Morgans discussed the highlights from ASCO GU regarding AR inhibitors and prostate cancer in an interview with Targeted Therapies in OncologyTM. “Whether in the metastatic setting, or in earlier stages of disease such as [in] neoadjuvant therapy, or in... hormone-sensitive disease, they are being investigated in all settings.”

AR Inhibition With PARP Inhibition

First-Line Olaparib Plus Abiraterone for mCRPC

An interim analysis of the randomized, double-blind phase 3 PROpel study (NCT03732820) presented at the ASCO GU meeting demonstrated significant improvement in radiographic PFS (rPFS) with PARP inhibitor olaparib (Lynparza) added to abiraterone acetate (Zytiga) vs placebo and abiraterone in the first-line setting for patients with newly diagnosed metastatic CRPC (mCRPC).5 Investigators randomized 796 patients with mCRPC to receive olaparib at 300 mg twice daily plus abiraterone at 1000 mg daily (n = 399) or placebo plus abiraterone (n = 397) after failure of ADT and independent of homologous recombinant repair (HRR) status.

Treatment with the olaparib combination sig-nificantly prolonged median rPFS (24.8 months) vs placebo (16.6 months; HR, 0.66; 95% CI, 0.54- 0.81; P <.0001).5 Median rPFS with olaparib was 27.6 months vs 16.4 months with placebo when evaluated by blinded independent central review, resulting in a 39% reduction in the risk of radiographic disease progression or death (HR, 0.61; 95% CI, 0.49-0.74; P <.0001). Investigators observed improvement in rPFS across all subgroups, including in patients with HRR mutations (HR, 0.50; 95% CI, 0.34-0.73) and those without (HR, 0.76; 95% CI, 0.60-0.97). A trend in OS favored the olaparib combination (HR, 0.86; 95% CI, 0.66-1.12; P =.29), although the median OS had not yet been reached in either arm; however, OS data are immature, with 228 (28.6%) deaths observed by the cutoff date.

Significant differences favoring the combination were also observed in time to first subsequent therapy or death (HR, 0.74; 95% CI, 0.61-0.90; P = .004), time to second progression or death (HR, 0.69; 95% CI, 0.51- 0.94; P = .0184), and objective response rates (ORRs; odds ratio, 1.60; 95% CI, 1.02-2.53; P = .0409) (TABLE 1).5 The investigators observed AEs in 97.2% of patients in the olaparib arm and 94.9% of the placebo arm, with grade 3 or higher AEs occurring in 47.2% and 38.4%, respectively.5 Treatment discontinuations due to AEs were more common in the olaparib arm (13.8%) vs the placebo arm (7.8%), as well as dose interruptions (44.7% vs 25.3%, respectively) and reductions (20.1% vs 5.6%).

“Patients without DNA repair defects are not expected to have a response to olaparib if they’re receiving it as a single agent,” Morgans said. “Simultaneous olaparib and abiraterone appears to make cancers sensitive to these targeted agents despite not having the mutations, which is quite compelling.” Morgans thinks when OS data are released, if not sooner, this could be an approach worth considering for younger, fit, or highly motivated patients.

Niraparib Plus Abiraterone in mCRPC

Results from the randomized, double-blind, phase 3 MAGNITUDE trial (NCT03748641) indicate that the addition of the PARP inhibitor niraparib (Zejula) to abiraterone acetate and prednisone in the first-line setting resulted in significantly improved rPFS for patients with mCRPC and HRR gene alterations.6 Patients with mCRCP and HRR gene alterations were randomly assigned to receive niraparib plus abiraterone (n = 212) or placebo plus abiraterone (n = 211). More than 40% of patients in each arm had BRCA2 alterations.

Niraparib significantly improved rPFS in comparison with placebo in patients with HRR alterations, with a 27% reduction in the risk of death by blinded central review (16.5 vs 13.7 months, respectively; HR, 0.73; 95% CI, 0.56-0.96; P = .0217) with a median follow-up of 18.6 months.6 By investigator assessment, edian rPFS was 19.0 months with niraparib vs 13.9 months without (HR, 0.63; 95% CI, 0.49-0.86; nominal P = .0022). The median rPFS in the BRCA1/2 population was 16.6 months with niraparib and 10.9 months withplacebobyblindedcentralreview(HR, 0.53; 95% CI, 0.36-0.79; P = .0014).

