Personalized treatment with PARP inhibitors in advanced urothelial carcinoma: a case report and literature review

Abstract

Bladder cancer (BC) poses a significant health challenge, particularly in metastatic cases, where the prognosis is unfavorable and therapeutic options are limited. Poly ADP-ribose polymerase (PARP) inhibitors have gained approval for use in various cancer types, but their application in BC remains controversial, despite the notable prevalence of DNA damage response alterations in advanced or metastatic urothelial carcinomas. In this report, we describe a 66-year-old heavy-smoking female diagnosed with muscle-invasive BC. She underwent multiple rounds of chemotherapy and radiation, yet her disease remained poorly controlled, leading to metastasis in the left obturator internus muscle. Comprehensive genomic profiling through FoundationOne^® Liquid CDx, examining a 324-gene panel using circulating tumor DNA from blood samples, revealed a pathogenic ATM gene alteration (p.Q654fs*10, c.1960delC), suggesting potential eligibility for PARP inhibitor therapy. Remarkably, the patient achieved a complete response to talazoparib, prompting an optimal investigation into BC candidates for this promising therapy.

Plain language summary

A new hope for advanced bladder cancer treatment: a case study on the success of PARP inhibitors

Bladder cancer is a significant health problem, particularly when it spreads to other parts of the body. The outcome for these advanced cases is often poor and treatment options are limited. One type of treatment, called PARP inhibitors, has shown success in treating other types of cancer, but its use in bladder cancer is still under investigation. This article presents the case of a 66-year-old heavy-smoker woman who was diagnosed with an aggressive form of bladder cancer. Despite several rounds of chemotherapy and radiation, her cancer was not well-controlled and spread to a hip muscle. A detailed genetic analysis revealed specific alterations that suggested she might benefit from treatment with a PARP inhibitor. This type of treatment works by blocking a protein that cancer cells need to repair their DNA, causing the cancer cells to die. The patient was treated with a PARP inhibitor called talazoparib and her cancer completely disappeared with this treatment. This positive response highlights the potential of PARP inhibitors as a promising treatment for bladder cancer, especially in patients who don’t respond to conventional treatments and whose cancer has specific genetic changes. Our study also provides an overview of clinical trials evaluating PARP inhibitors in bladder cancer and summaries reported bladder cancer cases in the literature showing a good response to PARP inhibitors, along with their respective genetic alterations. In conclusion, this case study contributes to the growing understanding of personalized medicine, where treatment is tailored to the specific genetic mutations of each patient’s cancer. It emphasizes the importance of identifying bladder cancer patients who could benefit most from PARP inhibitor therapy, offering a potential lifeline for those who haven’t responded to initial treatment.

Introduction

Bladder cancer (BC) is a significant global health concern, ranking among the top 10 most prevalent cancers worldwide. ¹ Most BC cases are classified as urothelial carcinomas (UC), with the primary risk factor being tobacco smoking.

The management of BC depends on the extent and aggressiveness of the disease. Metastatic BC carries a dismal prognosis, with a 5-year relative survival rate of less than 10%. ² Despite ongoing research efforts, treatment options remain limited. The standard treatment for locally advanced or metastatic UC is platinum-based chemotherapy. ³ However, about one-third of patients are ineligible for this treatment due to comorbidities, and only half respond to treatment. ⁴ In 2016–2017, immune checkpoint inhibitors were approved as second-line treatments for patients refractory to or ineligible for platinum-based therapy, ⁵ and in 2021, the antibody–drug conjugate enfortumab vedotin was introduced. ⁶ Yet, response rates vary widely due to patient characteristics and the presence of different genomic subtypes with distinct oncogenic mechanisms. ⁷ These challenges emphasize the need for further investigation into more personalized treatment strategies for metastatic BC. Recent advancements in BC treatment have underscored the importance of targeted therapies directed against specific biomarkers like fibroblast growth factor receptor 3 (FGFR3) ⁸ or human epidermal growth factor receptor 2 (HER2). ⁹

The role of DNA damage response (DDR) genes in BC is increasingly recognized, with about 34% of BC cases harboring DDR mutations. ⁴ This includes notable genes such as BRCA1 and BRCA2, which are found in approximately 6% and 12% of BC cases, respectively, according to the MSK/TCGA 2020 cohort (Supplemental Figure S1), ¹⁰ and play a crucial role in the homologous recombination repair (HRR) mechanisms. Among other significant DDR genes is ATM, found in 12% of BC cases. These mutations can lead to the accumulation of double-strand breaks (DSB) and heighten the susceptibility of tumors to poly ADP-ribose polymerase (PARP) inhibitors through a phenomenon known as synthetic lethality. ¹¹

While the use of PARP inhibitors has been validated for ovarian, breast, pancreatic, and recently prostate cancers, ¹² their application in BC is not yet approved. This highlights a potential avenue for therapeutic intervention given the significant role of DDR in BC.

