Kristie L. Kahl

The PET agent targeting prostate specific membrane antigen (PSMA) 

F-DCFPyL effectively detected recurrent lesions in prostate cancer patients with biochemical recurrence (BCR), according to a single center study presented at the 2021 American Urological Association Annual Meeting.

“It is well known that prostate cancer is No. 1 as far as new cases in men in the United States and second only after lung cancer as far as estimated deaths for the same year. So, we need better imaging tools,” Andrei Iagaru, MD, professor of radiology-nuclear medicine, chief, Division of Nuclear Medicine and Molecular Imaging, Stanford Health Care, said during a virtual presentation at the meeting.

In total, 242 patients were prospectively enrolled with biochemical recurrence after primary definitive treatment with prostatectomy (72%), radiotherapy (28%), or both (25%).

In total, 131 patients (54%) had a Gleason score of 7.

Among those who underwent radical prostatectomy and radiation therapy, respectively, the median times to first BCR were 34 months (range, 3-240) and 48 months (range, 3-192). Mean 

F-DCFPyL activity was 343.0±25.2 MBq, and time to acquisition after administration was 77.3±13.2 minutes.

F-DCFPyL based on PSA level (ng/mL) in patients who experienced BCRwere as follows: PSA <0.5, 65%; 0.5≤ PSA <1, 74%; 1≤ PSA <2, 90%; 2 ≤ PSA < 5, 93%; and PSA ≥ 5, 96%. Across all PSA levels, the detection rate was 81%. Among patients who underwent prostatectomy, the corresponding detection rates of 

F-DCFPyL by the same PSA ranges, respectively, were 65%, 73%, 90%, 96%, and 100%. Across all PSA levels the detection rate post-prostatectomy was 80%. And after radiotherapy, the corresponding detection rates were 100%, 100%, 100%, 88%, and 94%, respectively, with a detection rate of 92% across all PSA levels.

Further, researchers evaluated the detection rate of 

F-DCFPyL after prostatectomy based on PSA doubling time. After the first 3 months, 90% showed a positive scan, compared with 86% from months 3 through 6, 75% from months 6 through 12, and 61% for month 12 and beyond.

“Of course, the more aggressive the tumor, the lower the doubling time, the higher the positivity rate. And similarly, if we look at Gleason score, the more aggressive the tumor, the higher the percentage of positivity rate,” Iagaru said. “Now, whereas this positivity was just not unexpected, that number is higher in the prostate gland after radiation therapy. But then once you get into lymph nodes, and bones and other organs, the numbers are pretty similar between the 2 groups.”

F-DCFPyL PET/CT,46% on targeted radiotherapy, 28% on androgen-deprivation therapy, 8% on surveillance, and 18% considered “other,” changed management of their disease after a positive scan, compared with 24%, 7%, and 69%, respectively, who changed treatment management after a negative scan.

F-DCFPyL PET/CT holds great potential to be a ‘one-stop shop’ diagnostic tool in the work-up of BCR prostate cancer to identify possible extra-pelvic oligometastases for locally targeted therapy,” the researchers concluded in their abstract.

1. Song H, Nguyen J, Moradi F, et al. Prospective Evaluation of 

F-DCFPyL PET/CT in Biochemically Recurrent Prostate Cancer: analysis of 18F-DCFPyL uptake in possible extra-pelvic oligometastases. Presented at: 2021 American Urologic Association Annual Meeting; September 10-13, 2021; Virtual. Abstract LBA-02-06.

Articles

The PET agent targeting prostate specific membrane antigen (PSMA) 18F-DCFPyL effectively detected recurrent lesions in prostate cancer patients with biochemical recurrence.

18F-DCFPyL may be “one-stop shop” in detecting recurrence in prostate cancer with BCR

Induction therapy combining avelumab (Bavencio) and BCG appeared to be safe and well tolerated in patients with BCG-unresponsive non–muscle invasive bladder cancer (NMIBC), according to the phase 1b ABC Trial, presented during the 2021 American Urological Association Annual Meeting.

“We know that BCG installation causes a systemic immune response as measured by increased urinary cytokines and serum cytokines that occurs around 4 weeks into induction therapy. We also know that immunotherapy has a time bearing clearance based on pharmacokinetics,” Kelly Stratton, MD, urologic oncologist, Stephenson Cancer Center, University of Oklahoma, explained during a virtual presentation at the meeting.

The aim of the study was to evaluate the optimization of immunotherapy in patients with NMIBC who may require novel dosing regimens linked to BCG administration.

In the trial, patients received induction BCG therapy, followed by maintenance BCG therapy for up to 12 months. At each BCG treatment, patients also received an avelumab infusion. When patients were not receiving BCG, they received avelumab infusions every 2 weeks.

