The utilization of mitotane (Lysodren) in the adjuvant setting did not produce significant benefit for patients with adrenocortical carcinoma (ACC) at low or intermediate risk of recurrence, according to findings from the phase 3 ADIUVO trial (NCT00777244) presented at the 2022 ASCO Genitourinary Cancer Symposium.

“Adrenocortical carcinoma is an extremely rare malignancy with an expected incidence of about 0.7 [to] 2 new cases per million population per year in the western countries,” explained lead author Alfredo Berruti, MD, during the presentation of the data. “Surgery is the main stay of therapy; however, due to the rarity, the diagnosis is often delayed so that the surgery is usually feasible in about 50% of patients [who] have presentation. Even if radically operated [on, patients with] adrenocortical carcinoma are at high risk of relapse.”

Ninety-one patients were enrolled in ADIUVO, all of whom had stages I to III ACC, had undergone R0 resection, and had a Ki-67 percentage of 10.

Of the enrolled patients, 45 received adjuvant mitotane and 46 were observed. The median age (51 vs 50.5 years for the mitotane and observation arms, respectively), gender proportion (female, 73% vs 67%), percentage of patients with stage I ACC (20% vs 26%), percentage of patients with stage II ACC (67% vs 63%), percentage of patients with stage III ACC (13% vs 11%), ACC secretion (44% vs 36%), and Weiss score (5 vs 5) were relatively matched for both arms.

Patients were randomized 1:1 to adjuvant mitotane or active surveillance. Those who received adjuvant mitotane were administered a starting dose of 1.5 g per day, and if tolerated well, an increased dose from 2 g to 3 g per day on day 2, an increased dose of 3 g to 4.5 g per day on day 3, and an increased dose of 4 g to 6 g per day on day 4. After reaching 6 g per day, patients were administered this dose until first mitotane blood level was estimated.

The primary end point of ADIUVO was recurrence-free survival (RFS), and the secondary end points were overall survival (OS) and safety.

If patients refused randomization, they were eligible for enrollment in the ADIUVO OBSERVATIONAL study. This was a prospective study, where patients were managed in parallel with the ADIUVO study without the aspect of randomization. Of these patients, 42 received adjuvant mitotane and 53 went untreated. Similarly, baseline characteristics were matched between the 2 arms. This cohort was evaluated with the ADIUVO cohort to make up for low patient recruitment.

Results of the ADIUVO study showed that there were 8 recurrences in the adjuvant mitotane arm and 11 recurrences in the observation arm at a median follow up of 48 months. There were also 2 deaths in the adjuvant mitotane arm and 5 deaths in the observation arm; however, there was no significant difference between the RFS and OS when comparing the 2 arms.

In addition, investigators found that the HR for recurrence was 1.321 (95% CI, 0.55-3.32; 

 = .54) and the HR for death was 2.171 (95% CI, 0.52-12.12; 

As for the ADIUVO OBSERVATIONAL study, results confirmed those of ADIUVO. The number needed to treat (NNT) was determined as 55.

Given a 5-year RFS of 75%, the authors of this study pointed out that the findings do not support postoperative adjuvant mitotane treatment in patients with ACC at low-intermediate risk of recurrence, and that these outcomes provide “an important step toward personalization of ACC care.”

In his concluding remarks, Berruti said, “Of course, the smaller size than planned due to early interruption and the low accrual rate is the main limitation of this trial, however it should be noted that patients meeting the eligibility criteria of the ADIUVO trial have a relatively good outcomes, since they have a 25% risk of relapse and 14% risk of death at 5 years. So, 70% of patients could potentially be cured with surgery only.”

Berruti A, Fassnacht M, Libè R, et al. First randomized trial on adjuvant mitotane in adrenocortical carcinoma patients: The Adjuvo study. Paper presented at: 2022 ASCO Genitourinary Cancers Symposium; February 17-19, 2022; San Francisco, California. Abstract 1.

Articles

The utilization of mitotane in the adjuvant setting did not produce significant benefit for patients with adrenocortical carcinoma at low or intermediate risk of recurrence.

Adjuvant Mitotane Fails to Improve RFS in Patients with ACC at Low/Intermediate Risk of Recurrence

F-rhPSMA-7.3 imaging displayed a clinically meaningful correct detection rate (CDR), meeting the prespecified threshhold of assessing suspected biochemical recurrence in prostate cancer, according to findings from the phase 3 SPOTLIGHT trial (NCT04186845) presented at the ASCO 2022 Genitourinary Cancers Symposium.

“There’s excellent image quality,” said coordination investigator David M. Schuster, MD, FACR, Emory University School of Medicine, “and also the potential for low urinary secretion, which, as we know, is important for imaging prostate cancer.”

