Thao K . Huynh, PharmD , BCOP

In recent months, PARP inhibitors have propelled the field of metastatic castration-resistant prostate cancer (mCRPC) forward as the next class of therapeutics to advance outcomes. Approvals for 2 PARP agents, along with data from major medical conferences regarding the use of immunotherapeutics and other anticancer agents, show promise for the treatment of patients with advanced disease.

“We always knew that it was a matter of time for PARP inhibitors to get approved for patients with metastatic prostate cancer,” said 

). He is a professor in the Division of Oncology, Department of Medicine, at the University of Utah School of Medicine, and director of the Genitourinary Oncology Program at the Huntsman Cancer Institute in Salt Lake City.

The PARP inhibitor olaparib (Lynparza) gained FDA approval for treatment of mCRPC in May 2020, and was the first approval for this class of agent in prostate cancer with supporting efficacy data based on a randomized phase 3 clinical trial. The PROfound trial (NCT02987543) demonstrated improved radiographic progression-free survival (rPFS) with olaparib versus either enzalutamide (Xtandi) or abiraterone acetate (Zytiga) in patients whose mCRPC had deleterious or suspected deleterious germline or somatic mutations in homologous recombination repair (HRR) genes (7.4 months vs 3.6 months; HR, 0.34; 

“These were remarkable findings...olaparib was clearly superior by almost 4 months,” Agarwal said.

PARP Inhibitors in Advanced Prostate Cancer

PARP enzymes play a critical role in repairing single-strand DNA breaks. With the use of PARP inhibitors, these lesions remain unrepaired and often progress to double-strand breaks (DSBs), which are preferentially resolved by HRR. However, germline or somatic homologous recombination deficiency (HRD), which is present in up to 25% of patients with mCRPC, obliges tumor cells to repair DSBs via an error-prone alternative pathway, nonhomologous end joining (NHEJ). The genetic aberrations introduced by NHEJ often irreparably damage key cellular pathways, dooming cancer cells to apoptosis—hence the keen interest in treating tumors with HRD using PARP inhibitors.

 With limited treatment options for mCRPC, the development of PARP inhibitors has provided an important lifeline in this population, especially in the HRD setting (

The pivotal PROfound study was a prospective, randomized, multicenter, open-label, phase 3 clinical trial that randomized patients 2:1 to receive either olaparib or androgen receptor–targeted therapy (ART) consisting of enzalutamide or abiraterone. Patients with mutations in HRR genes 

made up cohort A (olaparib group, n = 162; ART group, n = 83). Patients with a mutation in any of 12 other HRR genes were treated in cohort B (olaparib; n = 94; ART, n = 48).

“The secondary analysis looking at additional genes [in cohort B] was exploratory; however, the exploratory analysis was only possible and statistically permitted if the primary analysis for 

, professor of oncology and urology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, said in an interview with 

. After the primary end point of rPFS in cohort A was met, a review of both cohorts combined demonstrated improvement in rPFS, at 5.8 months for olaparib versus 3.5 months with ART (HR, 0.49; 95% CI, 0.38-0.63; 

Additionally, an interim analysis showed that median overall survival (OS) in cohort A was 18.5 months with olaparib versus 15.1 months with ART (HR, 0.64; 95% CI, 0.43-0.97; 

= .02). This difference did not achieve statistical significance, however, due to the preset cutoff of 

“Patients who were randomized to the enzalutamide or abiraterone arm were allowed to cross over to the olaparib arm at the time of disease progression, and a large number of patients [82%] actually crossed over. Despite the crossover, the median OS [benefit] remained significant, at 3 months higher compared with abiraterone or enzalutamide,” Agarwal said. The interim median OS analysis of both cohorts significantly favored olaparib, at 17.5 months versus 14.3 months with ART (HR, 0.67; 95% CI, 0.49-0.93; 

Other secondary end points, including objective response rate (ORR) and median time to pain progression in cohort A, also significantly favored olaparib. Common adverse events (AEs) that occurred with olaparib included anemia, nausea, and fatigue or asthenia. Additionally, grade 3 or higher AEs occurred more frequently with olaparib compared with ART.

“I think the PROfound trial is the first large phase 3 randomized trial that showed a PARP inhibitor is superior to these standard-of-care [therapies] for patients who have disease progression on abiraterone or enzalutamide and are harboring mutations in DNA repair genes. It’s a very exciting development that’s happened in the last few months,” Agarwal said.

Further support for olaparib use in mCRPC was demonstrated in the phase 2 TAPUR trial (NCT02693535). Patients in this trial had exhausted all standard options, harbored germline or somatic 

mutations, had an ECOG performance score of 2 or less, had measurable disease, and had adequate organ function. The disease control rate was 68% (90% CI, 53%-77%) in the 25 patients evaluated. The interim median OS was 75.3 weeks (95% CI, 49.1-88.9). The results of this study demonstrated the utility of olaparib as a therapy option in patients with heavily pretreated mCRPC harboring germline or somatic 

Another PARP inhibitor that recently received accelerated approval for mCRPC is rucaparib (Rubraca).

 The TRITON2 trial (NCT02952534) showed encouraging antitumor activity of rucaparib in 57 patients with 

mutations, with an ORR of 43.9% (95% CI, 30.7%-57.6%).

There were 2 distinct differences between the patient groups approved for this PARP inhibitor and for olaparib, Agarwal indicated. The first was treatment history; consistent with the PROfound trial’s eligibility requirements, olaparib approval specified that patients need only have progressed on ART. “Rucaparib was approved based on the TRITON2 trial, in which patients had received both abiraterone or enzalutamide and docetaxel chemotherapy,” Agarwal noted.

“The number of eligible genes also differs. Rucaparib is only approved for 

[mutations],” Agarwal added, which contrasts with olaparib’s approval for mCRPC associated with mutations in multiple HRR genes.