The primary end point of the study was to complete a full induction course within 8 weeks of patients starting treatment, defined as at least 5 of 6 treatments of BCG plus avelumab. Secondary end points included tolerability, measured by the 6-month completion rate (completion of at least 2 of 3 maintenance treatments within a 5-week period at 6 months); 3- and 6-month CR rates; recurrence-free survival; cystectomy-free survival; and overall survival.

Key inclusion criteria consisted of histologically or cytologically documented NMIBC; BCG unresponsive; ECOG performance score of 0 to 2; aged 18 years or older; life expectancy of weeks or more; adequate hematologic and end-organ function; evidence of locally advanced or metastatic bladder cancer; evidence of extravesical bladder cancer; active central nervous system metastases; prior treatment with a PD-L1 inhibitor; and prior radiation to the bladder.

Median age was 70 years (range, 53-84). The majority of patients were male (78%), White (89%), and had T1 stage disease (n = 9).

“This was a heavily pretreated group, with 8 patients receiving multiple BCG induction treatments, and 4 patients previously enrolled on the SWOG 1602 trial,” Stratton said.

In total, 15 of 18 patients (83%) completed induction therapy, 16 patients received at least 5 BCG treatments, and 15 patients received at least 5 avelumab treatments, which exceeded the 60% anticipated completion rate, Stratton said.

At the 3-month cystoscopy, 13 of 15 patients (87%) remained on treatment, 10 of 15 (67%) experienced a complete response (CR), and 3 of 15 had persistent disease.

In addition, 5 patients (28%) have completed 12 months of treatment—all with CRs, and 2 patients remain on treatment.

Serious adverse events (AEs) occurred in 3 patients (17%), including 2 grade 3 AEs during induction (infusion reaction and sepsis) and 1 grade 3 AE during maintenance therapy (myasthenia gravis). No treatment-related grade 4/5 AEs were seen.

“This study evaluated induction therapy with combined BCG and avelumab, which appeared safe and well tolerated in BCG, unresponsive, non-muscle invasive bladder cancer patients,” Stratton said. “This study supports continued efforts to evaluate the optimal dosing regimen to synergize BCG and immunotherapy.”

1. Cookson M, Tripathi A, Patel S, et al. Novel Weekly Immunotherapy Dosing with Avelumab Tolerated During Bacillus Calmette-Guerin Induction Therapy: Initial Results of the ABC Trial. Presented at: 2021 American Urologic Association Annual Meeting; September 10-13, 2021; Virtual. Abstract LBA-02-04.

Data from the phase 1b ABC Trial showed that adding avelumab to BCG induction therapy may be safe and well tolerated in patients with BCG-unresponsive non–muscle invasive bladder cancer.



Avelumab/BCG induction appears safe, tolerable in BCG-unresponsive NMIBC

The use of bone-protecting agents (BPAs) during treatment with radium-223 (Xofigo) plus enzalutamide (Xtandi) controls the risk for fractures in men with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC), according to an updated safety analysis presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

“This safety analysis confirms the importance to give a bone-protecting agent when treating patients with CRPC and bone metastases,” Silke Gillessen, MD, Oncology Institute of Southern Switzerland, said during a presentation of the safety analysis.

In the randomized phase 3 EORTC-1333-GUCG/Peace-3 trial (NCT02194842), investigators randomized patients 1:1 to receive either enzalutamide at 160 mg daily plus radium-223 at 55 kBq/kg every 4 weeks for 6 cycles, or enzalutamide alone.

The study population included patients with bone-predominant mCRPC (≥2 bone metastases); asymptomatic or mildly asymptomatic disease; a WHO performance score of 0 or 1; no prior treatment with cyp17 inhibitors, enzalutamide, other radionucleotides, or hemibody radiotherapy; and no known brain or visceral metastases.

Radiographic progression-free survival served as the primary end point.

Following results of fractures occurring in the ERA223 trial (NCT02043678),

 the investigators of the EORTC-1333-GUCG/PEACE-3 trial decided to send out an urgent safety letter. “In this, it was made mandatory to use a bone-protecting agent in all patients for at least 6 weeks before starting radium-223. In April 2018, an IDMC analysis was done, and the recommendation was to continue the trial, but to use a bone-protecting agent in all patients from both arms,” explained Gillessen. “The IDMC is regularly monitoring the trial, and after the review in December last year, recommended to present the updated numbers regarding bone fractures to the scientific community.”

In her presentation at the 2021 ASCO Annual Meeting, Gillessen offered updated results of the safety analysis from the trial, highlighting the impact of BPAs on fracture rates.

As of the April 2021 cut-off, of the 267 patients randomized to both treatment arms, 74 in each were given BPAs.