Case presentation

In this context, we present a case of a 66-year-old woman with a history of heavy smoking who presented with dysuria, hematuria, and lower abdominal pain in February 2019. She was diagnosed with high-grade UC manifesting as muscle-invasive bladder cancer following transurethral resection of the bladder tumor (TURBT). A whole-body positron emission tomography and computed tomography (PET–CT) scan confirmed the primary malignancy, with a maximum bladder wall thickening of 1.6 cm (SUVmax = 8.5) and no evidence of regional adenopathy or distant metastases.

The patient received four cycles of neoadjuvant chemotherapy with cisplatin and gemcitabine, from March to May 2019, with stable disease. In July 2019, a second TURBT revealed a high-grade T1 tumor, leading to a complete cystectomy, continent diversion, neobladder construction, and radical pelvic lymphadenectomy in August 2019. The cystectomy specimen was negative for residual invasive carcinoma, but a microscopic focus of carcinoma in situ was noted near the urethral margin of resection. Overall, the patient’s postoperative course was favorable, except for left-sided perineal pain, managed with nerve and plexus blocks.

In November 2019, a CT scan of the abdomen and pelvis showed no recurrence. However, a PET-CT scan in September 2020 revealed a mass in the left posterior pelvis, measuring 6.5 × 4.7 cm with an SUV_max of 15.3, invading pelvic wall muscles, and suggestive of regional tumor recurrence. In response to the recurrence, the patient underwent five sessions of cisplatin chemotherapy with concurrent radiotherapy (22 fractions of 2 Grays each), for symptomatic relief and local disease control. Subsequent CT imaging in November 2020 demonstrated a partial response with a substantial decrease in the size of the pelvic mass to 2.4 × 1.7 cm.

Biomarker testing was performed on the second TURBT in November 2020. Programmed cell death ligand 1 (PD-L1) expression was negative, with a combined positive score of 5. The HER2/neu protein analysis, using the Ventana 4B5 assay with a multimer detection system, indicated a non-overexpression status, with a score of +0/3. Furthermore, the DNA mismatch repair proteins, including MLH1, MSH2, MSH6, and PMS2, were retained in the cells with normal DNA repair functioning. Due to elevated creatinine levels, the patient was not eligible for cisplatin-based therapy and, therefore, received six cycles of gemcitabine as adjuvant chemotherapy monotherapy from December 2020 to April 2021. The PET-CT scan of February 2021 showed interval resolution of the previously described mass.

However, in May 2021, 1 month after completing chemotherapy, the patient presented a new lesion in the left obturator internus muscle of 2.5 × 1.5 cm with an SUV_max of 6.3, consistent with disease relapse [Figure 1(a) and (c)]. This finding was further confirmed by magnetic resonance imaging of the pelvis, leading to the administration of five sessions of stereotactic body radiotherapy.

Figure 1.

Comparative PET-CT scans before (20 May 2021) and after (9 March 2022) PARP inhibitor therapy initiation, demonstrating complete response to treatment. (a) Before treatment sagittal section (SUV_max = 6.3); (b) during treatment sagittal section (no suspicious uptake); (c) before treatment coronal section (SUVmax = 6.3); (d) and during treatment coronal section (no suspicious uptake).

In June 2021, FoundationOne^® Liquid CDx testing of a 324-gene panel through blood-based comprehensive genome sequencing, analyzing circulating tumor DNA, identified a pathogenic biallelic mutation in the ATM gene (p.Q654fs*10, c.1960delC, with a variant allele frequency of 0.28%, likely somatic) suggesting potential eligibility for targeted therapy, and mutations in the BRCA2 (p.K3326*, c.9976A>T, rs11571833), and CHEK2 (p.R145Q, c.434G>A) genes, classified as variants of unknown significance (VUS) (Supplemental Table S1). The tumor was microsatellite stable, with a low blood tumor mutational burden of 1 mutation per megabase. Following the genetic analysis results, the patient started on talazoparib, a PARP inhibitor, initially at a daily dose of 1 mg, beginning in August 2021, followed by a reduced daily dose of 0.5 mg from September 2021 to April 2022 due to fatigue and dizziness. Subsequent PET-CT scans conducted in November 2021 and March 2022 revealed a complete response to treatment with no suspicious uptake [Figure 1(b) and (d)].

Unfortunately, the PARP inhibitor therapy was discontinued in April 2022 due to medication unavailability. Eight months later, in December 2022, a PET-CT scan revealed a recurrent lesion in the left posterolateral pelvic wall measuring 4.3 × 3.6 cm, with an SUV_max of 8.5, prompting the patient to resume PARP inhibitor treatment, receiving either talazoparib 1 mg every other day or olaparib 150 mg twice a day, based on drug availability.

