Jessica Hergert

Findings presented during the 2021 AUA Annual Meeting showed that adding the novel agent masitinib to frontline docetaxel significantly improved progression-free survival (PFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) and low metastatic involvement.

Specifically, results from the phase 3 Study AB12003 (NCT03761225) demonstrated that the frontline combination of masitinib/docetaxel reduced the risk of progression or death by 21% versus docetaxel alone in men with mCRPC and baseline alkaline phosphatase levels (ALP) of 250 IU/mL or less.

In the targeted subgroup (n = 450), the overall primary PFS was 6.3 months (95% CI, 5.6-7.6) with masitinib plus docetaxel compared with 5.4 months (95% CI, 4.6-6.0) with placebo plus docetaxel (hazard ratio [HR], 0.79; 95% CI, 0.64-0.97; 

 = .027). The HRs for overall PFS stratified by LRT sensitivity (95% CI, 0.64-0.97; 

 = .0087) and by intention-to-treat (ITT) sensitivity (95% CI, 0.63-0.96; 

No statistically significant PFS benefit was observed for the overall population irrespective of ALP. The overall primary PFS was 5.7 months (95% CI, 4.9-6.3) with masitinib/docetaxel vs 5.4 months (95% CI, 4.9-5.9) with placebo docetaxel (HR, 0.94; 95% CI, 0.81-1.10; 

“The combination of masitinib plus docetaxel may provide a new first-line treatment option for patients with mCRPC with low metastatic involvement,” lead study author Michel Pavic, MD, PhD, a professor of medicine in the Department of medicine at Université de Sherbrooke in Sherbrooke, Quebec, said in a presentation on the data.

Masitinib is an oral, small molecule agent directed toward mast cell and macrophage activity, which are key aspects of the tumor microenvironment and are associated with prostate cancer progression.

Previously reported data from the AB07004 trial demonstrated slowed disease progression with masitinib plus docetaxel in men with mCRPC, Pavic explained.

To be eligible for enrollment on the placebo-controlled, double-blind Study AB12003 trial, patients had to have chemotherapy-naïve, confirmed mCRPC and had progressed on previous abiraterone acetate (Zytiga) or were indicated for treatment with docetaxel. Patients had ECOG performance scores of 1 or less.

Study participants were randomized to first-line masitinib at a daily dose of 6.0 mg/kg in combination with intravenous docetaxel at a dose of 75 mg/m2 plus prednisone for up to 10 cycles or placebo plus docetaxel.

PFS by Prostate Cancer Clinical Trials Working Group 2 criteria served as the primary end point of the study. PFS comprised different variables, including radiographic progression by RECIST v1.1 criteria in the soft tissue and 2 new lesions confirmed 12 weeks apart in the bone; prostate-specific antigen (PSA) progression by at least a 25% increase in PSA above the nadir and at least a 2-ng/mL absolute increase confirmed 12 weeks apart; symptomatic progression of pain and analgesic by at least a 25% increase in Present Pain Intensity from baseline confirmed 12 weeks apart; or death.

Additionally, significant treatment effect was defined at an alpha level of 3.9% for the prespecified target subgroup, with the fallback procedure to conserve the overall alpha level at 5% for the overall population, Pavic said.

The primary analysis was performed on the overall population, as well as the targeted subgroup of patients with a lower risk of metastases with baseline ALP of 250 IU/mL or less.

In the overall cohort, the ITT population included 714 patients, the safety population included 712 patients, and the modified ITT (mITT) population included 712 patients. In the targeted subgroup, the ITT population, safety population, and mITT population included 451, 450, and 450 patients, respectively.