Before administering the safety letter, 45.2% of patients had not received a BPA, compared with just 3% who had not after the letter was sent out.

The cumulative incidence of fractures at 1 year was 37.1% (95% CI, 21.3%-53.0%) in the combination arm and 15.6% (95% CI, 5.6%-30.3%) in the enzalutamide alone arm. In men who received a BPA, the 1-year incidence of fractures was reduced to 2.7% (95% CI, 0.5%-8.5%) and 2.6% (95% CI, 0.5%-8.3%), respectively.

At 18 months, the cumulative incidence was 45.9% (95% CI, 28.6%-61.6%) in the combination arm and 21.9% (95% CI, 9.5%-37.5%) in the enzalutamide alone arm, without a BPA. With a BPA, the incidence was 4.3% (95% CI, 1.1%-10.9%) and 2.6% (95% CI, 0.5%-8.3%), respectively.

“According to our study, we will continue and want to motivate all investigators to include [bone-protecting agents in the treatment of] patients. And hopefully, we can still report efficacy results as well. Importantly, the IDMC will also continue to closely monitor the study,” Gillessen said.

Radium-223 is an alpha-emitting radiopharmaceutical that has demonstrated an overall survival benefit in men with mCRPC, with the hypothesis that combining it with a novel androgen receptor (AR) pathway inhibitor could improve clinical outcomes.

In the randomized, double-blind, placebo-controlled ERA223 trial, investigators evaluated the use of concurrent treatment with abiraterone acetate (Zytiga; 1000 mg once daily) plus prednisone (5 mg twice daily) or prednisolone (5 mg twice daily) and radium-223 (55 kBq/kg) in 806 patients with mCRPC.

 Symptomatic skeletal event-free survival served as the primary end point.

BPAs were only permitted in the trial if a patient was receiving them at baseline. Initiation of such agents during the study was prohibited to prevent confounding effects. Therefore, only 60% of patients had not received a BPA at study entry.

In a posthoc analysis of the trial, BPAs significantly reduced the rate of fractures in both treatment arms.

“To better understand the nature of these fractures, an independent review of the fracture events was performed. Interestingly, the maturity of fractures in both groups occurred at sites with no detectable metastasis and were considered osteoporotic or traumatic,” Gillessen explained.

“Treatment with [androgen-deprivation therapy (ADT)] can induce bone loss. And we know that bone-protecting agents can be used in this bone loss and also in osteoporotic fractures in men treated with ADT,” Gillessen said. “Bone protecting agents can also delay the time to a first skeletal-related event [SRE] in men with castration-resistant prostate cancer and bone metastasis.”

Skeletal complications may be common in patients with advanced prostate cancer and result in 2 distinct mechanisms, she added: frailty, or osteoporotic fractures are reported in 11% of patients and SREs occur in up to 40% of those treated with ADT and an AR pathway inhibitor.

“To prevent these SREs, many guidelines recommend using bone-protecting agents for patients with castration-resistant prostate cancer and bone metastasis. Combining gamma radiation and hormonal manipulation is a well validated treatment strategy in prostate cancer,” Gillessen said.

1. Gillessen S, Choudhury A, Rodriguez-Vida A, et al. Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACEIII trial combining Ra223 with enzalutamide versus enzalutamide alone: An updated safety analysis. 

. 2021;39:(suppl 15; abstr 5002). doi: 10.1200/JCO.2021.39.15_suppl.5002.

2. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. 

Adding bone-protecting agents to the treatment of men with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer helped to reduce their risk for fracture.

BPAs reduce fracture risk during radium-223/enzalutamide combo treatment in mCRPC 

Treatment with tivozanib (Fotivda) more than doubled median duration of response (DOR) compared with sorafenib (Nexavar) in patients with metastatic renal cell carcinoma (mRCC), according to long-term durability of response data from the phase 3 TIVO-3 trial presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

“Collectively, these data confirm and extend previous findings for tivozanib as an evidence-based treatment option for patients with relapsed and refractory RCC, including for patients whose disease has progressed after previous checkpoint inhibitor therapy,” the study authors concluded.

At the data cutoff for these analyses (January 15, 2021), the agent demonstrated clinically meaningful and statistically significant improvements in overall response rates (ORR) and duration of response (DOR), with similar overall survival (OS), compared with sorafenib.

Per investigator assessment, 41 (23%) patients in the tivozanib arm experienced a response to treatment, compared with 20 (11%) patients in the sorafenib arm. Similarly, the tivozanib group had a superior disease control rate compared with the sorafenib group (82% vs 69%, respectively), as well as a better partial response rate (23% vs 11%) and stable disease rate (59% vs 58%).