Antonarakis also noted some differences in the AE profiles of the 2 drugs: “The adverse effects that grabbed my attention [that] were present with olaparib and perhaps not with rucaparib were…a slightly higher risk of venous thromboembolic events…and a rare, but serious, [risk of] pneumonitis.”

Additional PARP Inhibitors on the Horizon

Other PARP inhibitors that show potential for FDA approval in mCRPC include niraparib (Zejula) and talazoparib (Talzenna). Niraparib is being explored in the setting of 

mutations after disease progression on ART and taxane chemotherapy. It was granted breakthrough therapy designation by the FDA based on the phase 2, multicenter, open-label GALAHAD trial (NCT02854436).

 Based on data presented at the European Society for Medical Oncology 2019 Congress, the agent demonstrated a 41% ORR in patients with mCRPC who have 

Talazoparib has also demonstrated benefit in patients with mCRPC driven by alterations in 

or other DNA damage repair genes after treatment with at least 1 taxane chemotherapy regimen and ART. An interim analysis of the TALAPRO-1 trial (NCT03148795) showed an ORR of 25.6% (95% CI, 13.5%-41.2%) in the overall cohort. The ORR was higher, at 50.0% (95% CI, 27.2%-72.8%), in the subset of patients with 

Commenting on the future of PARP inhibitors, Agarwal predicted that “there will be a time soon [when] we will be testing these PARP inhibitors in the up-front setting in patients with newly diagnosed prostate cancer who are harboring mutations in DNA repair genes.”

With the recent approvals of PARP inhibitors, the National Comprehensive Cancer Network has updated its guidelines to recommend tumor testing for HRR mutations. Additionally, both olaparib and rucaparib have been added to the list of systemic therapy options for patients with HRR-mutated mCRPC to reflect the current standard of care.

Antonarakis noted that in addition to PARP inhibition, “one of the most exciting developments [in prostate cancer treatment is the use of] radioligand treatment that targets prostate-specific membrane antigen [PSMA]–expressing prostate cancer. PSMA is almost ubiquitous in prostate cancer in castration-resistant disease and is present in more than 80% to 90% of castration-resistant metastasis. It’s a very reasonable target.”

The phase 2 TheraP trial (NCT03392428) randomized patients with mCRPC who had progressed after docetaxel to treatment with either lutetium 177–labeled PSMA-617 (177Lu-PSMA-617; LuPSMA) or cabazitaxel (Jevtana; a taxane). Antonarakis explained that Lu-PSMA “is a radioligand whereby a radioactive molecule, lutetium, gives off a type of radiation called b waves [and] binds to prostate cancer cells that are expressing PSMA. The lutetium is used to irradiate the cells that it binds.”

Patients were randomized to either Lu-PSMA (n = 98) every 6 weeks for up to 6 cycles or cabazitaxel (n = 85) every 3 weeks for up to 10 cycles. The percentage of patients meeting the primary end point of prostate-specific antigen (PSA) response rate (PSA reduction ≥50% from baseline) was almost doubled in the Lu-PSMA group compared with the cabazitaxel arm, at 66% versus 37%, respectively (

< .0001). A sensitivity analysis also favored the experimental arm and demonstrated a 23% difference in PSA response rate (

= .0016). Preliminary results demonstrated improved PSA PFS (defined as time from randomization to PSA progression) at a median follow-up of 13.3 months (HR, 0.69; 95% CI, 0.50-0.95; 

Additionally, grade 3/4 AEs occurred less frequently in the Lu-PSMA group (35%) compared with the cabazitaxel group (54%). Diarrhea, dysgeusia, and neuropathy of any grade occurred more frequently with cabazitaxel, whereas thrombocytopenia, dry mouth, and dry eye occurred more frequently with Lu-PSMA. Results of this study indicate that Lu-PSMA represents a potential novel class of effective therapy for mCRPC after progression on taxane chemotherapy.

“The theoretical advantage of Lu-PSMA…is that it will target bone and nonbone lesions—for example, soft tissue metastases,” Antonarakis said. “The phase 3 study with Lu-PSMA [VISION trial; NCT03511664] is awaiting results. Many of us in the field anticipate that Lu-PSMA will be FDA approved by the middle of 2021.”

Another notable study is the CARD trial (NCT02485691), which evaluated the use of cabazitaxel (n = 129) versus ART (n = 126; abiraterone or enzalutamide) after previous docetaxel and within 12 months of progression on ART. This was a multicenter, randomized, open-label trial with rPFS as the primary end point. The median follow-up was 9.2 months. Cabazitaxel improved median rPFS by more than 4 months compared with ART, at 8.0 months versus 3.7 months (HR, 0.54; 95% CI, 0.40-0.73; 

< .0001). Additionally, cabazitaxel improved median OS compared with ART, at 13.6 months versus 11.0 months (HR, 0.64; 95% CI, 0.46-0.89; 

Furthermore, analyses evaluating OS from various starting points—including diagnosis of metastatic disease, diagnosis of mCRPC, and initiation of first and second life-extending therapies—all favored cabazitaxel over ART. The survival benefit of cabazitaxel compared with ART was supported by a stratified multivariate analysis. Results of the CARD study support cabazitaxel over ART as the standard of care for patients previously treated with docetaxel and ART.

“What the CARD trial has taught us is that we should alternate ART with taxane chemotherapy,” Antonarakis said.

The pivotal CARD trial inspired the creation of other studies to evaluate different end points and patient populations. One of these studies was PROREPAIR-B (NCT03075735), a prospective trial evaluating the effects of germline mutations in HRR genes on the benefit of first, second, and subsequent lines of therapy. Of the 419 patients in this trial, 95 met the same inclusion criteria as those for the CARD study.