In an attempt to investigate the cause of an enlarging pelvic mass, a trial of dexamethasone 8 mg three times daily for 4 days was initiated to assess for potential radiation myositis. However, minimal improvement in symptoms suggested an alternative etiology.

A follow-up PET-CT scan performed in February 2023 demonstrated a further increase in tumor size to 5 × 4.6 cm. Given the disease progression, a CT needle biopsy was recommended for additional evaluation, but could not be performed due to the patient’s lethargy and syncope.

Regrettably, despite supportive care, the patient’s condition continued to deteriorate, and she succumbed to the disease in March 2023.

Discussion

This case report complies with the CARE guidelines ¹³ (Supplemental Material 1). A comprehensive, but not systematic, literature search was performed through PubMed/PMC and Medline, with some additional articles selected based on their clinical relevance, to capture the reported cases, ongoing clinical trials, and most important aspects of the topic.

The current case provides valuable insights into the potential of PARP inhibitors for BC patients who progress on prior treatments. The patient achieved a disease-free survival period of 1 year and 4 months, with disease recurrence coinciding with medication cessation due to drug unavailability.

Several clinical trials have explored PARP inhibitors in advanced or metastatic UC, as part of combination therapies with standard treatments like cisplatin ¹⁴ or anti-PD-L1 immunotherapy, ⁴ a standalone treatment for patients who experienced progression on prior treatments, or maintenance therapy for patients without progression. A summary of published and ongoing phase I or II trials is provided in Supplemental Table S2. These trials are categorized based on the different FDA-approved PARP inhibitors, encompassing olaparib, rucaparib, niraparib, and talazoparib. ¹² Some studies suggest talazoparib may exhibit superiority over olaparib against BC cells. ¹⁴

The majority of these studies reported either stable disease or a partial response to treatment. For instance, the BISCAY trial combined durvalumab with either FGFR inhibitor (AZD4547), olaparib, or vistusertib (TORC1/2 inhibitor), and none of the combination arms achieved a meaningful complete response. ¹⁵ The NICARAGUA trial, involving 19 patients with UC and kidney cancer, showed that niraparib plus cabozantinib resulted in a partial response in only three patients and the rest had stable disease. ¹⁶ Similar results were observed in the SEASTAR study. ¹⁷ Our study stands out by reporting a complete response to talazoparib, sustained throughout the treatment course and for 8 months after treatment suspension in a patient with an ATM alteration.

PARP inhibitors exhibit enhanced effectiveness when specific DDR genes are concomitantly mutated. These genes include ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, and RAD1, among others. ¹⁸ Some studies have highlighted favorable responses to PARP inhibitors in BC patients harboring these specific mutations, with a particular focus on BRCA1 and BRCA2 mutations (Table 1). In a phase I study, a patient with BC, who had a BRCA2 germline mutation and a VUS of ATM gene, achieved a partial response to talazoparib and carboplatin after undergoing three prior lines of platinum therapy. ¹⁹ Also, a phase II trial included a BC patient with PALB2 mutation who exhibited a positive response to talazoparib. ²⁰ However, none of these studies reported a complete response of BC to PARP inhibitors. Our study is the first to report a BC case with a pathogenic ATM mutation (p.Q654fs*10, c.1960delC) who achieved a complete response to talazoparib after chemotherapy failure, sustained longer than other studies.

Table 1.

Summary of studies documenting good response to PARP inhibitor monotherapies in patients with recurrent advanced or metastatic bladder cancer.

Study	Previous treatment(s)	DDR gene mutation	Other genetic findings	PARP inhibitor received	Response to treatment
Necchi et al., 2018 21	Anti-PD-L1, MVAC (6 cycles), vinflunine (4 cycles) with palliative RT	BRCA2 loss (homozygous); BRCA2 germline mutation (p.I267V)	MSS; TMB 7 mutations per megabase	Olaparib 400 mg PO b.i.d.	Partial response for more than a 5 months
Sweis et al., 2018 22	Gemcitabine-cisplatin (4 cycles)	BRCA1 (p.N1018fs*8) with VAF 62%; CHEK2 (p.T367fs*15)	MSS; TMB 4 mutations per megabase	Olaparib	Partial response for 1 year, then progressed
Sweis et al., 2018 22	Gemcitabine–cisplatin (6 cycles), alternating ifosfamide/doxorubicin and etoposide/cisplatin, RT (55 Gy) with capecitabine, pembrolizumab	BRCA2 (c.7436-294_7567del)	MSS; TMB 4 mutations per megabase	Olaparib 400 mg PO b.i.d., then reduced to 300 mg (due to thrombocytopenia)	Partial response for more than a 6 months
Piha-Paul et al., 2018 20	Taken but not reported	PALB2 (mutation not specified)	No additional genetic finding	Talazoparib 1 mg PO q.d.	Partial response
Yang et al., 2020 23	Gemcitabine–cisplatin (4 cycles)	BRCA2 germline mutation (p.L557*, c.1670T > A); BRCA1 somatic mutation	TMB decreased from 6.11 to 0.76 mutations per megabase after PARP inhibitor	Olaparib 300 mg PO b.i.d.	Partial response for more than a 4 months
Current study	Gemcitabine–cisplatin (4 cycles), cisplatin with RT (44 Gy), gemcitabine (6 cycles)	ATM deletion (p.Q654fs*10, c.1960delC) with VAF 0.28%; BRCA2 (p.K3326*, c.9976A>T)	MSS; TMB 1 mutation per megabase	Talazoparib 1 mg PO q.d., then reduced to 0.5 mg (due to fatigue and dizziness)	Complete response for 1 year and 4 months (8 months after treatment interruption)

