Wayne Kuznar

The FDA has granted a prior review designation to a new drug application (NDA) for the PSMA-targeted PET imaging agent 18F-DCFPyL (PyL) for prostate cancer.

The NDA is supported by data from the OSPREY and CONDOR studies. In the CONDOR study, 63.9% of men with biochemically recurrent prostate cancer who had no evidence of disease on standard-of-care imaging had a change in intended management after their 18F-DCFPyL–PET/CT scan.

Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the NDA by May 28, 2021.

“We are pleased that the FDA has accepted our PyL NDA for review and granted our application priority review, which is a significant milestone for Lantheus. We believe that there is a significant unmet need for reliable, targeted imaging in prostate cancer, particularly in the high risk and biochemically recurrent populations,” Istvan Molnar, MD, chief medical officer of Lantheus (Progenics), the manufacturer of PyL stated in a press release.

The multicenter phase 3 CONDOR study enrolled men with rising PSA after definitive therapy and negative or equivocal standard-of-care imaging. Patients were required to have a PSA level ≥0.2 if they had undergone radical prostatectomy (RP) or a PSA level ≥2.0 if they were treated with radiation therapy or cryotherapy.

The primary end point was correct localization rate (CLR), defined as percentage of patients with a 1:1 correspondence between at least 1 lesion identified by PyL–PET/CT and the composite standard of truth (pathology, correlative imaging, or PSA response). PyL scans were read by 3 blinded independent central readers.

Overall, there were 208 evaluable patients, about 85% of whom underwent RP, either alone or with radiation. Median PSA level of the cohort was 0.8 ng/mL, and 68.8% had a PSA level <2.0 ng/mL. Some 27.9% had received at least 1 prior systemic therapy.

Detection of disease as manifested by a positive 18F-DCFPyL–PET/CT scan was 65.9%, 59.6%, and 59.1% by the 3 readers.

The prespecified criterion for CLR success was for the lower limit of the 95% CI to exceed 20% for at least 2 of the 3 readers. For every reader, the lower bound of the 95% CI for the CLR was well in excess of the 20% benchmark, meeting the primary end point of the study.

The CLRs were 85.6% (95% CI, 78.8%-92.3%), 87.0% (95% CI, 80.4%-93.6%), and 84.8% (95% CI, 77.8%-91.9%) by the 3 readers.

Some 64% of the evaluable patients had a change in intended management due to the scan.

In the phase 2/3 OSPREY trial, PyL was assessed in 2 patients cohorts. Cohort A included men with high-risk, locally advanced prostate cancer, and the researchers assessed the capacity of PyL to detect prostate cancer in pelvic lymph nodes. Cohort B comprised patients with metastatic or recurrent disease and the researchers examined the performance of PyL in detecting distant metastases.

In cohort A, results for PyL in detecting disease in pelvic lymph nodes showed a specificity of 96%-99%, a sensitivity of 31%-42%, and positive predictive value (PPV) of 78%-91%. The sensitivity and PPV rates for detecting metastatic lesions in cohort B were 93%-99% and 81%-88%, respectively.

 as the first drug for PET imaging of PSMA-positive lesions in men with prostate cancer.

1. PDUFA action date of May 28, 2021 assigned by U.S. Food and Drug Administration. Published online December 9, 2021. https://bit.ly/2KtYerG. Accessed December 14, 2021.

2. Morris M, Carroll P, Saperstein L, et al. Impact of PSMA-targeted imaging with 18F-DCFPyL-PET/CT on clinical management of patients (pts) with biochemically recurrent (BCR) prostate cancer (PCa): results from a phase III, prospective, multicenter study (CONDOR). 

. 2020;38(15 suppl; abstr 5501). doi:10.1200/JCO.2020.38.15_suppl.5501

Articles

The new drug application for 18F-DCFPyL is supported by results from the OSPREY and CONDOR trials. 

FDA grants priority review to PSMA PET imaging agent 18F-DCFPyL for prostate cancer

Women with pelvic organ prolapse are more likely to have persistent overactive bladder (OAB) symptoms after transvaginal mesh surgery if they have a high versus low preoperative Overactive Bladder Symptom Score (OABSS) and International Prostate Symptom Score (IPSS).