F-rhPSMA-7.3, an investigational prostate‐specific membrane antigen (PSMA)‐targeted radiohybrid (rh) PET imaging agent, demonstrated an overall evaluable detection rate (DR) in this study population of 83% by majority read.

“Up to 40% of patients who undergo radical prostatectomy, and up to 50% of patients who undergo radiation therapy will develop local or distant recurrences within 10 years, and the ability to determine the extent and location of recurrent prostate cancer to inform appropriate clinical management for these men is key for physicians and their patients,” Schuster, said in a press release issued by Blue Earth Diagnostics.

 “Conventional imaging techniques have many limitations in prostate cancer identification and localization, and greater imaging accuracy is needed throughout the care continuum, to optimize therapeutic decision‐making.”

Therefore, researchers aimed to evaluate 

F‐rhPSMA‐7.3 PET imaging as a potential decision‐making aid to determine suspected biochemical recurrence of prostate cancer across a wide PSA range.

In the prospective, multicenter, single‐arm imaging study, conducted in the United States and Europe, 389 men (median PSA, 1.10 ng/mL [range, 0.03-134.6]) were enrolled. To meet the inclusion criteria, patients had to be male, over the age of 18, have a history of localized prostate cancer with prior curative intent treatment, have an elevated PSA suspicious of biochemical recurrence, and be potentially eligible for salvage therapy with curative intent.

Following an IV administration of 296 MBq 

F-rhPSMA-7.3, patients underwent PET for 50 to 70 minutes. At 60 days post-PET, investigators performed image-guided biopsies of PET lesions. At 90 days post-PET, investigators performed any confirmatory imaging. Scans were evaluated by 3 blinded central readers, with a final consensus of “majority read”. Each patient also underwent a separate Standard of Truth (SoT) via Truth Panel.

The coprimary endpoints were patient level CDR, or percentage of patients scanned with 1 true positive lesion, and region level positive predictive value (PPV), which was determined for all PET positive regions combined using histopathology and/or conventional imaging as a composite SoT. Analysis of these metrics were also performed in a group of patients with a histopathology-only SoT.

A strict imputation method was implemented in both primary end points, in which PET-positive lesions that were proven on conventional imaging were considered false positive, and the prespecified statistical threshold for CDR and PPV were set to 36.5% and 62.5%, respectively.

Results showed that the patient level CDR was 56.8% (95% CI, 51.6%-62.0%) in the 366 men (median PSA, 1.27 ng/mL [range, 0.03-134.6]) with a composite SoT. While this finding met the prespecified threshold, the region level PPV did not (59.7%; 95% CI, 54.7%-64.7%]).

However, Schuster said, “Keep in mind [that] the data from this cohort with a composite Standard of Truth are limited by the high proportion of scans, especially those of the prostate [and] bed that relied on conventional imaging, which is a suboptimal Standard of Truth in itself.”

Furthermore, investigators found that the patient level CDR was 81.2% (95% CI, 69.9%-89.9%) and the region level PPV was 71.6% for the subset of patients with a histopathology-only SoT. Both percentages would have met their prespecified thresholds.

There were no serious adverse events (AEs) related to 

F-rhPSMA-7.3. The most frequently reported AEs were hypertension (1.8%; n = 7), diarrhea (1.0%; n = 4), injection site reaction (0.5%; n = 2), and headache (0.5%; n = 2). In total, 4.1% of patients (n = 16) had at least 1 AE that could possibly be related to the novel theranostic.

In his concluding remarks, Schuster said, “Together, these data support the clinical utility of 

F-rhPSMA-7.3 PET in men with recurrent prostate cancer across a wide PSA range.”

F-rhPSMA-7.3 PET in Patients with Suspected Prostate Cancer Recurrence: Results from a Phase 3, Prospective, Multicenter Study (SPOTLIGHT). Paper presented at: 2022 ASCO Genitourinary Cancers Symposium; February 17-19, 2022; San Francisco, California. Abstract #9.

Blue Earth Diagnostics Press Release. Blue Earth Diagnostics Announces Key Results from Phase 3 SPOTLIGHT Study of 

F‐rhPSMA‐7.3, an Investigational PET Imaging Agent, in Biochemical Recurrence of Prostate Cancer. Published February 15, 2022. Accessed February 18, 2022. 

The utilization of 18F-rhPSMA-7.3 imaging displayed a clinically meaningful correct detection rate.

18F-rhPSMA-7.3 Imaging Favorable Detection Rates in Men with Recurrent Prostate Cancer

The combination of pembrolizumab (Keytruda) plus olaparib (Lynparza) produced promising antitumor activity in men with molecularly unselected docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC), according to results study presented at the 2021 European Society for Medical Oncology (ESMO). 