In the overall population, cabazitaxel (n = 60) demonstrated improved rPFS compared with ART (n = 35; abiraterone/enzalutamide), at 6.0 months versus 3.7 months, respectively (

= .03). No difference in OS was detected, perhaps due in part to the 60% rate of crossover from ART to cabazitaxel. However, subgroup analyses revealed that patients with germline HRR mutations had a significantly worse prognosis, with poor hazard ratios for OS (HR, 1.9) and rPFS (HR, 2.4), as well as no improvement in OS (4.5 months vs 3.7 months; 

= .8) or rPFS (2.5 months vs 3.8 months; 

= .8) with cabazitaxel compared with ART. The PROREPAIR-B findings further support the results of the CARD trial for unselected patients, favoring the use of cabazitaxel over ART.

However, the poor outcomes with both regimens in patients with germline HRR–mutant mCRPC support the need for novel treatments in this setting.13 “There is accumulating evidence, although it’s not conclusive yet, that perhaps patients with HRR mutations—especially 

] germline mutation—may actually be a bit more taxane resistant and more hormone therapy sensitive, which might sound like a bit of a paradox,” Antonarakis said. “The [data] are immature but provocative…and should be further studied.”

In a preplanned analysis of the CARD trial, patient-reported outcomes were evaluated using a questionnaire, the EuroQol Group’s 5-dimension, 5-level (EQ-5D-5L) utility index score and visual analogue scale (VAS). The investigators evaluated the scores at baseline, on day 1 of each cycle, and at the end of treatment. At baseline, patients randomized to the cabazitaxel versus ART groups had similar EQ-5D-5L utility index scores (0.7 in both groups) and VAS (65.8 with cabazitaxel vs 66.3 for ART). Pain response (a reduction in pain from baseline) was reported in a significantly greater proportion of the cabazitaxel group (45.9%) compared with the ART group (19.3%; 

< .0001). Cabazitaxel also delayed the time to pain progression compared with ART (HR, 0.55; 95% CI, 0.32-0.97; 

= .03). Additionally, the safety profile of cabazitaxel was manageable, with fewer grade 3 or higher cardiac disorders compared with ART (0.8% vs 4.8%).

As another novel approach for treating mCRPC, immunotherapeutics are making their way into the treatment landscape. Agarwal remarked that because “cabozantinib [Cabometyx] and atezolizumab [Tecentriq] have synergistic action…they were found to suppress the immune-suppressive cells and upregulate immunostimulatory cells.”

This was the rationale for exploring the small-molecule multityrosine kinase inhibitor/PD-L1 inhibitor combination of cabozantinib and atezolizumab in the phase 1b COSMIC-021 (NCT03170960) trial, with multiple cohorts of patients with 1 of 12 types of advanced solid tumors, including mCRPC. Patients enrolled in cohort 6 had mCRPC with radiographic progression in soft tissue after ART, measurable disease, and an ECOG performance status of 0 or 1. The primary end point of ORR was 32% (80% CI, 23%-42%) for the first 44 patients enrolled, including 3 patients with complete responses and 11 who achieved partial responses. Furthermore, 21 patients (48%) achieved stable disease, for a disease control rate of 80%.

Commenting on the study results, Agarwal stated that “we have never seen this magnitude of response in the context of any immunotherapy in prostate cancer in the metastatic setting in the history of castration-resistant prostate cancer.” Additionally, the median time to objective response was 1.6 months (range, 1-7), and the median duration of response was 8.3 months (range, 2.8-12.5+). Agarwal noted, “These responses were not only very high in number…but they were also durable. That is the other exciting aspect of this regimen: Once patients responded, they were likely to continue to respond.”

The majority (82%) of patients enrolled had high-risk mCRPC (with visceral and/or extrapelvic lymph node metastases), and the median age was 70 years (range, 49-90). The most common treatment-related AEs were fatigue, diarrhea, nausea, decreased appetite, and dysgeusia.

The landscape of mCRPC is rapidly evolving. These new treatment modalities—including PARP inhibition, PSMA-targeting agents, and immunotherapy—are shifting the treatment paradigm in mCRPC and providing patients with more therapeutic options.

“The field is...evolving in 2 key directions in mCRPC. One will be targeted therapy, and [the other] will be immunotherapy,” said Antonarakis. “I think overall, the future looks promising, and I tell my patients I need to keep them going only for the next few years because after that, we will see a new wave of therapy coming up.”

Antonarakis discussed the future of mCRPC in terms of novel approaches to treatment. “Perhaps [with] combination strategies using PD-1 inhibitors or other modalities, such as PSMA-targeted BiTEs, or bispecific T-cell engagers, or PSMA CAR [chimeric antigen receptor] T cells,” he said, “we might have a drug that will [further] improve outcomes for our patients.”

FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. FDA. Updated May 20, 2020. Accessed August 5, 2020. https://bit.ly/3ic71dD

de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. 

. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440

Christenson ES, Antonarakis ES. PARP inhibitors for homologous recombination-deficient prostate cancer. 

. 2018;23(2):123-133. doi:10.1080/14728214.2018.1459563

FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer. FDA. May 15, 2020. Accessed July 27, 2020. https://bit.ly/3kjRf2m

Abida W, Campbell D, Patnaik A, et al. 846 PD: preliminary results from the TRITON2 study of rucaparib in patients (pts) with DNA damage repair (DDR)-deficient metastatic castration-resistant prostate cancer (mCRPC): updated analyses. 

. 2019;30(suppl 5):v327-v328. doi:10.1093/annonc/mdz248.003

Janssen announces U.S. FDA breakthrough therapy designation granted for niraparib for the treatment of metastatic castration-resistant prostate cancer. News release. Johnson & Johnson; October 3, 2019. Accessed July 27, 2020. https://bit.ly/2XtVheI

Smith MR, Sandhu SK, Kelly WK, et al. Pre-specified interim analysis of GALAHAD: a phase II study of niraparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD

. 2019;30(suppl 15):v884-v885. doi:10.1093/annonc/mdz394

De Bono JS, Mehra N, Higano CS, et al. TALAPRO-1: a phase II study of talazoparib (TALA) in men with DNA damage repair mutations (DDRmut) and metastatic castration-resistant prostate cancer (mCRPC)—first interim analysis (IA). 