The addition of niraparib also resulted in delays to the time to first cytotoxic chemotherapy, time to symptomatic progression, and time to prostate-specific antigen (PSA) progression, and resulted in an improved ORR (TABLE 2).6 Interim data for OS are immature, with only 27% of deaths observed at the time of the analysis, but the data showed an emerging trend favoring the niraparib regimen. A prespecified multivariate analysis for OS demonstrated that accounting for baseline characteristics still showed favor for the PARP regimen (HR, 0.767; 95% CI, 0.525-1.119; nominal P = .1682).

Grade 3 or higher TEAEs were observed in 67% of patients receiving niraparib vs 46.4% with placebo, and drug-related serious AEs were reported in 11.3% of patients receiving niraparib and 2.8% receiving placebo.

Treatment discontinuations occurred in 9% and 3.8% of patients receiving niraparib and placebo, respectively.6 These results indicate that niraparib plus abiraterone is a potential first-line combination for patients with mCRPC and HRR gene alterations.

“A consistent message is combination [with] PARP inhibitors can be of greater benefit vs abiraterone alone. Abiraterone is a very effective control arm that is a standard of care[and] augmenting the power of that is truly meaningful for patients, especially if results hold up in OS benefit,” Morgans said about the 2 trials.

Extended Settings

Darolutamide in Metastatic Hormone- Sensitive Prostate Cancer
Results from the randomized, double-blind phase 3 ARASENS trial (NCT02799602) show a significant improvement in OS and secondary end points. The trial evaluated patients with metastatic, hormone-sensitive prostate cancer (mHSPC) treated with darolutamide 600 mg twice daily added to ADT and docetaxel (Taxotere) vs placebo plus ADT and docetaxel, as presented at ASCO GU 2022 and published in the New England Journal of Medicine.7,8

“ARASENS is the most imminently practice changing of the trials presented at ASCO GU 2022,” stated Morgans. “Darolutamide is currently only approved for nonmetastatic castration-resistant disease, but I wonder if [the] data may lead to an expanded indication in the mHSPC setting. The overall survival advantage is especially encouraging because of the favorable [adverse] effect and tolerability profile.”

The median OS was not evaluable in the darolutamide arm (n = 651) but the rate at 1 year was 62.7% compared with a median of 48.9 months (95% CI, 44.4-not evaluable) and a 1-year rate of 50.4% in the placebo arm (n = 655). A significant decrease in the risk of death by 32.5% was observed in the darolutamide group vs placebo (HR, 0.68; 95% CI, 0.57-0.80; P < .001).

The improvement in OS occurred despite a greater percentage of patients in the placebo group receiving subsequent systematic antineoplastic therapy (75.6%) compared withthedarolutamidegroup(56.8%).7,8 The time to first subsequent antineoplastic therapy was significantly different between the 2 arms (HR, 0.39; 95% CI, 0.33-0.46; P <.001).

The darolutamide group also experienced significantly delayed time to CRPC (HR, 0.36; 95% CI, 0.30-0.42; P <.001) and time to pain progression (HR, 0.79; 95% CI, 0.66-0.95; P =.01) vs the placebo group (TABLE 37,8).

Treatment-emergent adverse events (TEAEs) were similar between groups with grade 3 or greater TEAEs occurring in 66.1% of patients receiving darolutamide vs 63.5% of patients receiving placebo.7,8 TEAEs were most frequent during the overlap period with docetaxel for both groups, and 13.5% of patients who were receiving darolutamide discontinued treatment due to TEAEs vs 10.6% of patients receiving placebo; docetaxel was also discontinued in 8.0% of patients in the darolutamide arm and in 10.3% of the placebo arm.

Enzalutamide Post Progression in mCRPC

Results from the phase 3b PRESIDE trial (NCT02288247) reveal improved PFS for patients with mCRPC receiving enzalutamide vs placebo who experienced progression after initial enzalutamide therapy.9 The PRESIDE trial enrolled chemotherapy-naïve men with mCRPC who received open-label enzalutamide at 160 mg daily and ADT (n = 687). Those who achieved a PSA response of 50% or more and then later progressed were enrolled in phase 2 (n = 273) and were then randomly assigned to further enzalutamide or placebo, both with docetaxel and prednisone.