Further results from sensitivity analyses revealed that the 12-, 18-, and 24-month PFS rates were significantly improved with masitinib plus docetaxel compared with placebo plus docetaxel in the target subgroup population. The 12-month PFS rate was 32.0% with masitinib/docetaxel vs 19.6% with placebo/docetaxel (relative improvement, 1.6-fold; 

 = .0035). The 18-month PFS rates were 27.6% vs 14.6%, respectively (relative improvement, 1.9-fold; 

 = .0001). The 24-month PFS rates were 23.1% vs 12.0%, respectively (relative improvement, 1.9-fold; 

Additionally, sensitivity analyses revealed that a greater treatment effect was observed with masitinib in patients with lower ALP levels, and therefore, less advanced metastatic disease. In patients with ALP of 200 IU/mL or less, the median PFS was 6.9 months (95% CI, 5.8-7.9) with masitinib/docetaxel (n = 178) vs 5.6 months (95% CI, 4.6-6.2) with placebo/docetaxel (n = 176; HR, 0.73; risk benefit percentage, 27%; 

 = .013). In patients with ALP of 150 IU/mL or less, the median PFS was 6.9 months (95% CI, 5.6-8.5; n = 134) vs 5.5 months (95% CI, 4.6-6.9; n = 133), respectively (HR, 0.63; risk benefit percentage, 37%; 

 = .001). In patients with ALP 100 IU/mL or less, the median PFS was 9.0 months (95% CI, 7.6-10.7; n = 59) vs 6.9 months (95% CI, 5.5-7.9; n = 72), respectively (HR, 0.53; risk benefit percentage, 47%; 

Regarding safety, “masitinib in combination with docetaxel only slightly increased the overall incidence rate ratio [IRR] of adverse [effects; AEs] with respect to placebo,” Pavic noted.

Moreover, the safety profile observed in this study was consistent with the known toxicities associated with masitinib, and included neutropenia, anemia, diarrhea, and skin reactions. No new safety signals were reported with the agent.

In the safety cohort, 96.6% of patients who received masitinib plus docetaxel (n = 355) vs 96.4% of patients who received placebo plus docetaxel (n = 357) experienced any-grade AEs (IRR, 1.0). Severe, grade 3 or 4 AEs were observed in 79.2% vs 73.1% of patients, respectively (IRR, 1.1). AEs leading to death were reported in 5.4% vs 6.2% of patients, respectively (IRR, 0.9). Non-fatal serious AEs were observed in 27.6% vs 18.8% of patients, respectively (IRR, 1.5).

Treatment-emergent AEs that led to treatment discontinuation were experienced by 26.5% of patients who received masitinib/docetaxel compared with 18.5% of those who were given placebo/docetaxel (IRR, 1.4).

“The positive outcome of Study AB12003 provides further clinical evidence associating mast cells with the pathophysiology of mCRPC,” Pavic concluded.

1. Pavic M, Hermine O, Spaeth D, et al. Masitinib plus docetaxel as first-line treatment of metastatic castrate refractory prostate cancer: results from study AB12003. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract LBA02-11.

Articles

Adding the investigational agent masitinib to standard frontline docetaxel significantly reduced the risk of disease progression or death in men with metastatic castration-resistant prostate cancer and baseline alkaline phosphatase levels (ALP) of 250 IU/mL or less.

Frontline masitinib combo delays progression in mCRPC with low metastatic involvement

A secondary analysis of the phase 3 HERO trial showed that relugolix (Orgovyx) failed to significantly improve castration resistance–free survival (CRFS) versus standard leuprolide (Lupron) in patients with advanced prostate cancer.

Results presented during the 2021 American Urological Association Annual Meeting showed that at 48 weeks, the castration resistance–free survival (CRFS) rate was 74.3% with relugolix versus 75.3% with leuprolide in the metastatic disease cohort (n = 434; HR, 1.03; 

 = .84). Similar CRFS rates were observed in the overall modified intention-to-treat population (mITT; n = 1074).

A posthoc, stepwise, multivariate Cox regression analysis showed that the baseline characteristics of prostate-specific antigen (PSA) of 20 or higher (

 <.0001), and former or current smoker (

 = .0284) were associated with a CRFS event.

Additionally, all patients were under the castration threshold of less than 50 ng/dL at the time of their CRFS event except for 2 treated with leuprolide who died without attaining castration.