 2020;38(suppl 6; abstr 119). doi:10.1200/JCO.2020.38.6_suppl.119

Pisick E, Garrett-Mayer E, Halabi S, et al. Olaparib (O) in patients (pts) with prostate cancer with BRCA1/2 inactivating mutations: results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study. 

. 2020;38(suppl 15; abstr 5567). doi:10.1200/JCO.2020.38.15_suppl.5567

NCCN. Clinical Practical Guidelines in Oncology. Prostate cancer, version 2.2020. Accessed August 1, 2020. https://bit.ly/2Dr8jT8

Hofman MS, Emmett L, Sandhu SK, et al. TheraP: a randomised phase II trial of 177Lu-PSMA-617 (LuPSMA) theranostic versus cabazitaxel in metastatic castration resistant prostate cancer (mCRPC) progressing after docetaxel: initial results (ANZUP protocol 1603). 

 2020;38(suppl 15; abstr 5500). doi:10.1200/JCO.2020.38.15_suppl.5500

Tombal BF, Castellano D, Kramer G, et al. CARD: overall survival (OS) analysis of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving cabazitaxel versus abiraterone or enzalutamide. 

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Romero-Laorden N, Lozano R, Llacer Perez C, et al. Cabazitaxel versus enzalutamide/abiraterone in CARD eligible mCRPC patients with or without germline HRR defects. 

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Articles

PARP inhibitors have propelled the field of metastatic castration-resistant prostate cancer forward as the next class of therapeutics to advance outcomes.

PARP Inhibitors Gain Indications in Advanced Prostate Cancer

Looking at the long list of different therapeutic modalities being explored across treatment settings, thought leaders in the field eagerly await positive trial results that will determine the next breakthrough.

The complexity of glioblastoma has eluded many traditional treatment approaches through the years. Since 2005, the standard of care for patients with newly diagnosed glioblastoma following surgery has been chemotherapy with temozolomide (Temodar) and radiation therapy.1,2 Novel approaches to glioblastoma treatment are poised to change the paradigm of therapy in a field formerly plagued by limited options.

“No one thought temozolomide or tumor-treating fields were going to be a breakthrough,” said Roger Stupp, MD, in an interview with Targeted Therapies in Oncology, expressing hope that these numerous novel modalities may provide fresh advances in glioblastoma treatment. Stupp is chief of neuro-oncology in the Department of Neurology at Northwestern University Feinberg School of Medicine and co-director of the Northwestern Medicine Lou and Jean Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, Illinois.

Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO) immunotherapy uses a live modified attenuated poliovirus to directly target malignant cells. PVSRIPO specifically targets CD155, a receptor found predominantly on tumor cells, causing cell lysis and activating the immune response toward tumor cells.

, investigators led by Annick Desjardins, MD, evaluated the use of PVSRIPO by convection-enhanced delivery via a catheter inserted directly into the tumor after biopsy in 61 patients with recurrent World Health Organization (WHO) grade IV malignant glioma in a dose-escalation and dose-expansion clinical trial. Results of the phase 1 trial (NCT01491893) were compared with a historical control at the same institution and demonstrated a median overall survival (OS) of 12.5 months (95% CI, 9.9-15.2) in the PVSRIPO group versus the historical control group at 11.3 months (95% CI, 9.8-12.5).

Notably, the OS rate in the experimental group plateaued between 24 and 36 months, with an OS rate of 21% at both time points; conversely, the OS rate in the historical control group declined over time, at 14% at 24 months and 4% at 36 months.

Stupp astutely reviewed the survival data. “Looking at the [supplementary] appendix for patients who have been surviving longer than 2 years, all but 1 patient had favorable prognostic tumor characteristics based on either an isocitrate dehydrogenase [IDH] mutation or methylguanine-DNA methyltransferase [MGMT] promoter methylation status. We would expect these patients to live beyond 2 years,” he said.

Stupp noted, “it would be interesting to know for all patients the survival they had from initial diagnosis.”

Grade 1/2 adverse events (AEs) attributed to PVSRIPO occurred in most patients (69%). Common AEs included headache, pyramidal tract syndrome, seizure, dysphasia, and cognitive disturbance. Because the virus is modified, normal tissue is not affected, with no evidence of viral shedding or neuropathogenicity such as encephalomyelitis, poliomyelitis, meningitis, or systemic autoimmune reactions in any patients.

A phase 2 trial examining the safety and efficacy of PVSRIPO in adult patients with recurrent WHO grade IV malignant glioma is currently recruiting (NCT02986178).

Another agent at the forefront of glioblastoma treatment is ofranergene obadenovec (VB-111), an anticancer gene therapy that induces targeted tumor vascular endothelial cell lysis and leads to an immune response targeted to tumor cells.

VB-111 was studied in patients with recurrent glioblastoma in a phase 1/2 prospective, open-label, dose-escalating, multicenter study (NCT01260506). Patients were stratified into 4 treatment groups: a subtherapeutic group that received initial doses below the therapeutic dose of 1 × 1013 viral particles; a limited exposure (LE) group receiving VB-111 monotherapy every 56 days until progression; a primed combination group receiving VB-111 monotherapy every 56 days until progression, followed by VB-111 plus bevacizumab (Avastin) every 2 weeks; and an unprimed combination group receiving VB-111 every 28 days plus bevacizumab every 2 weeks.