PFS was significantly improved for patients receiving enzalutamide (HR, 0.72; 95% CI, 0.53-0.96; P =.027) with a median PFS of 9.53 months (95% CI, 8.25-10.87) vs 8.28 months (95% CI, 6.28-8.71) for placebo.9 Continuing enzalutamide was also associated with a longer time to PSA progression (8.44 vs 6.24 months; HR, 0.58; 95% CI, 0.41-0.82; P =.002) compared with placebo. ORRs were 31.6% (95% CI, 23.9%-40.1%) for continued enzalutamide vs 25.9% (95% CI, 18.8%-34.2%) for placebo (P =.142). Subgroup analyses for PFS favored continued enzalutamide for almost all groups, with the exception of patients with bone-only disease (HR, 1.14; 95% CI, 0.71-1.84).

Rates of overall TEAEs were similar between continued enzalutamide (97.8%; n = 133) and placebo (97.0%; n = 131) along with grade 3 or greater TEAEs (61.8% vs 62.2%, respectively). Treatment discontinuation due to TEAEs was reported in 8.8% of the enzalutamide arm compared with 6.7% of the placebo arm.

“In clinical practice, [these] data may inform treatment for patients with 1 or 2 areas of progression but with other sites of stable disease,” Morgans said. She also said that the somewhat minimal benefit in PFS is unlikely to substantially affect clinical practice.

Darolutamide in mCRPC

Pooled data from 3 phase 1/2 studies (NCT02363855, NCT01317641/NCT01429064, and NCT01784757) in patients with mCRPC indicate that darolutamide treatment of more than 2 years has comparable safety data and tolerability to that of previously published studies.10 Prior studies had suggested that darolutamide was well tolerated in patients with mCRPC for up to 25 months. The authors of this study were aiming to show the safety of darolutamide in mCRPC given its 2019 approval by the FDA for nmCRPC.11

The study was small overall, with 13 patients evaluable for safety and receiving darolutamide for more than 2 years; 6 of them received therapy for over 4 years.10 The median patient age was 68 years (range, 55-81) and the majority of patients were White (n = 12); most had normal renal function (n = 10), hepatic function (n = 10), and ECOG perfor- mance status of 0 (n = 12). No patient received prior chemotherapy; systemic anticancer agents received by more than 1 patient included bicalutamide (Casodex, n = 10), cyproterone (Sandoz, n = 3), triptorelin (Trelstar, n=2), and leuprorelin (n = 2). Dosing varied depending on the original study, with twice-daily doses of 600 mg (n = 9), 700 mg (n = 2), 300 mg (n = 1), and 200 mg (n = 1).

AEs were experienced by all 13 patients, with 6 experiencing grade 3 AEs. Treatment-related AEs were reported in 5 patients and were all grade 1 or 2.10 A single patient, who received treatment for more than 2 years, discontinued darolutamide due to a non–drug-related new neoplasm.

Neoadjuvant Abiraterone for High-Risk Disease

Results from the phase 2 ACDC-RP trial (NCT02543255) indicate that patients with high-risk prostate cancer experience significantly improved rates of pathologic com- plete response (pCR) or minimal residual disease (MRD) when receiving abiraterone acetate prior to radical prostatectomy (RP).12 Patients were randomized to 2 groups, both receiving abiraterone acetate at 1000 mg daily and leuprolide at 22.5 mg ever 3 months; 1 group received the addition of cabazitaxel (Jevtana) at 20 mg/m2 every 3 weeks for 6 months prior to RP. Seventy patients completed treatment and underwent RP, with 31 (44%) achieving CR and MRD across both groups. MRD was defined as 5% or less of prostate volume involved by the tumor.

There was no significant difference in results between patients receiving caba- zitaxel or not.12 Among those who received cabazitaxel chemotherapy (n = 37), 5% achieved pCR alone, 57% had MRD, and 43% achieved both pCR and MRD. In the abiraterone acetate/leuprolide group (n = 33), 9% achieved pCR, 55% had MRD, and 45% achieved both pCR and MRD. Additionally, there was no difference in PSA progression between the 2 groups (P =.75), but patients achieving pCR or MRD experienced a more significant time to PSA progression (P =.096).

Apalutamide in mCSPC

A greater percentage of patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide achieved rapid and deep PSA responses, defined as a 90% or greater decline in PSA levels (PSA90), compared with patients receiving enzalutamide, according to real-world study data presented at ASCO GU 2022.13 PSA90 was achieved by 70.4% of patients receiving apalutamide (n = 174) vs 62.5% of patients receiving enzalutamide (n = 177) by the 12-month end of the follow-up period (HR, 1.49; 95% CI, 1.05-2.11; P ≤.024). Apalutamide induced PSA90 more rapidly than enzalutamide, with a median time to PSA90 of 3.13 months vs 5.20 months, respectively.