“Results suggest that low testosterone levels on androgen deprivation therapy (ADT) are not a driver of early castration resistance,” said lead study author Fred Saad, MD, FRCS, professor and chairman of urology, director of Genitourinary Oncology, the Raymond Garneau Chair in Prostate Cancer Research, director of clinical research, and director of the Molecular Oncology Research Laboratory in Prostate Cancer, at the University of Montreal Hospital Center, during a virtual presentation of the data.

ADT, consisting of gonadotropin-releasing hormone (GnRH) agonists or antagonists, remains the cornerstone of treatment for patients with prostate cancer, Saad explained.

Relugolix is a first-in-class, oral, highly selective GnRH receptor antagonist that was approved by the FDA in December 2020 for use in adult patients with advanced prostate cancer.

 The approval was based on initial findings from the HERO trial, in which 96.7% of patients treated with relugolix had suppression of testosterone to castrate levels vs 88.8% with leuprolide.

 Relugolix was also associated with a 54% lower risk of major adverse cardiovascular effects compared with leuprolide.

This analysis of the HERO trial sought to further characterize the efficacy profile of relugolix in the context of CRFS, a clinically relevant indicator of disease progression and a prespecified secondary end point, in the mITT population and the metastatic disease population.

Patients enrolled on the HERO trial were randomized 2:1 to receive 120 mg of oral relugolix once daily after a single loading dose of 360 mg, or leuprolide injections every 12 weeks for 48 weeks.

Patients were stratified by geographic region, the presence or absence of metastatic disease, and age.

CRFS was defined as the time from the date of the first dose of treatment to the date of confirmed PSA progression per the Prostate Cancer Clinical Trials Working Group 3 criteria while castrated or death from any reason, whichever occurred earlier.

In the mITT population, 717 patients received relugolix and 357 received leuprolide. In the metastatic cohort, 290 patients received relugolix vs 144 who received leuprolide.

Baseline patient and clinical characteristics were similar between the mITT and metastatic disease populations.

Overall, most patients were aged 75 years or younger with a median age of 71 years. Most patients were European. Additionally, most patients had bone only metastasis at the time of study entry versus lymph node only, visceral only, or multiple sites of metastasis.

In the mITT population, testosterone values at the time of CRFS events with relugolix were 0 ng/dL to 10 or less ng/dL (n = 33), 10 ng/dL to 20 or less ng/dL (n = 43), 20 ng/dL to 30 or less ng/dL (n = 7; plus 1 death), 30 ng/dL to 40 or less ng/dL (n = 1), 40 ng/dL to 50 or less ng/dL (n = 3), or above 50 ng/dL (n = 0). In the leuprolide group, testosterone values were 0 ng/dL to 10 or less ng/dL (n = 22; plus 4 deaths), 10 ng/dL to 20 or less ng/dL (n = 13; plus 1 death), and above 50 (2 deaths).

Last testosterone values after CRFS events during treatment with relugolix were 0 ng/dL to 10 or less ng/dL (n = 36), 10 ng/dL to 20 or less ng/dL (n = 39), 20 ng/dL to 30 or less ng/dL (n = 7), 30 ng/dL to 40 or less ng/dL (n = 1), 40 ng/dL to 50 or less ng/dL (n = 1), or above 50 ng/dL (n = 4). In the leuprolide group, testosterone values were 0 ng/dL to 10 or less ng/dL (n = 27), 10 ng/dL to 20 or less ng/dL (n = 11), 20 ng/dL to 30 or less ng/dL (n = 1), and above 50 (n = 3).

Regarding safety, the frequencies of adverse effects (AEs) were similar for relugolix vs leuprolide in the metastatic disease cohort, and no new safety signals were observed.

In the metastatic disease cohort, 94.2% of men treated with relugolix and 89.6% of men treated with leuprolide experienced at least 1 AE.