At a minimum of 11.4 months follow-up, 15 out of 102 patients (14.7%) from cohort A of the phase 1b/2 KEYNOTE-365 trial (NCT02861573) exhibited a confirmed prostate-specific antigen (PSA) response, with an overall response rate of 6.9% and a disease control rate of 26.5%.

A total of 102 patients received treatment. Those who were treated received pembrolizumab on the first day of every 3-week dosing cycle for up to 35 weeks (approximately 2 years) and olaparib, 400-mg (first 41 patients enrolled) capsules or 300-mg tablets orally twice a day continuously. Treatment was discontinued when there was confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients who discontinued 1 drug were permitted to continue the other until discontinuation from the previously stated criteria.

Over the course of the study, 52 patients discontinued treatment due to progressive disease, 19 discontinued due to clinical progression, 17 discontinued due to adverse events (AEs), 3 discontinued due to withdrawal of consent, and 1 discontinued due to the physician’s decision.

Median age of enrolled patients was 69.5 years (range, 47-84 years), median initial PSA value was 109.4 ng/mL (range, 1.2-5000.0 ng/mL), 58 patients (56.9%) had measurable disease, and 40 patients (39.2%) had previously been treated with cabazitaxel (Jevtana). Additionally, 24 patients (23.5%) had previously been treated with abiraterone (Zytiga) only, 24 (23.5%) had previously been treated with enzalutamide (Xtandi) only, and 46 patients (45.1%) had previously been treated with both.

Confirmed response rate was 19.0% (11/58) in patients with measurable disease and 9.1% (4/44) in patients with nonmeasurable disease. In patients with both measurable and nonmeasurable disease, PSA reduction from baseline was 50.0% (51/102) and the median time to PSA progression was 4.0 months (range, 3.0-4.9 months).

Other outcomes include target lesion change from baseline for patients with both measurable and nonmeasurable disease, which was 58.6% (34/58), as well as Kaplan Meier estimates of median radiographic progression-free survival (rPFS) and overall survival (OS), which was 5.2 months (range, 4.1-6.5 months) and 14.4 months (range, 10.4-17.9 months), respectively.

Overall, 93 patients (91.2%) experienced treatment-related AEs (TRAEs) of any grade and 49 patients (48.0%) experienced grades 3 to 5 TRAEs. The most-experienced TRAEs were anemia (41.2% any grade, 27.5% grade 3-5), nausea (41.2% any grade, 2.0% grade 3-5), decreased appetite (30.4%any grade, 0.0% grade 3-5), and fatigue (30.4% any grade, 5.9% grade 3-5). Six patients died of AEs, 2 of which were considered treatment-related and the remaining 4 not treatment-related. Immune-mediated AEs were also experienced among patients, with 12 (11.8%) patients experiencing any grade of any immune-mediated AE and 4 (3.9%) experiencing grades 3 to 5 immune-mediated AEs.

“The safety and tolerability profile of pembrolizumab plus Olaparib therapy is consistent with the individual profiles of each agent…The promising rPFS and overall survival data support further evaluation of pembrolizumab plus olaparib in molecularly unselected patients with mCRPC who received prior docetaxel treatment,” the authors concluded.

The phase 3 KEYLYNK-010 trial (NCT03834519) is currently investigating the combination of pembrolizumab plus olaparib vs abiraterone or enzalutamide in patients with mCRPC who have previously been treated with abirtaterone or enzalutamide. It is a randomized, global, parallel-group, double-blind study.

Yu E, Piulats JM, Gravis G, et al. Pembrolizumab (pembro) plus olaparib in patients with docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC): update of KEYNOTE-365 Cohort A with a minimum of 11 months of follow-up for all patients. Paper presented at 2021 European Society for Medical Oncology Annual Meeting; September 16-21, 2021; virtual. Abstract 612P

The combination of pembrolizumab plus olaparib produced promising antitumor activity in men with molecularly unselected docetaxel-pretreated metastatic castration-resistant prostate cancer. 

Pembrolizumab/Olaparib Combo Shows Promising Antitumor Activity in mCRPC

The combination of olaparib (Lynparza) and pembrolizumab (Keytruda) continued to demonstrate antitumor activity in patients with metastatic castration-resistant prostate cancer (mCRPC) who previously received docetaxel, according to updated data from the ongoing phase 1b/2 KEYNOTE-365 trial presented during the 2021 AUA Annual Meeting.

“With a minimum of 11.4 months follow-up, pembrolizumab plus olaparib demonstrated antitumor activity and an acceptable safety profile for men with molecularly unselected, docetaxel-pretreated mCRPC,” said author Luke T. Nordquist, MD, FACP, medical oncologist and CEO of the Urology Cancer Center & GU Research Network, Omaha, Nebraska.