The study included clinical data from 69 community urology practices in the United States with patients classified by their first filled prescription for apalutamide or enzalutamide.13 Due to the reliance on clinical data, the study was unable to address inaccuracies or omissions, clinically meaningful differences, or differences in long-term outcomes. Further research would be required to determine if there is a true advantage to apalutamide over enzalutamide.

Novel Therapy

ARV-110 in Heavily Pretreated mCRPC

Novel agent ARV-110 (bavdegalutamide) demonstrated clinical activity in heavily pretreated patients with mCRPC who received 1 to 2 prior hormonal agents in the ongoing phase 1/2 ARDENT trial (NCT03888612).14 ARV-110 is a first-in-class, oral proteolysis-targeting chimera (PROTAC) protein degrader selective for AR. The phase 1 trial established safety and dose recommendations for phase 2, with 420 mg daily selected as the recommended dose. Patients in phase 2 had received 1 to 2 prior novel hormonal agents with or with- out chemotherapy and were stratified into 3 subgroups by mutations in biomarkers AR T878 and/or H875Y, AR L702H or AR-V7, and wild-type AR or other AR alterations.

Investigators observed the greatest activity in patients with 1 month or more of PSA follow-up in 28 patients with AR T878 and/or H875Y mutations.14 They observed a best PSA decline of 50% or more (PSA50) and PSA decline of 30% or more (PSA30) in 46% and 57% of these patients, respectively. Some patients without AR T878/H875Y mutations also experienced PSA50 declines. Tumor shrinkage was observed in 6 (2 with confirmed partial response and 3 with stable disease) of 7 RECIST-evaluable patients with AR T878 and/or H875Y mutations, and 3 remain on treatment. Investigators observed no grade 4 or higher treatment-related AEs in 138 treated patients. The most common AEs included nausea (48%), fatigue (36%), vomiting (26%), decreased appetite (25%), diarrhea (20%), and alopecia (14%). The most common grade 3 treatment-related AE was anemia (5%).

Other Studies of Interest

TALAPRO-3

The combination of the PARP inhibitor talazoparib (Talzenna) and enzalutamide for patients with mCSPC harboring DDR/ HRR alterations will be evaluated in the randomized, double-blind, multinational phase 3 TALAPRO-3 trial (NCT04821622).15 The study will include approximately 550 patients with prostate cancer, alterations in 12 DDR/HRR genes known to be sensitive to PARP inhibitors, and meta- static disease excluding brain metastases will be randomly assigned to talazoparib at 0.5 mg plus enzalutamide at 160 mg or placebo plus enzalutamide.16 Talazoparib has previously been FDA approved for use in BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer.17 The trial’s primary end point is rPFS.15

PROTEUS

PROTEUS (NCT03767244) is a randomized, double-blind, phase 3 multicenter trial recruiting 2000 patients with localized/locally advanced high-risk/ very high-risk prostate cancer who are candidates for RP with peripheral lymph node dissection.17 Investigators will randomize patients to apalutamide at 240 mg daily plus ADT or placebo plus ADT. Patients will receive neoadjuvant therapy for 6 months followed by RP, then adjuvant therapy initiated 4 weeks post RP for another 6 months. The primary end points are pCR and metastasis-free survival.

In closing, Morgan said, “There’s enthusiasm for moving PARP inhibitors to earlier in the disease state because benefits appear to be more durable when drugs are used earlier, and there may be an opportunity to get treatment to more patients when they are stronger before their cancer progresses. If we can prevent the cancer from recurring, we increase cure rates for prostate cancer, which is our ultimate goal.”

REFERENCES:

1. Saad F, Bögemann M, Suzuki K, Shore N. Treatment of nonmetastatic castration-resistant prostate cancer: focus on second-generation androgen receptor inhibitors. Prostate Cancer Prostatic Dis. 2021;24(2):323-334. doi:10.1038/s41391-020-00310-3

2. Parker C, Castro E, Fizazi K, et al; ESMO Guidelines Committee.Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol.2020;31(9):1119-1134. doi:10.1016/j.annonc.2020.06.011NCCN.

3. Clinical Practice Guidelines in Oncology. Prostate cancer,version 3.2022. Accessed March 11, 2022. https://bit.ly/35Rrkwz

4. EAU.Guidelines.Prostate cancer. Accessed March 11, 2022. https://bit.ly/3q3BzEN

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