The AEs reported in at least 5% of patients treated with relugolix included hot flush (n = 146; 50.3%), fatigue (n = 67; 23.1%), arthralgia (n = 47; 16.2%), constipation (n = 45; 15.5%), hypertension (n = 34; 11.7%), nausea (n = 32; 11.0%), diarrhea (n = 29; 10.0%), back pain (n = 28; 9.7%), weight gain (n = 26; 9.0%), nasopharyngitis (n = 24; 8.3%), peripheral edema (n = 23; 7.9%), asthenia (n = 21; 7.2%), musculoskeletal pain (n = 21; 7.2%), insomnia (n = 20; 6.9%) , urinary tract infection (n = 20; 6.9%), extremity pain (n = 19; 6.6%), increased alanine aminotransferase (ALT; n = 18; 6.2%), and urinary incontinence (n = 18; 6.2%).

The AEs reported in at least 5% of patients treated with leuprolide included hot flush (n = 66; 45.8%), fatigue (n = 29; 20.1%), arthralgia (n = 13; 9.0%), constipation (n = 22; 15.3%), hypertension (n = 14; 9.7%), nausea (n = 10; 6.9%), diarrhea (n = 7; 4.9%), back pain (n = 22; 15.3%), weight gain (n = 13; 9.0%), nasopharyngitis (n = 5; 3.5%), peripheral edema (n = 13; 9.0%), asthenia (n = 10; 6.9%), musculoskeletal pain (n = 8; 5.6%), insomnia (n = 11; 7.6%) , urinary tract infection (n = 6; 4.2%), extremity pain (n = 10; 6.9%), increased ALT (n = 4; 2.8%), and urinary incontinence (n = 8; 5.6%).

1. Saad F, George DJ, Cookson MS, et al. Relugolix vs leuprolide effects on castration resistance-free survival from the phase 3 HERO study in men with advanced prostate cancer. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract MP24-07.

2. FDA approves relugolix for advanced prostate cancer. News release. FDA. December 18, 2020. Accessed September 11, 2021. https://bit.ly/3z4UCQP

3. Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. 

2020;382(23):2187-2196. doi:10.1056/NEJMoa2004325

A secondary analysis of the phase 3 HERO trial showed that relugolix failed to significantly improve castration resistance–free survival versus standard leuprolide n patients with advanced prostate cancer.

Relugolix does not significantly delay onset of castration resistance in prostate cancer

The abundance of frontline regimens in metastatic renal cell carcinoma (mRCC) and the lack of head-to-head comparative data has made personalized medicine essential, explained Primo Lara, Jr, MD.

 Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, a program hosted by Physicians’ Education Resource®, LLC (PER®), Lara, discussed frontline RCC treatment options and strategies, including novel combination approaches with immunotherapy and tyrosine kinase inhibitors (TKIs).

“When you’re elbow-to-elbow with an individual with mRCC, you must stratify risk, seek multidisciplinary input, and always consider active surveillance and cytoreduction for the appropriate patient,” said Lara, director of the University of California (UC) Davis Comprehensive Cancer Center, professor of medicine, and executive associate dean for Cancer Programs at UC Davis School of Medicine.

“[Next], address that patient’s eligibility for immunotherapy. Immune-based combination therapies [are] the standard of care in 2021, but there will be some subset of patients who you consider for monotherapy, whether with an immunotherapy agent or a VEGFR[-directed] TKI. As time goes on these subsets [of patients] will keep diminishing as we improve the performance of our combination therapies,” Lara added.

Risk stratification should be considered prior to making any treatment-related decisions as some patients may be eligible for active surveillance, said Lara. Additionally, risk score, per the International Metastatic RCC Database Consortium can inform eligibility for cytoreductive nephrectomy.

“The decision [of whether to pursue cytoreductive nephrectomy] must be individualized to the patient according to risk of recurrence, regression, and death,” said Lara. “Most favorable-risk patients and some intermediate-risk patients remain candidates for cytoreduction, especially those who have large and/or symptomatic tumors with low-volume metastatic disease.”

Highly selected patients may also be candidates for metastasectomy. Although data are mostly limited to retrospective studies, patients with good performance status who have isolated or oligometastatic disease, a disease-free interval of longer than 2 years post nephrectomy, no lymph node involvement, and/or lung-only disease may benefit from metastasectomy, Lara explained.