Median DOR was 20.3 months (95% CI, 9.8-29.9) with the potent and highly selective VEGFR TKI tivozanib, compared with 9.0 months with sorafenib (95% CI, 3.7-16.6). Moreover, 13 (7%) patients treated with tivozanib had continued ongoing responses at the time of data cutoff—32% of the response group—compared with 3 (2%) patients treated with sorafenib.

With the prolonged follow-up, tivozanib demonstrated superior OS, compared with sorafenib (HR, 0.91; 95% CI, 0.716-1.165; 

 = .47); however, this did not reach statistical significance.

“[A] statistically significant improvement in PFS and ORR had previously been shown and continues to improve with longer follow-up,” the study authors wrote. “OS relative to sorafenib continues to improve with longer follow-up.”

In the open-label, randomized-controlled phase 3 TIVO-3 trial (NCT02627963), investigators compared the efficacy and safety of tivozanib with sorafenib as a third- or fourth-line therapy in patients with metastatic RCC.

 In a poster presentation at the ASCO annual meeting, the study authors reported on the long-term durability of response based on an investigator assessment and updated OS in patients from the trial.

Between May 24, 2016, and August 14, 2017, investigators randomized patients 1:1 to receive treatment with either tivozanib at 1.5 mg orally once daily for 3 weeks on, and 1 week off in 4-week cycles (n = 175) or sorafenib at 400 mg orally twice daily continuously in 4-week cycles (n = 175) until progression or unacceptable toxicity.

Patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk category (favorable, intermediate, or poor), and type of prior therapy (2 prior VEGFR TKIs, VEGFR TKI plus checkpoint inhibitor, or VEGFR TKI plus any other systemic agent). To be eligible for the trial, patients had to have advanced clear cell mRCC, progressed on 2 or 3 prior systemic therapies including 1 or more VEGFR TKIs, and an EGOG performance score of 0 or 1.

Progression-free survival (PFS) by independent review in the intention-to-treat population served as the primary end point. Secondary end points included OS, ORR, DOR, and safety.

Median follow-up was 19.0 months (IQR, 15.0-23.4).

The study authors noted that baseline patient demographics and disease characteristics were balanced and typical of those seen in patients with mRCC. Patients treated with tivozanib were a median age of 62 years (range, 34-88). The majority on the tivozanib arm were male (72%), had intermediate-risk disease (62%), received 2 prior systemic therapies (62%), including 2 VEGFR TKIs (45%).

—showed that median PFS was significantly longer in the tivozanib arm (5.6 months; 95% CI, 5.29-7.33), compared with the sorafenib arm (3.9 months; 95% CI, 3.71-5.55; HR, 0.73; 95% CI, 0.56-0.94; 

 = .016). In addition, ORR was 18% versus 8% (

The most common grade 3/4 treatment-related adverse event (TRAE) in the tivozanib and sorafenib arms was hypertension (20% vs 14%, respectively). Serious TRAEs occurred in 19 (11%) patients treated with tivozanib and in 17 (10%) patients treated with sorafenib. No treatment-related deaths were reported.

As a result of the initial study results, in March 2021, the FDA approved tivozanib for adult patients with relapsed or refractory advanced RCC following 2 or more prior systemic therapies.

“Tivozanib is a potent and highly selective vascular endothelial cell growth factor (VEGFR) tyrosine kinase inhibitor (TKI) with a long half-life that is an effective treatment option for patients with previously treated mRCC,” the study authors wrote, adding that the agent is approved in the EU for patients who are not previously treated with a VEGFR TKI or mTOR inhibitor.

1. Verzoni E, Escudier B, Hutson TE, et al. TIVO-3: Durability of response and updated overall survival of tivozanib versus sorafenib in metastatic renal cell carcinoma (mRCC). 

. 2021;39(suppl 15; abstr 4546). doi:10.1200/JCO.2021.39.15_suppl.4546.

2. Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. 

. 2020;21(1):95-104. doi:10.1016/S1470-2045(19)30735-1.

3. FDA News Release. FDA approves tivozanib for relapsed or refractory advanced renal cell carcinoma. Published:March 10, 2021. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-tivozanib-relapsed-or-refractory-advanced-renal-cell-carcinoma. Accessed June 4, 2021.

Tivozanib is approved by the FDA for the treatment of patients with relapsed or refractory advanced renal cell carcinoma who have received 2 or more prior systemic therapies. 

Kristie L. Kahl

Articles

18F-DCFPyL may be “one-stop shop” in detecting recurrence in prostate cancer with BCR

Avelumab/BCG induction appears safe, tolerable in BCG-unresponsive NMIBC

BPAs reduce fracture risk during radium-223/enzalutamide combo treatment in mCRPC

Long-Term follow-up shows doubled DOR with tivozanib in mRCC