Two studies presented at the 2022 ASCO Genitourinary Cancers Symposium explored the role of poly (ADP-ribose) polymerase (PARP) inhibitors in urothelial cancer: ATLANTIS and BAYOU.^1,2 Results suggest that PARP inhibitors may be useful in certain genetic subgroups and perhaps in combination with other drugs.

The ATLANTIS trial showed that maintenance therapy with the PARP inhibitor rucaparib extended progression-free survival in a cohort of patients with DNA repair deficiency (DRD), biomarker-positive metastatic urothelial cancer, but it did not significantly improve the secondary endpoint of overall survival.¹ The BAYOU trial found that the combination of durvalumab plus olaparib did not improve progression-free survival in previously untreated, platinum-ineligible patients with metastatic urothelial cancer compared with durvalumab plus placebo, missing the primary endpoint of the trial.²

Sandy Srinivas, MD

“The field is rich for urothelial cancer, with many ongoing trials of PARP inhibitors in combinations in various setting. However, thus far, the studies raise more questions than answers,” said invited discussant of these two trials, Sandy Srinivas, MD, Professor of Medicine/Oncology at Stanford University School of Medicine, Palo Alto, California.

ATLANTIS Trial

ATLANTIS is a multicenter, umbrella trial in the UK that screened patients with advanced urothelial cancer for biomarkers while receiving first-line chemotherapy. Patients were eligible to participate in multiple phase II studies evaluating targeted agents as maintenance therapy in biomarker-defined subgroups.

Patients assigned to the rucaparib arm were positive for the DRD biomarker, defined as 10% or greater genome-wide loss of heterozygosity; alteration in any of 15 different genes associated with DNA repair; or BRCA1 or BRCA2 germline alteration. At baseline, the median age of patients was 69.5 years. Most patients were male, and most had pure transitional cell -carcinoma.

Patients were randomly assigned 1:1 to receive maintenance treatment within 10 weeks of completion of chemotherapy with either rucaparib at 600 mg twice daily or placebo until disease progression. The study was shut down after 40 patients were recruited for two reasons: the COVID pandemic and data from the JAVELIN Bladder 100 trial showing a survival advantage for avelumab immunotherapy in this treatment setting.

Treatment with rucaparib achieved a median progression-free survival of 35.3 weeks vs 15.1 weeks with placebo. For the secondary endpoint of overall survival, median overall survival was not reached in the rucaparib arm vs 72.3 weeks in the placebo arm, but this difference was not statistically significant.

“Based on these results, further investigation of PARP inhibition is warranted in urothelial carcinoma within a molecularly selected group of patients,” said lead author Simon J. Crabb, BSc, MBBS, MRCP, PhD, of Southampton Experimental Cancer Medicine Centre, UK. “The difference in progression-free survival between the two arms in this trial appears to have been primarily because of maintenance of a preexisting response to prior chemotherapy, rather than induction of new objective responses during maintenance treatment,” he added.

“Based on these results, further investigation of PARP inhibition is warranted in urothelial carcinoma within a molecularly selected group of patients.”

— Simon J. Crabb, BSc, MBBS, MRCP, PhD

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The safety profile of the drug was consistent with prior reports of rucaparib when used to treat cancers. Rucaparib is currently approved in previously treated patients with deleterious BRCA mutation–associated metastatic castration-resistant prostate cancer; as maintenance treatment in recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that was responsive to platinum-based chemotherapy; and in patients with pretreated deleterious BRCA mutation–associated advanced ovarian cancer.

The most frequent treatment-related adverse events of any grade were fatigue (63.2% with rucaparib vs 30.0% with placebo), nausea (36.9% vs 5.0%), and rash (21.1% vs 0%). More patients in the rucaparib arm experienced anemia, lymphopenia, and low phosphate levels. No treatment-related deaths were reported.

Dr. Crabb said he is “fairly convinced” that PARP inhibition should be developed in molecularly selected patients. “Should that be in combination with avelumab or in competition with it? I think you could answer that either way,” he continued. “But most likely in a combination approach and within a molecularly selected subset of patients.”

Regarding which gene alterations were related to response, Dr. Crabb said he and his colleagues are analyzing progression-free survival in patients with a DRD gene alteration compared with those who had high loss of heterozygosity alone.

“This was an exploratory analysis, and this was post hoc, and the numbers start to get a bit small. However, it does look as though the progression-free survival benefit may be in those patients who had a gene alteration rather than in those who had high loss of heterozygosity alone,” he proposed. “It starts to make you think that in a gene-selected group of patients, potentially there is a way forward here.”

BAYOU Trial

The BAYOU trial enrolled treatment-naive, platinum-ineligible patients with metastatic urothelial cancer. They were randomly assigned 1:1 to first-line treatment with durvalumab plus olaparib or durvalumab plus placebo.