Lara explained that it is important to recognize which patients are not eligible for immune-based therapies, including those with active autoimmune disease who are likely to develop unacceptable toxicity from immunotherapy. Other patients who should not receive immunotherapy are those with a history of solid organ transplantation, those receiving supraphysiologic corticosteroids or chronic immunosuppressive therapy, and those whose have a personal preference against intravenous treatment administration.

If a patient is indicated as a candidate for immunotherapy, nuanced treatment selection is needed to determine whether a single-agent or combination regimen is optimal, Lara said.

“Monotherapy has its advantages. It is lower cost, simpler, and better tolerated than combination therapy. [It also] offers a reduced risk of drug-drug interactions, and, by the mere fact that there is only 1 drug being given, adherence is likely to be higher,” said Lara.

Historically, the frontline mRCC paradigm was dominated by single-agent angiogenesis inhibitors, such as sunitinib (Sutent), pazopanib (Votrient), cabozantinib (Cabometyx), axitinib (Inlyta), sorafenib (Nexavar), and bevacizumab (Avastin). However, the field expanded rapidly in recent years favoring combination regimens as standard, frontline options.

Across all risk groups, combinations of immunotherapy and TKIs including, pembrolizumab (Keytruda)/axitinib, nivolumab (Opdivo)/cabozantinib, pembrolizumab/lenvatinib (Lenvima), and avelumab (Bavencio)/axitinib, have demonstrated activity in patients with RCC compared with sunitinib alone.

The combination of cabozantinib and nivolumab, which was approved by the FDA for the frontline treatment of patients with advanced RCC on January 22, 2021, demonstrated a 49% reduction in the risk of disease progression or death compared with sunitinib.

Data from CheckMate 9ER (NCT03141177 ) demonstrated that the combination elicited a median progression-free survival (PFS) of 16.6 months (95% CI, 12.5-24.9) vs 8.3 months (95% CI, 7.0-9.7) with sunitinib (HR, 0.51; 95% CI, 0.41-0.64; 

 <.0001). At a median follow-up of 10.6 months, the median overall survival (OS) was not reached (NR) in either arm but demonstrated a 40% reduction in the risk of death with the combination (HR, 0.60; 95% CI, 0.40-0.89; 

Most recently, findings from the phase 3 CLEAR trial (NCT02811861), presented during the 2021 Genitourinary Cancers Symposium, demonstrated an improvement in OS, PFS, and overall response rate (ORR) with the combination of frontline lenvatinib and pembrolizumab vs sunitinib in patients with advanced RCC.

Although the combination is not approved for patients with RCC, results showed that the median PFS was 23.9 months (95% CI, 20.8-27.7) with the combination compared with 9.2 months (95% CI, 6.0-11.0) with sunitinib. The median OS was NR in either arm but represented a 34% reduction in the risk of death with the combination vs sunitinib (HR, 0.66; 95% CI, 0.49-0.88; 

The CLEAR trial also demonstrated improved PFS and ORR, but not OS, with the combination of lenvatinib plus everolimus (Afinitor) vs sunitinib.

“This trial was designed to compare each of the doublets to the sunitinib control arm, but the doublets were not designed to be compared with each other,” added Lara.

Another approved option for patients is the immunotherapy doublet of nivolumab plus ipilimumab (Yervoy) is an approved frontline option for patients with intermediate- or poor-risk disease.

Frontline checkpoint inhibitor monotherapy with either pembrolizumab or nivolumab may be considered in select patients who are ineligible for or refuse VEGFR-directed TKI–containing combinations or are averse to ipilimumab. Single-agent pembrolizumab has demonstrated an ORR of 33.6% (95% CI, 24.8%-43.4%) and a median PFS of 6.9 months (95% CI, 5.1-NR) in patients (n = 110) with mRCC.

 Nivolumab monotherapy demonstrated an ORR of 31.7% (95% CI, 27.4%-46.1%) and a median PFS of 8.3 months (95% CI, 5.5-10.9) in patients with mRCC (n = 123).