The KEYNOTE-365 trial (NCT02861573) was launched to assess the efficacy and safety of the olaparib/pembrolizumab regimen in patients with mCRPC. Prior results shared from cohort A showed promising clinical activity in molecularly unselected patients who had previously received docetaxel.

In the study, at a mean follow-up of 19.3 months (range, 11.4-45.9), patients received 200 mg of pembrolizumab intravenously every 3 weeks and 400 mg or 300 mg of olaparib orally twice daily, until disease progression, unacceptable toxicity, or withdrawal of consent. Standard bone scanning, CT, or MRI were also performed every 9 weeks for 54 weeks, and then every 12 weeks until disease progression. Primary end points were prostate-specific antigen (PSA) response rate, objective response rate determined by RECIST v1.1 through a blinded independent central review, and safety. Secondary end points included time to PSA progression, disease control rate, duration of response, radiographic progression-free survival, and overall survival.

“Cohort A of KEYNOTE-365 examined specifically the safety and efficacy of the combination of pembrolizumab and olaparib in molecularly unselected patients with mCRPC,” Nordquist said.

Patients were enrolled if they had molecularly unselected, docetaxel-pretreated mCRPC that had progressed within 6 months of screening. They also must have been treated previously no more than once with chemotherapy for mCRPC and no more than twice with second-generation hormonal therapies.

Of the 104 patients who enrolled, 102 were treated and 92 discontinued their treatment, mainly due to the progression of their disease (51%). Median age of enrolled patients was 69.5 years (range, 47-84), 29 patients (28.4%) were PD-L1 positive, 34 (33.3%) had visceral disease, and 58 (56.9%) had measurable disease. Twenty-four patients (23.5%) had previously been treated with abiraterone (Zytiga) only, 24 (23.5%) had previously been treated with enzalutamide (Xtandi) only, and 46 patients (45.1%) had previously been treated with both.

PSA response rate in all patients with a PSA measurement at baseline (n = 102) was 14.7% (95% CI, 8.5-23.1) and in the 58 pts who had measurable disease, confirmed objective response rate was 6.9% (95% CI, 1.9-16.7; 4 partial responses).

“The overall disease control rate was 26% for the total population, and clinical activity was consistent across PD-L1 and HR mutation subgroups,” Nordquist said.

Additionally, investigators found the median time to PSA progression was 4 months (range, 3.0-4.9 months), the median duration of response was not reached (range, 7.2+ to 37.8+ months), the disease control rate was 26.5% (95% CI, 18.2-36.1), the median radiographic progression-free survival was 5.2 months (range, 4.1-6.5) and the median overall survival was 14.4 months (range, 10.4-17.9).

There were high rates of treatment-related adverse events (TRAEs), which occurred in 93 patients (91.2%). The most frequent AEs (≥30%) were anemia (41.2%), nausea (41.2%), decreased appetite (30.4%), and fatigue (30.4%). A smaller, but significant rate of grade 3-5 TRAEs occurred in 49 patients (48.0%). Six patients (5.9%) died of AEs and 2 deaths were treatment related.

“The safety profile of pembrolizumab plus olaparib in combination is consistent with individual profiles of each agent. These results do support further evaluation of this combination in mCRPC,” concluded Norquist.

The phase 3 KEYLYNK-010 trial (NCT03834519) will further investigate pembrolizumab plus olaparib by comparing their efficacy vs abiraterone or enzalutamide in abiraterone- or enzalutamide-pretreated patients with mCRPC who have experienced disease progression on or after docetaxel for mCRPC.

Nordquist LT, Yu EY, Piulats JM, et al. Pembrolizumab (Pembro) plus olaparib in patients with docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC): updated results from KEYNOTE-365 cohort A with a minimum of 11 months of follow-up for all patients. Paper presented at the 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract MP24-14

Yu EY, Piulats JM, Gravis G, et al. KEYNOTE-365 cohort A updated results: Pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). 

 2020;38(suppl 6):100. doi:10.1200/JCO.2020.38.6_suppl.100

Yu EY, Massard C, Retz M, et al. Keynote-365 cohort a: Pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC). 

2019;37(suppl 7):145. doi:10.1200/JCO.2019.37.7_suppl.145

The combination of olaparib and pembrolizumab continued to demonstrate antitumor activity in patients with metastatic castration-resistant prostate cancer who previously received docetaxel.

Janelle Hart

Articles

Adjuvant Mitotane Fails to Improve RFS in Patients with ACC at Low/Intermediate Risk of Recurrence

18F-rhPSMA-7.3 Imaging Favorable Detection Rates in Men with Recurrent Prostate Cancer

Pembrolizumab/Olaparib Combo Shows Promising Antitumor Activity in mCRPC

Olaparib/Pembrolizumab Combo Continues to Show Promising Activity in mCRPC