Olaparib Bolsters Lutetium Lu 177 Vipivotide Tetraxetan Activity in mCRPC

Shahneen Sandhu, PhD, MBBS, FRACP

Enhanced antitumor activity was shown with the addition of the PARP inhibitor olaparib (Lynparza) to the radioligand lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617) in patients with metastatic castration-resistant prostate cancer (mCRPC), according to early findings from the phase 1 LuPARP study (NCT03874884).¹

Among 32 patients treated across dose levels, the prostate-specific antigen (PSA) response rate of at least 50% was observed in 66% of patients, with 14 of the 32 patients (44%) achieving a PSA response of at least 90%. The overall response rate was 78%. Further, safety findings showed that no dose-limiting toxicities were reported across dose levels.¹

“I think this is intriguing data, although early, but may be suggestive of a deepening of responses from the combination therapy,” Shahneen Sandhu, PhD, MBBS, FRACP, said in a presentation of the data during the 2023 ASCO Annual Meeting. “And the reason that’s important is we do know, based on other data sets, that a PSA response of 90% does in fact, translate into improved progression-free survival [PFS].”

“Lutetium-PSMA-617 is a radioligand therapy that is directed to prostate-specific membrane antigen [PSMA] and has previously been shown to improve both PFS and overall survival [OS],” Sandhu, who is an associate professor in the Department of Medical Oncology and a consultant medical oncologist and researcher in the melanoma and uro-oncology units at the Peter MacCallum Cancer Center in Melbourne, Australia said.

“Olaparib is a potent PARP inhibitor that has also been shown to improve PFS and OS in men with mCRPC with an underlying DNA repair defect or homologous recombination repair defect. Both Lutetium-PSMA-617 and olaparib are very well-tolerated and are widely used. Lutetium-PSMA-617 delivers a payload of beta radiation to PSMA-expressing tumors. Lutetium-PSMA-617 predominantly causes single strand DNA breaks. And these DNA breaks are repaired by PARP-dependent base excision repair. Therefore, blocking PARP could result in conversion of DNA single strand breaks to more lethal double strand breaks [via] fork collapse.”

Forty-eight patients with prostate-specific membrane antigen (PSMA) avidity were enrolled to LuPARP. This was defined as those with a minimum uptake of SUVmax of 15 at a site of disease, and SUVmax greater than 10 at other sites of disease measuring at least 10 mm identified using 68Ga/18F-PSMA PET/CT.²

Patients received olaparib 50 to 300 mg orally in a 3 + 3 dose escalation lutetium Lu 177 vipivotide tetraxetan was administered every 6 weeks for 6 cycles at 7.4 GBq. Biomarker collection and imaging occurred as follows: PSMA PET/CT at baseline and every 12 weeks for 48 weeks, then every 24 weeks; FDG PET at baseline; bone scan and CT-CAP at baseline then every 12 weeks; blood and biomarker analysis for PBMC, circulating tumor cells, circulating tumor DNA, serum levels were done very 12 weeks and at disease progression; tumor biopsies were obtained for archival storage at base line, between weeks 2 to 4, and at disease progression.¹

Nine cohorts were included in the dose-escalation design. Patients in cohort 1 (n = 3) received olaparib at 50 mg, at 100 mg in cohort 2 (n = 3), at 150 mg in cohort 3 (n = 3), at 200 mg in cohort 4 (n = 3), at 250 mg in cohort 5 (n = 4), and at 300 mg in cohort 6 (n = 3). Each of these cohorts had olaparib administered on days 2 through 15. Those in cohort 7 (n = 4) received olaparib at 200 mg and those in cohort 8 received the agent at 300 mg on days –4 through 14. Finally, those in cohort 9 (n = 6) received olaparib at 300 mg on days –4 through 18. The median number of treatment cycles across populations was 5 (range, 2-6). Specifically for cohorts 1-9 the median cycles of treatment were 4 (range, 4-5); 6 (range, 5-6); 6 (range, 2-6); 3 (range, 2-4); 6 (range, 4-6); 6 (range, 5-6); 5.5 (range, 3-6); 4 (range, 3-6); and 3 (range, 2-5).¹

Overall, most adverse events (AEs) were grade 1 or 2. Grade 1 events included anemia (n = 5), neutropenia (n = 1), thrombocytopenia (n = 5), nausea (n = 13), dry mouth (n = 22), constipation (n = 7), vomiting (n = 3), gastroesophageal reflux (n = 2), diarrhea (n = 3), weight loss (n = 1), anorexia (n = 6), dry eye (n = 2), and fatigue (n = 15). Grade 2 events were anemia (n = 3), thrombocytopenia (n = 2), nausea (n = 6), dry mouth (n = 3), constipation (n = 2), vomiting (n = 1), gastroesophageal reflux (n = 1), and weight loss (n = 1).¹

Grade 3 events occurred in cohorts 5 and 6 at the 250-mg and 300-mg dose levels for olaparib, respectively. In cohort 5, these events 1 each of anemia, thrombocytopenia, and neutropenia, which was deemed a serious treatment-related AE and classified as febrile neutropenia. In cohort 6, the grade 3 events were 1 instance each of anemia and neutropenia. No grade 4 events were reported.¹

Dose reductions because of treatment-related AEs occurred in 9% of patients overall, including 1 patient each from cohorts 3, 5, and 6. Two dose delays were reported 1 each in cohorts 3 and 6.