Alternatively, VEGFR-directed TKI monotherapy with cabozantinib may be considered for certain patients who are ineligible for, intolerant of, or refuse immunotherapy. Patients with bone-only metastases or non–clear cell histology, such as papillary RCC, may also be considered.

Data from the open-label phase 2 PAPMET SWOG S1500 trial (NCT02761057) was presented during the 2021 Genitourinary Cancers Symposium. The trial randomized patients with metastatic papillary RCC who had 0 or 1 prior line of therapy that was not sunitinib to receive single-agent sunitinib, cabozantinib, crizotinib (Xalkori), or savolitinib. The median PFS was 9.0 months with cabozantinib, 2.8 months with crizotinib, 3.0 months with savolitinib, and 5.6 months with sunitinib, showing that cabozantinib monotherapy was superior to sunitinib in this patient population (HR, 0.60; 95% CI, 0.37-0.97; 

Additionally, responses favored cabozantinib vs sunitinib irrespective of papillary RCC subtype (type 1, type 2, mixed/other, or missing/not available).

Other treatment considerations for frontline therapy include high-dose interleukin-2 (IL-2) monotherapy and mTOR inhibitor monotherapy; however, these options are reserved for a very limited number of patients. High-dose IL-2 may be used in robust patients with excellent performance status and normal end-organ function, but it requires inpatient treatment and is associated with significant toxicity. mTOR inhibitors, such as temsirolimus (Torisel), have lost their place in the landscape for the treatment of patients with poor-risk mRCC.

“Temsirolimus was originally tested in a registration trial in a poor-risk context using composite criteria, but in the era of more active, life-prolonging therapies there is very little justification for routine temsirolimus use,” Lara said.

Taken collectively, treatment selection for patients with mRCC requires careful consideration of data from multiple frontline regimens. “Cost, convenience, physician experience, and patient preference will have to always apply [to treatment selection. Being an astute clinician requires you to incorporate all of these considerations at the bedside,” Lara concluded.

1. Lara P. Targeted therapies in renal cell carcinoma: monotherapy vs combination therapy. Presented at: 

Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies. March 12-13, 2021; virtual.

2. Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase III CheckMate 9ER trial. 

2020;31(suppl 4):S1159. doi:10.1016/j.annonc.2020.08.2257.

3. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. 

. Published online ahead of print February 13, 2021. doi:10.1056/NEJMoa2035716

4. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA. April 16, 2018. Accessed March 12, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-ipilimumab-combination-intermediate-or-poor-risk-advanced-renal-cell

5. Tykodi SS, Donskov F, Lee JL, et al. First-line pembrolizumab (pembro) monotherapy in advanced clear cell renal cell carcinoma (ccRCC): updated results for KEYNOTE-427 cohort A. 

2019;37(suppl 15):4570. doi:10.1200/JCO.2019.37.15_suppl.4570

6. Atkins MB, Jegede O, Haas NB, et al. Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced renal cell carcinoma (RCC) (HCRN GU16-260). 

2020;38(suppl 15):5006. doi:10.1200/JCO.2020.38.15_suppl.5006

7. Pal SK, Tangen C, Thompson IM Jr, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. 

2021;397(10275):695-703. doi:10.1016/S0140-6736(21)00152-5

Primo Lara, Jr, MD, highlights the multitude of available treatments in frontline renal cell carcinoma, and the need for individualized, multidisciplinary treatment in this setting.

Personalized medicine essential in crowded frontline RCC setting

Early-phase date shared during the 2021 Genitourinary Cancers Symposium showed that the investigational agent VERU-111 showed promising activity in patients with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on androgen receptor (AR)–targeted therapy.1

In a phase 1b study, VERU-111 induced a prostate-specific antigen (PSA) decline in 6 of 10 men who received at least four 21-day cycles of continuous dosing with the investigational tubulin inhibitor. Further, PSA declines of ≥30% and ≥50% were achieved by 4 and 2 patients, respectively.

Two men experienced partial responses and 8 men experienced stable disease as best objective tumor response. Two additional objective responses occurred in patients who did not reach 4 cycles of continuous dosing.