The primed combination group demonstrated extended survival compared with the LE and unprimed combination groups, with a median OS of 414 days versus 223 days (HR, 0.48; 95% CI, 0.23-0.998; 

 = .043) and 141.5 days (HR, 0.24; 95% CI, 0.09-0.66; 

Progression-free survival (PFS) was also prolonged in the primed combination group (90 days) compared with the LE group (60 days; HR, 0.36; 95% CI, 0.140.93; P = .032). VB-111 proved to be safe, with no dose-limiting toxicities, and the maximum tolerated dose was not reached.

The most common AEs across all groups included pyrexia, fatigue, chills, headache, nausea, and seizure. Additionally, postinfusion febrile reaction was associated with improved survival, with a median OS of 448 days in patients with fever versus 235 days in those without (HR, 0.34; 95% CI, 0.18-0.62; 

Based on positive findings in early clinical trials such as the one described above, the pivotal phase 3 GLOBE trial (NCT02511405) evaluated the combination of VB-111 and bevacizumab versus bevacizumab alone in patients with recurrent glioblastoma. The study failed to demonstrate a benefit of the combination versus bevacizumab monotherapy, however, with median OS of 6.8 months versus 7.9 months (HR, 1.20; 95% CI, 0.91-1.59; P = .19) and objective response rates of 27.3% versus 21.9%, respectively (P = .26).

“Trials in the recurrent setting are difficult to conduct,” Stupp said. “The phase 3 trial was appropriately designed; however, the median survival was on the lower end [for] recurrent disease, demonstrating lack of signal activity.”

The conflicting survival results from the phase 1/2 and phase 3 trials may be explained by the lack of VB-111 priming in the phase 3 trial, with the GLOBE investigators hypothesizing that coadministration of VB-111 and bevacizumab may have blocked VB-111’s antitumor effect.6 However, given the impressive results from previous studies with VB-111, the agent was set to move forward in a 3-arm phase 2 surgical trial examining its use as neoadjuvant and adjuvant treatment for recurrent glioblastoma. The study will evaluate early immunologic pharmacodynamic parameters to examine the primary end point of the effect of neoadjuvant VB-111 on density of tumor- infiltrating T cells.

In the area of oral drug therapies for glioblastoma, 2 targeted agents currently under investigation stand out.

Paxalisib (formerly GDC-0084) is a novel targeted agent that potently inhibits the PI3K pathway, which is altered in more than 85% of glioma cases. Its ability to traverse the bloodbrain barrier (BBB) makes this drug a particularly attractive option in glioblastoma.

A dose-escalation and -expansion phase 2 study in patients with newly diagnosed glioblastoma with unmethylated MGMT promoter status is evaluating paxalisib as adjuvant therapy following surgical resection and chemoradiation with temozolomide (NCT03522298). Interim results from the escalation cohort (n = 9) demonstrated a median OS of 17.7 months compared with 12.7 months for similar patients treated with temozolomide in previous work. Additionally, median PFS in all evaluable patients (n = 30) was 8.5 months with paxalisib versus 5.3 months with temozolomide. Common AEs reported for paxalisib included hyperglycemia, oral mucositis, and low-grade rash.

“From the press release, the data look encouraging for testing the agent in the up-front setting,” Stupp said. “However, additional results are necessary, including full patient characteristics and how MGMT status was [collected], in order to determine the outcome data.”

In addition to paxalisib, “there has been renewed interest in PARP inhibition in the field of glioblastoma over the last few years,” Stupp said. “Veliparib has the advantage that it crosses the blood–brain barrier better than the other agents. That is one thing that is key, but results to date in unselected populations have not been conclusive.”

The PARP inhibitor olaparib (Lynparza) has shown efficacy in glioma cells with IDH mutations and has enhanced the effects of temozolomide when used in combination.

 A phase 2 study (NCT03212274) is evaluating the use of olaparib in the metastatic or treatment-refractory disease setting. Eligible patients may have several solid tumor types, including glioma, with IDH1/2 mutations.

Immunotherapy, Chemotherapy, and Vaccines

The era of creative innovation in glioblastoma therapy has also ushered in multiple immunotherapeutic agents and vaccines in clinical trials that directly target malignant cells while minimizing negative effects on normal tissue.

AV-GBM-1 is a novel immunotherapy that uses autologous dendritic cells loaded with autologous tumor-associated antigens, allowing it to directly target stem cells responsible for tumor growth. A single-arm, phase 2 clinical trial included patients with newly diagnosed disease who had recovered from surgery and were about to start concurrent chemotherapy and radiation (NCT03400917). Interim results demonstrated improved survival in the AV-GBM-1 group (n = 50) compared with standard of care (n = 287), with an OS rate of 76% at both 12 months and 15 months compared with 61% at 12 months and 48% at 15 months, respectively.11 When trial data were initially presented in November 2019, the first 16 patients demonstrated an immune response associated with a decrease in tumor biomarkers.

An open-label, single-arm, phase 2 clinical trial (NCT03050736) is evaluating the maximum tolerated dose of VAL-083, a small- molecule chemotherapeutic, in combination with the standard-of-care radiation regimen used to treat patients with newly diagnosed glioblastoma with unmethylated MGMT promoter status. According to an interim analysis, of the 15 patients assessed for tumor progression, 7 demonstrated complete response and 8 had stable disease. The most common AE was myelosuppression, which was consistent with the investigators’ previous experience. VAL-083 functions as a bifunctional DNA-targeting agent that induces double-strand breaks and circumvents MGMT-mediated repair.

Another innovative approach being examined for treatment of glioblastoma is chimeric antigen receptor (CAR) T-cell therapy, with one such agent currently under evaluation in a phase 1 dose-escalation trial of patients with recurrent or progressive glioblastoma following standard therapy (NCT04214392). The therapy in this trial has an unusual CAR design with a recognition domain derived from chlorotoxin, a component of scorpion venom. The trial’s primary goals are to evaluate the safety and efficacy of the therapy and any dose-limiting toxicities. In cell-based assays and animal models, the chlorotoxin-directed CAR T cells recognized and eliminated glioblastoma cells without toxic effects on nontumor cells and other organs.