Sixteen patients will be enrolled to the dose-expansion phase to receive the recommended dose of olaparib: 300 mg orally on days –4 to 18 of each 6-week cycle. The primary end points are dose-limiting toxicities (DLTs) and recommended phase 2 dose. The secondary end points are safety and antitumor activity including radiographic PFS, PSA response rate, PSA PFS, overall response rate, and OS. Following completion of therapy, patients are required to attend an end of treatment visit and will be followed for PFS and OS outcomes.¹

Of note at the time of data cutoff, patients enrolled in cohorts 8 and 9 were in early treatment cycles.

The median age was 71 years (range 52-84) with 56% of patients having an ECOG performance status of 0 and the remaining 44% having a status of 1. The median PSA was 50 ug/L (range, 7-536) at baseline. Gleason scores at diagnosis were 8 or higher in 62% of patients, 7 or lower in 31%, and unknown for 6% of patients. Measurable disease per RECIST criteria was available in 38% of patients.¹

Prior systemic therapies received by patients included enzalutamide or abiraterone acetate or other androgen receptor pathway inhibitor (ARPI; 66%), enzalutamide and abiraterone acetate/other ARPI (22%), enzalutamide/abiraterone acetate/other ARPI (12%), and docetaxel (97%).¹

In PSMA expression collected at baseline (n = 26), circulating tumor cells were detectable in 88% of patients and 65% had PSMA plus circulating tumor cells detectable. Fifteen paired samples were available at week 12. Seven of 15 (47%) had circulating tumor cell clearance to 0 and 12 of 15 (80%) had a decrease in total cell count. Thirteen of 15 samples had cleared PSMA positivity and circulating tumor cells to 0. One patient had an increase in PSMA positivity and circulating tumor cells.¹

Three case studies were presented with the findings. In patient 1 enrolled in cohort 2, had baseline PSA of 67 ug/L. After 6 cycles of lutetium Lu 177 vipivotide tetraxetan and olaparib (100 mg), the PSA was 6.42 ug/L. In follow-up, PSA levels captured at 5, 11, 17, 29 months poststudy were 2.4 ug/L, 1.0 ug/L, 0.58 ug/L, and 0.27 ug/L.¹ “What’s intriguing is over the past 2.5 years, I have not had to introduce any additional systemic therapy,” Sandhu said. “His PSA continues to decline, in parallel with the molecular tumor volume, as well as circulating tumor cells. He’s also had a RECIST[-defined] complete response.”

A patient treated in cohort 7 of 200 mg olaparib administered on days –4 to 14 had a baseline PSA of 6.7 ug/L. After 5 cycles of treatment—the sixth was withheld because of response, Sandhu explained—the PSA was 0.1 ug/L and 2 months later remained 0.1 ug/L. Six months later the PSA rose to 0.36 ug/L and investigators plan to for additional doses of lutetium Lu 177 vipivotide tetraxetan and olaparib.¹

Finally, in case study 3, a second patient from cohort 7 had a baseline PSA of 14.5 ug/L. Over the first 3 months of treatment the PSA rose to 15.7 ug/L before reducing to 8.60 ug/L after 6 months. In follow-up, 9 months after treatment began the PSA was 3.46 ug/L; however, at 15 months from the start of treatment the PSA was 20.0 ug/L with the patient demonstrated progressive disease on PSMA-PET. “[This patient had] a germline BRCA2 mutation, and previously received docetaxel and enzalutamide,” Sandhu said. “[He had] predominantly bone, bulky bone disease, and has had a PSA response. But you can see that the duration of response is fairly modest.”

In conclusion, Sandhu noted that ongoing translational work in progress to better understand the interplay of these 2 agents and that further data will report out as follow-up matures.

References

1. Sandhu S, Joshua AM, Emmet L, et al. LuPARP: phase 1 trial of 177Lu-PSMA-617 and olaparib in patients with metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(suppl 16):5005. doi:10.1200/JCO.2023.41.16_suppl.5005
2. 177Lu-PSMA-617 therapy and olaparib in patients with metastatic castration resistant prostate cancer (LuPARP). ClinicalTrials.gov. Updated November 17, 2022. Accessed July 5, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03874884