The median duration of treatment without progression was greater than 11 months (range, 6.0-22.0). Three men remain on study and have a median duration of treatment without progression of more than 10.5 months (range, 4.2-22+).

“The data from the phase I study showed VERU-111 is safe and well tolerated at continuous daily dosing,” said Mark Christopher Markowski, MD, PhD, lead study author and assistant professor of oncology at Johns Hopkins Medicine. “We are excited to develop an oral therapy for men with metastatic prostate cancer that does not directly target the AR signaling pathway. In the future, VERU-111 may serve as an alternative to intravenous taxane chemotherapies in men with advanced disease.”

VERU-111, a “railroad tracks disruptor” that targets the cytoskeleton, binds to the α and β tubulin subunits of microtubules. Furthermore, the agent targets the colchicine binding site to crosslink these subunits, inhibit microtubule polymerization, and downregulate intermediate filaments of the cytoskeleton.

The agent demonstrated high oral bioavailability in preclinical studies, with a favorable toxicity profile and activity against taxanes, vinca alkaloids, doxorubicin, enzalutamide (Xtandi), and abiraterone acetate (Zytiga)–resistant prostate cancers.

The open-label, phase 1b, dose-escalation portion of the study utilized a 3+3 design. Eligible patients (n = 39) had to have mCRPC and received 1 prior AR-targeted therapy. Additionally, patients who had received up to 1 prior line of taxane-based chemotherapy for mCRPC were included.

In part 1 of the phase 1b trial, patients received oral VERU-111 daily on days 1 through 7 of a 21-day cycle. In part 2, patients who tolerated the 7-day dosing schedule escalated to a 14-day schedule every 21 days. If the 14-day schedule was tolerated, patients escalated to continuous daily dosing of VERU-111 until disease progression or unacceptable toxicity.

Patients (n = 39) were a median age of 74 years (range, 61-92) and had a median sum Gleason score of 8 (range, 5-10). The majority of patients (n = 28; 72%) were Caucasian, and the remainder of patients were African American (n = 8; 21%) or Hispanic (n = 3; 8%).

Over half of patients (n = 21; 54%) had an ECOG performance status (PS) of 0; 41% and 8% had an ECOG PS of 1 and 2, respectively.

Sites of metastatic disease included bone only (n = 21; 55%), lymph node only (n = 6; 16%), bone and lymph node (n = 8; 21%), visceral (n = 1; 3%), and visceral and bone (n = 1; 3%).

Prior therapies included abiraterone (n = 14; 36%), enzalutamide (n = 8; 20%), abiraterone and enzalutamide (n = 17; 44%), and taxane-based chemotherapy (n = 9; 23%).

An efficacy analysis of patients who received the recommended phase 2 dose (RP2D) of 63 mg and were evaluable for efficacy (n = 16) showed that the median duration of treatment without progression was greater than 5.8 months (range, 0-22+). Excluding patients who discontinued treatment because of adverse effects (AEs), the median duration of treatment without progression was great than 9.8 months (range, 2-22+).

Notably, the poster presentation included 2 patient case studies.

The first patient had a Gleason score of 9 and node-only mCRPC. Prior treatments included sipuleucel-T (Provenge), enzalutamide, and abiraterone. The patient remained on study for more than 22 months and experienced a 63% decline in PSA from baseline at initiation of the first 21-day cycle.

A screening CT scan from March 8, 2019 showed a 1.7 cm by 1.5 cm measurable target lesion in the retroperitoneal lymph node. A 15-month follow-up scan completed on June 10, 2020 showed a 33% decrease in size to a nonpathologic node; the tumor shrunk to 1.1 cm by 1.0 cm.

The second case study highlighted a 73-year-old patient who received the 72-mg dose of VERU-111. The patient had bone- and node-positive mCRPC, a Gleason score of 8, and progression on leuprolide acetate (Lupron), sipuleucel-T, enzalutamide, and abiraterone.