Investigators Uncover Potential Prognostic Biomarkers

In addition to efforts to develop multiple novel agents for treating glioblastoma, clinicians have worked toward implementing liquid biopsy as a minimally invasive tool for molecular profiling and disease monitoring.

In a single-center, post hoc analysis of 42 patients with newly diagnosed glioblastoma in a previously enrolled prospective cohort, MRI scans were used in conjunction with histopathology to assess plasma cell-free DNA (cfDNA) concentration and circulating tumor DNA (ctDNA) detection. The investigators were seeking to identify factors associated with cfDNA concentration, which is typically low in glioblastoma and can limit the ability to detect ctDNA.

“In addition to anatomical imaging, we looked into other advanced imaging metrics, including dynamic contrast-enhanced MRI, which measures the blood–brain barrier permeability, and we found a significant correlation between the volume of the tumor [and] increased permeability of blood–brain barrier beyond a certain threshold compared with contralateral white matter and cfDNA,” Seyed Ali Nabavizadeh, MD, lead study author as well as assistant professor of radiology at the Hospital of the University of Pennsylvania, in Philadelphia, said in an interview with 

Results of the study demonstrated that factors associated with increased plasma cfDNA concentration included BBB disruption (

 = .001), increased tumor macrophage density (

 = .011), and increased tumor vessel size (

“We also looked at mutations in ctDNA, and we found that there was an inverse relationship between the perivascular macrophages and the detection of ctDNA in the plasma,” Nabavizadeh said. “atients who had higher perivascular macrophage density had lower ctDNA detection in the plasma, which indicates that the immune microenvironment of the tumor, mainly tumor associated macrophages, can affect the detectability of ctDNA.”

The identification of plasma cfDNA- associated characteristics in this study may help clinicians select patients who will benefit from liquid biopsy, a minimally invasive approach used in conjunction with imaging studies to assess disease progression. Nabavizadeh noted that “liquid biopsy could play a more vital role in the future of glioblastoma if advances in targeted treatment provided improved survival outcomes [for patients who may] be medically managed with long-term follow-up. In addition, if future studies corroborate our findings that liquid biopsy can inform us about tumor-associated macrophages, that could be an additional application of liquid biopsy for monitoring targeted treatment against tumor-associated macrophages.

“More advanced imaging, such as amino acid PET and immuno-PET imaging, can provide the opportunity for real-time monitoring of the tumor-immune microenvironment and metabolism and would be important to be included in future studies,” Nabavizadeh added.

Another imaging study was able to identify biomarkers predicting PFS to chemotherapy response in patients with glioblastoma. Retrospective MRI data from newly diagnosed patients were analyzed and a radiomic risk score (RRS) was built using 25 radiomic features from the tumor habitat captured on routine pretreatment MRI. It was trained on data from 130 patients and tested with data from 73.

The RRS was associated with PFS in both the training cohort (

 <.00001) and the independent test group (

 = .0117).16 Additionally, augmenting the MRI-based RRS with clinical parameters such as age and gender, molecular features such as MGMT and IDH status, and extent of resection improved the prediction of PFS in training (

This was also the first clinical study to bridge the gap between tumor radiomic features and genetics. Using gene ontology and single-sample gene set enrichment analyses, significant correlations were found between the radiomic features and molecular signaling pathways associated with cell differentiation, cell adhesion, and angiogenesis (

 <.05).16 The results of this study may provide further insight into ways to predict tumor recurrence and evaluate the efficacy of chemoradiation therapy in patients with glioblastoma.

“We’re still in the exploratory phase of advancing glioblastoma treatment, and what we need are definitive results [from randomized clinical trials],” Stupp said. Meanwhile, clinicians and patients eagerly await new treatment approaches that will extend survival.

NCCN. Clinical Practice Guidelines in Oncology. Central nervous system cancers, version 2.2020. Accessed May 13, 2020. https://bit.ly/3bo6Rfm

Temodar approved for treating GBM in combination with radiotherapy. Cancernetwork. Published April 1, 2005. Accessed May 3, 2020. https://bit.ly/2Z10dJh

University Hospitals Seidman Cancer Center treats its first glioblastoma patient with genetically modified poliovirus. News release. University Hospitals; January 24, 2020. Accessed April 26, 2020. https://bit.ly/3bpKGpf

Desjardins A, Gromeier M, Herndon JE 2nd, et al. Recurrent glioblastoma treated with recombinant poliovirus. 

. 2018;379(2):150-161. doi:10.1056/NEJMoa1716435

Brenner AJ, Peters KB, Vredenburgh J, et al. Safety and efficacy of VB-111, an anticancer gene therapy, in patients with recurrent glioblastoma: results of a phase I/II study. 

. 2020;22(5):694-704. doi:10.1093/neuonc/noz231

Cloughesy TF, Brenner A, de Groot JF, et al; GLOBE Study Investigators; Patrick YW. A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE). 

. 2020;22(5):705-717. doi:10.1093/neuonc/noz232

Cloughesy T, Butowski N, Harats D, et al. Clinical trial in progress: a study of neo-adjuvant and adjuvant VB-111 for treatment of recurrent GBM. 

. 2019;21(suppl 6;abstr ATIM-09). doi:10.1093/neuonc/noz175.009

Paxalisib. Kazia Therapeutics. Accessed April 26, 2020. https://bit.ly/2Wr7v7y

Kazia’s paxalisib shows positive overall survival signal in phase II glioblastoma study. News release. Kazia Therapeutics Limited; April 7, 2020. Accessed April 26, 2020. https://prn.to/35TZkE5

PARP inhibitors may be effective in brain, other cancers with IDH mutations. NIH National Cancer Institute. Published April 24, 2017. Accessed April 26, 2020. https://bit.ly/2WsqH4T

AIVITA Biomedical provides update of ongoing phase 2 glioblastoma trial from year-end survival analysis. News release. AIVITA Biomedical; April 8, 2020. Accessed April 29, 2020. https://bit.ly/2Aqu1oH

AIVITA Biomedical announces new positive phase 2 glioblastoma data at SITC Annual Meeting podium presentation. News release. AIVITA Biomedical; November 12, 2019. Accessed April 29, 2020. https://bit.ly/3cuY7Wa

Chen Z-p, Guo C, Yang Q-y, et al. Clinical trial of VAL-083 in newly diagnosed MGMT-unmethylated GBM: half-way report. 