In a retrospective study of 102 patients who underwent transvaginal mesh surgery by a single surgeon, a preoperative IPSS storage subscore ≥10 was the most useful predictive factor for the persistence of preoperative OAB symptoms after surgery, reported Atsushi Otsuka, from Hamamatsu University, Hamamatsu, Japan, and colleagues in the journal 

“Interestingly, the present study demonstrated that the preoperative IPSS voiding subscore was also a useful predictive factor for the persistence of preoperative OAB symptoms after surgery although the predictive power did not exceed the preoperative IPSS storage subscore,” the authors wrote. “Although IPSS may not be familiar to gynecologists and urogynecologists, this minimally invasive self-reported questionnaire is useful in counseling preoperative pelvic organ prolapse patients with OAB symptoms.”

The investigators found that among the 54 women in the study with OAB, 20 (37%) had persistent symptoms after surgery, while 34 (63.0%) saw their symptoms disappear.

Among the 20 patients with persistent OAB symptoms postoperatively, 15 had an improvement in their OAB symptoms, while the remaining 5 had unchanged or worsened symptoms.

Total OABSS was significantly higher in patients with persistent preoperative OAB symptoms than in patients without persistent symptoms. On the IPSS, the total score, voiding and storage subscores, and individual component scores were significantly higher in patients with persistent preoperative OAB symptoms than in patients without them.

According to the receiver operating characteristics (ROC) analysis, the area under the curve (AUC) was 0.768 (95% CI, 0.640-0.896; 

 = .001) for total IPSS; 0.819 (95% CI, 0.694-0.944; 

 <.001) for IPSS storage subscore; 0.735 (95% CI, 0.596-0.873; 

 = .004) for IPSS voiding subscore; and 0.693 (95% CI, 0.550-0.835; 

The cutoff value for the IPSS storage subscore that indicated nearly equivalent sensitivity and specificity and that retained the greatest efficiency was 9.5.

The sensitivity of the IPSS storage subscore was 68.4% (95% CI, 43.5-87.4), the specificity was 91.2% (95% CI, 76.3-98.1), the positive predictive value was 81.3% (95% CI, 54.4-96.0), and the negative predictive value was 83.8% (95% CI, 68.0-93.8).

The sensitivity and specificity at the of the preoperative IPSS voiding subscore at the cutoff value of 7.5 was 60.0% and 70.6%, respectively.

“In contrast, several preoperative parameters (age, body mass index, parity, pelvic organ prolapse stage) had no significant impact on the persistence of preoperative OAB symptoms,” Otsuka et al wrote.

They continued, “An advantage of the present study is that minimally invasive self-reported questionnaires were used to determine predictive factors for persistence of preoperative OAB symptoms after pelvic organ prolapse surgery. Further, all patients underwent the same surgical procedure using transvaginal mesh by a single surgeon, reducing bias engendered by the type of vaginal surgery.”

Limitations of the research included the retrospective design and the absence of urodynamic study to evaluate detrusor overactivity and bladder outlet obstruction.

The percentages of patients who had relief of symptoms and persistent symptoms postoperatively “are in line with those generally reported for OAB symptom resolution following surgery for significant prolapse,” Alan J. Wein, MD, PhD (hon), co-director of the Voiding Function and Dysfunction Program at Penn Medicine, Philadelphia, wrote in an editorial comment on the research published in the 

. “It is generally agreed that parity and body mass index are not predictive for OAB symptoms after prolapse surgery,” added Wein.

1. Otsuka A, Watanabe K, Matsushita Y, et al. Predictive factors for persistence of preoperative overactive bladder symptoms after transvaginal mesh surgery in women with pelvic organ prolapse. 

. 2020;12:167-172. doi: 10.1111/luts.12299

. 2020;204(3):623-624. doi: 10.1097/JU.0000000000001180

“Although IPSS may not be familiar to gynecologists and urogynecologists, this minimally invasive self-reported questionnaire is useful in counseling preoperative pelvic organ prolapse patients with OAB symptoms," researchers write.

Preoperative bladder symptom score best predictor of transvaginal mesh surgery success 

Litoxetine, an investigational oral selective serotonin reuptake inhibitor and multifunctional serotonin agonist and antagonist, significantly reduced the rate of incontinence events and was safe and well tolerated in a placebo-controlled randomized phase 1/2 study of patients with urinary incontinence.

