Olaparib Enhances Lutetium Lu 177 Vipivotide Tetraxetan Activity in mCRPC

Shahneen Sandhu, PhD, MBBS, FRACP

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

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

I think these are intriguing, albeit early, data, but they could suggest an insight into responses from combination therapy, said Shahneen Sandhu, PhD, MBBS, FRACP, in a data presentation at ASCO’s 2023 annual meeting. the reason it matters is that we know, based on other datasets, that a 90% PSA response actually translates into better progression-free survival [PFS].

Lutetium-PSMA-617 is a radioligand therapy directed at 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 widely used. Lutetium-PSMA-617 delivers a payload of beta radiation to PSMA-expressing tumors. Lutetium-PSMA-617 predominantly causes single-stranded DNA breaks. And these DNA breaks are repaired by PARP-dependent base excision repair. Therefore, PARP blockade could result in the conversion of DNA single-strand breaks into more lethal double-strand breaks [via] fork collapse.

Forty-eight patients with prostate-specific membrane antigen (PSMA) avidity were enrolled for LuPARP. This was defined as those with a minimum uptake of SUVmax of 15 at one disease site and SUVmax greater than 10 at other disease sites measuring at least 10mm 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; baseline FDG PET; bone scan and CT-CAP at baseline, then every 12 weeks; blood and biomarker tests for PBMCs, circulating tumor cells, circulating tumor DNA, serum levels were performed every 12 weeks and at disease progression; tumor biopsies were obtained for archiving at baseline, between weeks 2 and 4, and at disease progression.¹

Nine cohorts were included in the dose escalation design. Patients in cohort 1 (n = 3) received olaparib 50 mg, 100 mg in cohort 2 (n = 3), 150 mg in cohort 3 (n = 3), 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 received olaparib on days 2 to 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 to 14 Finally, those in cohort 9 (n = 6) received olaparib at 300 mg on days 4 to 18. The median number of treatment cycles across populations was 5 (range, 2-6). Specifically for cohorts 1-9, the median treatment cycles were 4 (range, 4-5); 6 (range, 5-6); 6 (range, 2-6); 3 (interval, 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, the majority of 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 included 1 each of anemia, thrombocytopenia, and neutropenia, which was considered a treatment-related serious adverse event and classified as febrile neutropenia. In cohort 6, the grade 3 events were 1 case each of anemia and neutropenia. No Grade 4 events were reported.¹

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

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

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

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 the base. Gleason scores at diagnosis were 8 or higher in 62% of patients, 7 or lower in 31%, and unknown in 6% of patients. Disease measurable by RECIST criteria was available in 38% of patients.¹

Patients’ prior systemic therapies included enzalutamide or abiraterone acetate or other androgen receptor pathway inhibitors (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 detectable circulating tumor cells. Fifteen paired samples were available at week 12. Seven of 15 (47%) had clearance of circulating tumor cells to 0 and 12 of 15 (80%) had decreased total cell counts. Thirteen of 15 samples had PSMA positivity and circulating tumor cells brought down to 0. One patient had an increase in PSMA positivity and circulating tumor cells.¹

Three case studies with results were presented. In patient 1 enrolled in cohort 2, he had a 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 after the study were 2.4 ug/L, 1.0 ug/L, 0.58 ug/L, and 0.27 ug/L .¹ What’s interesting is that I haven’t had to introduce any additional systemic therapy for the past 2.5 years, Sandhu said. His PSA continues to decrease, paralleling the molecular volume of the tumor, as do the circulating tumor cells. She has also had a RECIST[-defined] complete answer.

One patient in cohort 7 treated with olaparib 200 mg administered on days 4 to 14 had a baseline PSA of 6.7 ug/L. After 5 courses of treatment, the sixth was stopped due to response, Sandhu explained, PSA was 0.1 ug/L and 2 months later remained 0.1 ug/L. Six months later the PSA had risen to 0.36 ug/L and the investigators plan 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. During the first 3 months of treatment, PSA rose to 15.7 ug/L and then decreased to 8.60 ug/L after 6 months. In follow-up, 9 months after starting treatment, PSA was 3.46 ug/L; however, at 15 months of treatment initiation PSA was 20.0 ug/L with the patient showing progressive disease on PSMA-PET. [This patient had] a germ line BRCA2 mutation, and previously received docetaxel and enzalutamide, Sandhu said. [He had] predominantly bone, large bone disease and had a PSA response. But you can see that the response duration is quite modest.

In conclusion, Sandhu noted that there is ongoing translation work to better understand the interaction of these 2 agents, and that additional data will be reported 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. Therapy with 177Lu-PSMA-617 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