. 2019;21(suppl_6;abstr ACTR-06). doi:10.1093/neuonc/noz175.050

Marquez L. From scorpion to immunotherapy: City of Hope scientists repurpose nature’s toxin for first-of-its kind CAR T cell therapy to treat brain tumors. News release. City of Hope; March 4, 2020. Accessed April 29, 2020. https://bit.ly/2WQQx1w

Nabavizadeh SA, Ware JB, Guiry S, et al. Imaging and histopathologic correlates of plasma cell-free DNA concentration and circulating tumor DNA in adult patients with newly diagnosed glioblastoma. 

. 2020;2(1):vdaa016. doi:10.1093/noajnl/vdaa016

Beig N, Bera K, Prasanna P, et al. Radiogenomic-based survival risk stratification of tumor habitat on Gd-T1w MRI is associated with biological processes in glioblastoma. 

. 2020;26(8):1866-1876. doi:10.1158/1078-0432.CCR-19-2556

Treatment of glioblastoma has seen few advancements since the approval of temozolomide plus radiotherapy in 2005 for newly diagnosed disease. Recently, promising clinical data have reinvigorated hope for novel therapies in this tumor type. 

Investigators Employ a Range of Novel and Established Systemic Therapies for Advanced Glioblastoma

Recently reported data on Bruton tyrosine kinase (BTK) inhibitors for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) may herald a shift in the standard of care, reducing the need for chemoimmunotherapy in certain patient sets and promoting the most efficacious treatments to earlier lines of therapy.

The use of agents targeting BTK have moved into the standard of care for the treatment of CLL/SLL in recent years. New data have indicated that more effective therapy by way of combination regimens and newly approved agents may further improve the prognosis of this disease.

In a relatively short time, BTK inhibitors for CLL have shown drastic improvements in patient response to therapy. "It's amazing to see how quickly the field has developed," Michael Choi, MD, associate clinical professor of medicine at the University of California, San Diego, said in an interview with 

). "A year ago, we had data showing BTK inhibitor therapy, ibrutinib [Imbruvica], was superior to chemoimmunotherapy. Now, we're already improving on that with combination therapies. It's exciting and promising for our patients. We're close to the point where patients with CLL will have full lives [in which they are] not necessarily on continuous therapy."

BTK is a crucial component of B-cell receptor signaling and is overexpressed in CLL, making its inhibition an attractive therapeutic target.

Ibrutinib was the first BTK inhibitor to receive FDA approval in 2013 for mantle cell lymphoma, with an expanded indication for patients with CLL who received at least 1 prior therapy granted in 2014.

Since then, next-generation BTK inhibitors have been developed for the treatment of hematologic malignancies, including zanubrutinib (Brukinsa) and acalabrutinib (Calquence; 

). To date, the only FDA-indicated use for zanubrutinib is in patients with mantle cell lymphoma.

In November 2019, acalabrutinib received FDA approval for use in patients with CLL or SLL based on results of the ELEVATE-CLL TN and ASCEND trials.

ELEVATE-CLL TN was an open-label phase III trial in 535 treatment-naive patients with CLL that evaluated acalabrutinib as a single agent, acalabrutinib in combination with the CD20 inhibitor obinutuzumab (Gazyva), or obinutuzumab plus chlorambucil. Prior to the approval of ibrutinib, obinutuzumab plus chlorambucil was considered the standard of care for CLL. Baseline characteristics were similar across all 3 treatment arms.

Median progression-free survival (PFS) was superior for acalabrutinib plus obinutuzumab (HR, 0.10; 95% CI, 0.06-0.17; 

<.0001) and acalabrutinib alone (HR, 0.20; 95% CI, 0.13- 0.31; 

<.0001) compared with chlorambucil plus obinutuzumab. Adverse events (AEs) led to discontinuation in 11.2%, 8.9%, and 14.1% of patients receiving acalabrutinib plus obinutuzumab, acalabrutinib monotherapy, and obinutuzumab plus chlorambucil, respectively.

ASCEND was a randomized, multicenter, open-label phase III trial investigating the efficacy and safety of single-agent acalabrutinib versus idelalisib (Zydelig) plus the CD20 inhibitor rituximab (Rituxan; IdR) or bendamustine plus rituximab (BR) in 310 patients with relapsed/ refractory (R/R) CLL. At a median follow-up of 16.1 months, median PFS was not reached in the acalabrutinib monotherapy group compared with 16.5 months for the combined IdR/BR group (HR, 0.31; 95% CI, 0.20-0.49;

Data presented at the 2019 American Society of Hematology Annual Meeting & Exposition (ASH) demonstrated that acalabrutinib continued to show long-term efficacy and a tolerable safety profile at 42 months in the phase I/II ACE-CL-001 trial.

"Acalabrutinib in relapsed or refractory disease in 134 patients [demonstrated promising results with about 4 years of follow-up], with a 45-month PFS of 62%, showing similar results to ibrutinib." Jennifer A. Woyach, MD, associate professor in the Division of Hematology at The Ohio State University Comprehensive Cancer Center in Columbus, said in an interview with TTO. Efficacy end points assessed in the ACE-CL-001 study included median duration of response, event-free survival, and PFS; these had not yet been reached at the time of assessment.