After 8 weeks of treatment, litoxetine at a dosage of 30 mg twice daily reduced the number of incontinence events by 1.96/day compared with a reduction of 0.76 events/day in patients randomized to placebo, for a treatment difference of 1.19 events/day (

 = .017). In addition, 21.6% of subjects in the litoxetine arm versus 0% in the placebo arm became continent following treatment (

 = .043), reported Roger Dmochowski, MD, at the 2020 European Association of Urology Virtual Congress.

“Overall, there was significant reduction in incontinence episodes in the active arm versus the placebo arm,” said Dmochowski, professor, Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville. “This particular serotonin reuptake inhibitor was safe and well tolerated with twice daily administration in the study population as defined. Tolerability was further improved by a dose escalation regimen and a fixed dose overall period for exposure. Litoxetine also significantly decreased incontinence episode frequency as compared to placebo.”

The therapeutic potential of litoxetine given twice daily was assessed in 84 patients aged 18 to 70 years old with urinary incontinence, defined as ≥7 incontinence episodes per week. Study subjects were entered into a 2-week screening placebo run-in period followed by 8 weeks of double-blind treatment during which they were randomized 2:1 to a dose-titration schema of litoxetine (n = 53) or placebo (n = 29). Patients randomized to litoxetine received 10 mg twice daily for 1 week followed by 20 mg twice daily for 1 week, and subsequently 30 mg twice daily for 6 weeks. Treatment was followed by a 1-week dose tapering period and 4 weeks of safety follow-up. Two patients were not treated due to randomization error. Incontinence events were measured by patient bladder diary.

Patients’ median age was 58.5 years, their median body mass index was 29.8 kg/m2, and median incontinence episode frequency was 17.5 events/week at baseline. About one-fourth (26%) were men.

In the randomized phase 1 portion of the study, in the overall study population, the decrease in the rate of incontinence events per week by dosage was 1.97 with 40 mg twice daily litoxetine, 1.94 with 20 mg twice daily, and 1.59 with 10 mg twice daily, compared with 1.37 in the placebo arm.

In patients with more severe urinary incontinence, the rate of incontinence events was reduced by 3.72/week with 40 mg twice daily of litoxetine (

 <.05 vs placebo), 3.53/week with 20 mg twice daily of litoxetine (

 <.05 vs placebo), 2.60/week with 10 mg twice daily of litoxetine, and 2.02/week in the placebo recipients.

The effect of litoxetine on incontinence episodes was found to be similar between men and women.

Scores on the Patient’s Perception of Bladder Condition (PPBC) showed gradual improvement from baseline to assessments made at weeks 4, 8, and 12. Following the treatment period, 56% of patients who receive 40 mg twice daily of litoxetine and 32% of patients assigned to placebo reported “no/very minor/some minor problems” on the PPBC.

Up to 71% of patients treated with 40 mg twice daily of litoxetine had a clinically significant improvement of ≥15% in the King’s Health Questionnaire (KHQ). More than 70% of the litoxetine group, irrespective of dosage, had an improvement of ≥10 units on the general health domain of the KHQ, versus 54% of the placebo group; 64% to 82% of litoxetine recipients had a ≥10-unit improvement on the physical limitations domain, versus 63% of the placebo group; 72% to 79% of those assigned to one of the litoxetine groups had a ≥10-unit improvement on the emotions domain, compared with 63% of the placebo group; and 59% to 74% of the litoxetine group had a ≥10-unit improvement on the sleep/energy domain versus 59% of the placebo arm.

Litoxetine was well tolerated: 3.8% of the patients on litoxetine discontinued the study due to a treatment-emergent adverse event (TEAE) compared with 3.4% of the placebo recipients. Some 37.7% of patients assigned to litoxetine and 34.5% assigned to placebo reported a TEAE. On logistic regression analysis, there was no statistical difference in TEAEs between study arms. Psychiatric evaluations did not show any difference between study groups. There were no serious adverse events in either arm.

Dmochowski is a scientific advisor to Ixaltis SA.

Dmochowski R. Litoxetine (LTX) shows significant treatment effect in urinary incontinence (UI). 2020 European Association of Urology Virtual Congress. July 17-26, 2020. Abstract 358.

<<<More from the 2020 EAU Annual Congress

Treatment with litoxetine, an investigational oral selective serotonin reuptake inhibitor, led to nearly 22% of patients becoming continent. 