“Treatment for metastatic urothelial cancer is a high unmet need, especially for platinum-ineligible patients,” explained lead author Jonathan Rosenberg, MD, Chief of the Genitourinary Oncology Service in the Division of Solid Tumor Oncology and Enno W. Ercklentz Chair at Memorial Sloan Kettering Cancer Center, New York. “In this randomized, phase II trial, olaparib plus durvalumab in platinum-ineligible patients did not meet the prespecified endpoint of improved progression-free survival in the intent-to-treat population,” he said.

“Olaparib plus durvalumab after platinum therapy did not meet the prespecified endpoint of an objective response rate of 35%.”

— Jonathan Rosenberg, MD

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At baseline, both treatment arms were well balanced. More than 60% had visceral metastasis. More than 20% had homologous recombinant repair (HRR) genes, “which render cells responsive to PARP inhibition,” Dr. Rosenberg noted. In the combination-therapy arm, 22% had HRR-mutated disease vs 18% in the control arm.

Visceral metastases were present in 67% of the combination arm and 63% of the control arm. Lymph node disease alone was observed in 63% and 37%, respectively. About 10% of patients in both arms received previous treatment.

The authors used the Foundation One assay to test tumor samples for aberrations in 15 HRR genes: ATM, BARD1, CHEK1, PALB2, RAD51C, BRCA1, BRIP1, CHEK2, PPP2R2A, RAD51D, BRCA2, CDK12, FANCL, RAD51B, and RAD54L. HRR mutations were found in 7 of the 15 genes analyzed. The most frequently identified genetic abnormality was ATM, which was identified in 8.5% of all tumors and in 41.9% of patients in the HRR-mutated subset; BRCA2 was found in 4.6% of all tumors and in 22.6% of the HRR-mutated subgroup. Across all patients, the most common HRR gene mutations were loss of p53 function (59.5%) and TERT promoter mutations (55.6%).

Median follow-up of both arms was about 10 months. The addition of olaparib did not prolong progression-free survival. In an intent-to-treat analysis of 154 patients, median investigator-assessed progression-free survival with the doublet (n = 78) was 4.2 months vs 3.5 months with durvalumab alone (n = 76). In a prespecified secondary analysis related to HRR-mutated status, longer progression-free survival was observed in patients receiving durvalumab and olaparib compared to durvalumab and placebo: a median of 5.8 months vs 1.8 months (P < .001).

In an exploratory analysis, overall survival was inferior in those with HRR mutations compared with HRR wild-type. Objective response rate was 28.2% with combination therapy vs 18.4% with durvalumab alone in the intent-to-treat analysis. Median duration of response in the investigative arm was 8.9 months vs 14.8 months in the control arm. A separate analysis of the HRR-mutated subset reported an objective response rate of 35% with the combination vs 0% with durvalumab alone.

There were no new safety signals in the trial. Any-grade treatment-related adverse effects were experienced by 72.4% of patients who received the doublet and 60.5% of those given monotherapy.

“All results of this trial were hypothesis-generating,” Dr. Rosenberg stated. “There might be a potential role for PARP inhibition in HRR-mutant metastatic urothelial cancer, and I believe further investigation is warranted.” 

DISCLOSURE: The ATLANTIS trial was funded by Cancer Research UK, Exelixis, Clovis Oncology, and Astellas Europe. The BAYOU trial was funded by AstraZeneca. Dr. Crabb disclosed relationships with, and/or support from, Astellas Pharma, AstraZeneca, Bayer, Janssen, MSD, Roche, BeiGene, EMD Serono, Novartis, Pfizer, Roche, Astex Pharmaceuticals, Clovis Oncology, Merck/Pfizer, Bayer, Bristol Myers Squibb, and Janssen. Dr. Rosenberg has served as a consultant to Alligator Biosciences, Astellas Pharma, AstraZeneca/MedImmune, Bayer, BioClin Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Immunomedics/Gilead, Infinity Pharmaceuticals, Janssen Oncology, Lilly, Merck, Mirati Therapeutics, Pfizer/EMD Serono, Pharmacyclics, QED Therapeutics, Roche/Genentech, Seagen, and Tyra Biosciences; and has received institutional research funding from Astellas Pharma, AstraZeneca, Bayer, Genentech/Roche, QED Therapeutics, and Seattle Genetics. See page 26 for Dr. Srinivas’ disclosures.

REFERENCES

1. Crabb SJ, Hussain SA, Soulis E, et al: A randomized, double-blind, biomarker selected, phase II clinical trial of maintenance PARP inhibition following chemotherapy for metastatic urothelial carcinoma: Final analysis of the ATLANTIS rucaparib arm. 2022 ASCO Genitourinary Cancers Symposium. Abstract 436. Presented February 18, 2022.

2. Rosenberg JE, Park SH, Dao TV, et al: BAYOU: A phase II, randomized, multicenter, double-blind study of durvalumab in combination with olaparib for the first-line treatment of platinum-ineligible patients with unresectable, stage IV urothelial carcinoma. 2022 ASCO Genitourinary Cancers Symposium. Abstract 437. Presented February 18, 2022.