The data we have for acalabrutinib in a fairly similar patient population to that of ibrutinib-treated patients show durable responses," said Woymach.

Commonly reported AEs with acalabrutinib included headache, neutropenia, diarrhea, anemia, and upper respiratory tract infection.

Compared with data [that have] been shown with ibrutinib, [there have been] less hypertension and atrial fibrillation with acalabrutinib, with a caveat [of fewer] patients treated with acalabrutinib and shorter follow-up. Some of those [data] might get closer together with longer follow-up," said Woyach.

Investigators also evaluated acalabrutinib as part of a triplet regimen in combination with the BCL2 inhibitor venetoclax (Venclexta) plus obinutuzumab. In an open-label, single-arm, phase II trial, they treated patients with CLL by sequentially starting the 3 agents: After a lead-in cycle with acalabrutinib, they added obinutuzumab to the regimen, followed by venetoclax ramp-up. Patients discontinued obinutuzumab after 6 months but continued on acalabrutinib plus venetoclax. After cycles 15 and 24, patients could discontinue therapy if they achieved complete response (CR) with bone marrow undetectable minimal residual disease (MRD); the rest remained on acalabrutinib plus venetoclax.

At cycle 8 restaging, among patients with

-aberrant disease, investigators found undetectable MRD in the peripheral blood of 78% of patients and in the bone marrow of 33%. With a median follow-up of 11 cycles, the overall response rate (ORR) was 100% after cycles 8 and 16. Furthermore, 12.5% of patients had achieved a CR with undetectable MRD in the bone marrow after cycle 16.

Common AEs included fatigue (81%), headache (76%), neutropenia (68%), and bruising (43%). At baseline, 97% of patients were at medium to high risk for tumor lysis syndrome (TLS), which was reduced to 9% at the start of venetoclax therapy. Having unfavorable disease characteristics, such as unmutated 

-aberrant disease, did not diminish the efficacy of acalabrutinib in combination with obinutuzumab and venetoclax.

BTK combination therapy is still under investigation, with the goal of further extending patient survival outcomes. "Combination [therapy data in studies presented thus far] appear tolerable. What we don't know yet is PFS with this limited duration of therapy [with] BTK inhibitor plus BCL2 inhibitor with or without an antibody, or whether the time off treatment is enough to justify the up-front toxicity and cost," said Woyach.

Zanubrutinib demonstrated high response rates in patients with CLL/SLL, regardless of deletion of chromosome 17p13.1 (del[17p]) status, in both the SEQUOIA and AU-003 trials.

SEQUOIA is an ongoing open-label, multi-center, phase III trial that includes a nonrandomized cohort of 109 patients with del(17p) CLL/SLL who have not received prior treatments (arm C). In preliminary data for arm C, the ORR was 92.7% (95% CI, 86.0%-96.8%). This high response rate was particularly impressive given the unfavorable prognosis associated with del(17p). With a median follow-up of 10.0 months, the majority of patients (78.9%) achieved a partial response (PR), and 2 (1.9%) achieved CR. Additionally, the vast majority (95%) of patients across all subgroups had a duration of response lasting at least 6 months. The most common grade >3 AEs included neutropenia (10.1%), pneumonia (3.7%), and hypertension (2.8%).

AU-003 was an open-label, multicenter, phase I/II trial in patients with various B-cell malignancies with indication-specific expansion cohorts. Patients with CLL/SLL (n = 123) demonstrated efficacy results similar to those in the SEQUOIA trial, with an ORR of 96% at a median follow-up of 29.5 months. The study included patients with both treatment-naive and R/R CLL/SLL. In treatment-naive patients, the PFS rate was 95% at 1 year and 97% at 2 years, indicating potential durable responses; these rates compared with 97% and 91%, respectively, in the R/R group. Common AEs included contusion, upper respiratory tract infection, diarrhea, cough, headache, and fatigue.

Investigators recently presented an integrated analysis of the RESONATE and RESONATE-2 trials at 2019 ASH, with 271 patients stratified by number of prior therapies.

"RESONATE and RESONATE-2 were both phase III studies of ibrutinib [that] led to the FDA approval of the agent in CLL. RESONATE compared ibrutinib alone with ofatumumab [Arzerra; a CD20 inhibitor] in relapsed or refractory CLL. RESONATE-2 was a frontline study [that] included patients aged 65 and older, randomized to either chlorambucil or ibrutinib," said Woyach.

With long-term follow-up of 5 and 6 years for RESONATE-2 and RESONATE, respectively, the risk of disease progression or death was reduced by 68% with first-line treatment compared with treatment after >3 prior lines (HR, 0.32; 95% CI, 0.21-0.49). The CR rate was 30% in the first-line treatment group compared with 12% and 10% for 1 to 2 and >3 prior lines of therapy, respectively.

"[Results continue to demonstrate] superiority of ibrutinib over previous standard-of-care regimens and that patients can do well for many years on ibrutinib," said Woyach.

Treatment discontinuation because of AEs occurred in 19% of all patients randomized to ibrutinib.

Besides hypertension, a cumulative toxicity, and atrial fibrillation, which can occur at any time, no other toxicities have come out as cumulative and concerning for long-term administration [of ibrutinib]," said Woyach.

Investigators also explore ibrutinib as part of a combination regimen in the phase III E1912 trial, which randomized 529 treatment-naive patients >70 years in a 2:1 ratio to receive ibrutinib plus rituximab (IR) or chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR). Patients with del(17p) were excluded because this group is known to have a poor response to FCR. The median follow-up was 33.6 months, with significantly longer median PFS and overall survival (OS) in the IR group compared with the FCR group.

The use of agents targeting Bruton tyrosine kinase have moved into the standard of care for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma in recent years. New data have indicated that more effective therapy by way of combination regimens and newly approved agents may further improve the prognosis of this disease.

Thao K . Huynh, PharmD , BCOP | Authors

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