Litoxetine reduces rate of incontinence episodes

Two-year data from the blinded, randomized WATER study showed similar durable outcomes between aquablation and transurethral resection of the prostate (TURP) as treatments for men with moderate-to-severe lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia. Retreatment rates were low for both arms of the study, said Neil Barber, BSc, MB, BS, during the 2020 European Association of Urology Virtual Congress.

At 2 years of follow-up, the mean International Prostate Symptom Score (IPSS) was similarly improved in men randomized to either aquablation or TURP. Men randomized to aquablation experienced a reduction in mean IPSS from 22.9 at baseline to 8.3 at 2 years (improvement of 14.6 points), and men randomized to TURP had a reduction from a mean of 22.0 at baseline to 7.0 (improvement of 15.0 points) at the 2-year follow-up (

“Aquablation of the prostate achieved exactly the same improvements in IPSS at 6 months and this is maintained out to 2 years. When one looks at the subanalysis of storage and voiding symptoms from the IPSS questionnaire, we see similar mirroring of improvement,” said Barber, consultant urologist, Weymouth Street Hospital, London, UK.

The global phase 3 WATER study randomized 184 men with moderate-to-severe LUTS related to BPH and a prostate volume of 30 to 80 mL to aquablation using the AquaBeam system (n = 117) or TURP (n = 67). Mean age at baseline was about 66 years, mean prostate volume was 54.1 mL in the aquablation arm and 51.8 mL in the TURP arm, and slightly more than half in each arm had a middle lobe.

Assessments included the IPSS, Male Sexual Health Questionnaire (MSHQ), International Index of Erectile Function (IIEF), and uroflow. WATER demonstrated that aquablation was noninferior to TURP on the primary efficacy study end point of reduction in IPSS at 6 months. In addition, aquablation proved superior (

 = .0149) for the primary safety end points of incontinence, erectile dysfunction, ejaculatory dysfunction, and events requiring pharmacologic treatment, blood transfusion, or endoscopic, surgical, or radiologic intervention as assessed by the Clavien-Dindo classification. Of the patients who underwent aquablation and transurethral prostate resection, 26% and 42%, respectively, experienced a primary safety end point at 3 months.

In addition to improvement on the IPSS, 2-year improvements in maximum flow rate (Qmax) were similarly large in both groups: 11.1 cc/sec in the aquablation arm versus 8.7 cc/sec in the TURP arm (

 = .1902). At 2 years, serum prostate-specific antigen level was reduced significantly in both groups, by 0.7 and 1.1 points, respectively (

 = .3930), “suggesting equivalent prostate volume reduction using this surrogate marker,” said Barber. The 2-year retreatment rates were 4.3% for aquablation and 1.5% for TURP.

“Complication rates in terms Clavien-Dindo 2+ were equivalent between both groups, but there was an advantage overall in terms of complications for aquablation over TURP thanks to a lower risk of negative impact upon erectile dysfunction and dry ejaculation on the whole,” said Barber. Scores on the MSHQ were stable in the aquablation arm and decreased slightly in the TURP arm.

Another advantage to aquablation is that prostate size has little to no influence on the length of the procedure, he said.

Among the plethora of options for treatment of BPH, “I would offer [aquablation] to anybody you might offer a TURP or a laser to, who is particularly keen on reducing his risk of essentially dry ejaculation,” he said. “There are some caveats to that. I have stayed away from patients who are taking anticoagulants, and from my experience, that’s not an insignificant portion of patients. Beyond that, you could offer it to anybody. The real dilemma is there are potentially clear advantages in the very large prostate, once you mover over 80 or 100 mL, but it’s really that range of 50 to 80 mL where there are many options available in the guidelines, be it minimally invasive surgical treatments like UroLift and Rezum versus cavitating options including aquablation.”

Barber N, Gilling P, Bidair M, et al. Two-year outcomes after aquablation compared to TURP: Results from a blinded randomized trial. 2020 European Association of Urology Virtual Congress. July 17-26, 2020. Abstract 201.

Retreatment rates were low with both aquablation and transurethral resection of the prostate.

Wayne Kuznar

Articles

FDA grants priority review to PSMA PET imaging agent 18F-DCFPyL for prostate cancer

Preoperative bladder symptom score best predictor of transvaginal mesh surgery success

Litoxetine reduces rate of incontinence episodes

Improvement in LUTS with aquablation maintained to 2 years with lower risk of sexual dysfunction versus TURP