At baseline, the patient had a 7 cm by 3.1 cm target lesion in the right obturator lymph node. Subsequent scans showed tumor shrinkage to 7 cm by 2.4 cm at 4 months and 5.4 cm by 2.4 cm at 5 months, representing a best reduction of 23%. Overall, the patient received VERU-111 for 7 months and obtained a 36% decline in PSA from baseline at initiation of the first 21-day cycle.

Regarding safety in the overall dose-escalation cohort, the most common all-grade treatment-related AEs (TRAEs) reported in more than 2 patients across all dosing levels included diarrhea (n = 38), fatigue (n = 24), and nausea (n = 21). Other all-grade TRAEs included anemia (n = 6), anorexia (n = 3), decreased appetite (n = 8), dizziness/lightheadedness (n = 3), dysgeusia (n = 4), elevated alanine transaminase (n = 5), elevated aspartate transaminase (n = 5), hyponatremia (n = 4), neutropenia/neutrophil decrease (n = 5), vomiting (n = 8), and weight loss (n = 8).

Of these TRAEs, grade 3 events included anemia (n = 1), diarrhea (n = 3), fatigue (n = 3), nausea (n = 1), and vomiting (n = 1).

In the 25 patients who received the RP2D of oral VERU-111 for at least 1 cycle, the majority of AEs were grade 1 or 2. All AEs observed included diarrhea (n = 17; 68%), nausea (n = 8; 32%), decreased appetite (n = 5; 20%), constipation (n = 4; 16%), fatigue (n = 4; 16%), vomiting (n = 4; 16%), dysgeusia (n = 3; 12%), weight loss (n = 3; 12%), abdominal cramping (n = 2; 8%), edema in the lower extremity (n = 2; 8%), and low white blood cell count (n = 2; 8%).

All drug-related AEs included diarrhea (n = 14; 56%), nausea (n = 6; 24%), decreased appetite (n = 3; 12%), fatigue (n = 3; 12%), dysgeusia (n = 3; 12%), weight loss, (n = 3; 12%), vomiting (n = 2; 8%), and low white blood cell count (n = 2; 8%).

Additionally, 1 patient experienced a grade 3 or greater, drug-related fatigue at the 63-mg dose. The patient was reduced to a 54-mg dose, and the fatigue resolved.

A phase 2 trial of VERU-111 in patients with mCRPC who are resistant to an AR-targeted agent who have not received prior intravenous chemotherapy is ongoing (NCT03752099).

 Patients will start on 63 mg of continuous, daily VERU-111. If unacceptable toxicity occurs, patients will be reduced to 54 mg of continuous, daily dosing.

The primary end point of the study is radiographic progression-free survival (rPFS). Initial results reported that objective tumor responses have been observed, including a complete response. PSA responses, including PSA declines of more than 50%, have also been observed. Patients have remained on study for more than 9 months, and the safety profile appears similar to that observed in the phase 1b study.

“Our data suggests [that] VERU-111 warrants further study. Enrollment on the phase 2 portion of the study is complete, and we look forward to sharing those results,” Markowski added.

The investigators also reported that a positive meeting with the FDA regarding VERU-111 took place in July 2020. As such, the pivotal phase 3 VERACITY trial is set to launch in early 2021. Because rPFS is set to be the primary end point, the sample size of the phase 3 study could include between 200 and 300 men.

1. Markowski MC, Eisenberger MA, Tutrone RF, et al. Clinical study of VERU-111, an oral cytoskeletal disruptor in men with metastatic castration resistant prostate cancer (mCRPC) who failed an androgen receptor targeting agent. 

. 2021(suppl 6):131. doi:10.1200/JCO.2021.39.6_suppl.131

2. To evaluate safety and tolerability of VERU-111 in men with advanced metastatic castration resistant prostate cancer. ClinicalTrials.gov. Posted November 23, 2018. Updated February 2, 2021. Accessed February 11, 2021. 

https://clinicaltrials.gov/ct2/show/NCT03752099

3. VERU-111. Veru Inc. 2021. Accessed February 11, 2021. 

https://verupharma.com/pipeline/veru-111/

 The investigational tubulin inhibitor was also safe and well tolerated at continuous daily dosing.

Jessica Hergert

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