^aThe term ‘more than’ indicates that the patient was still showing a positive response to the treatment at the time of reporting the case.

ATM, ataxia-telangiectasia mutated; b.i.d. (bis in die), twice a day; BRCA1, breast cancer gene 1; BRCA2, breast cancer gene 2; CHEK2, checkpoint kinase 2; DDR, DNA damage response; MSS, microsatellite stable; MVAC, methotrexate, vinblastine, doxorubicin and cisplatin; PALB2, partner and localizer of BRCA2; PARP, poly ADP-ribose polymerase; PD-L1, programmed cell death ligand 1; PO (per os), orally; q.d. (quaque die), once a day; RT, radiotherapy; TMB, tumor mutational burden; VAF, variant allele frequency.

To avoid apoptosis, cells respond to threats to their genetic material by activating the DDR system to repair DNA DSBs. The two major DSB repair pathways are HRR and nonhomologous end joining (NHEJ).^24,25 The ATM protein is at the core of this signaling network and participates in many HRR-mediated cellular processes. ²⁴ ATM mutations are observed in about 12% of BC cases (Supplemental Figure S1) and have been described as an independent prognostic factor associated with chemotherapy resistance and poor overall survival (hazard ratio: 2.25–2.82) in advanced UC.^24,26 This could be due to backup mechanisms like the upregulation of ATR signaling, which prevents the replication of damaged DNA, or the activation of alternative pathways like NHEJ via DNA-dependent protein kinases catalytic subunit (DNA-PKcs).^24,25 Therefore, ATM-deficient cancer cells seem to be particularly susceptible to ATR inhibitors and DNA-PKcs inhibitors.

Despite promising results with PARP inhibitors, many patients fail to maintain a good response. A phase II trial investigating olaparib monotherapy in metastatic UC patients with DDR gene alterations was discontinued as none of the 19 participants achieved a partial response. ²⁷ Two other ongoing studies (NCT03448718 and NCT03375307) are evaluating olaparib monotherapy, but the results are yet to be determined. Some patients initially respond to PARP inhibitors but later become resistant, by increasing drug efflux or restoring functional HRR. ²⁵ The combination of PARP inhibitors and ATR inhibitors has demonstrated synergistic effects against ATM-deficient prostate cancer cells in vitro ²⁸ and promising outcomes in ovarian cancer patients. ²⁵ DNA-PKcs inhibitors could offer another therapeutic option in tumors with ATM loss, as ATM-defective cells strongly depend on DNA-PKcs for DNA repair. ²⁴ However, the efficacy of these treatments in BC needs to be further validated in clinical trials.

In addition to the ATM alteration, the patient in our case had other mutations in DDR genes, such as BRCA2 (p.K3326*, c.9976A>T, rs11571833) and CHEK2 (p.R145Q, c.434G>A), which may enhance the tumor’s susceptibility to PARP inhibition. Although these mutations were initially described as VUS, the BRCA2 (p.K3326*) mutation holds particular relevance, as it has been associated with various cancer types, including breast cancer, ²⁹ small-cell lung cancer, and squamous cell carcinoma of the skin. ³⁰ Another study revealed an increased predisposition to urinary tract cancers among patients with the BRCA2 (p.K3326*) mutation. ³¹

The patient did not receive immunotherapy given its reduced efficacy in microsatellite-stable tumors with low tumor mutational burden and negative PD-L1 expression, although the dynamism of PD-L1 expression hampers its use as a reliable biomarker.^7,22

Conclusion

In conclusion, this study reports a compelling case of advanced BC harboring DDR mutations conferring an excellent response to talazoparib after cisplatin-based chemotherapy failure. In addition, it offers a comprehensive overview of trials investigating PARP inhibitors in BC. The variation in molecular profiles and treatment responses underscores the need for a patient-tailored approach and emphasizes the importance of understanding the specific profiles of BC patients who could benefit most from PARP inhibitor therapy after progression on initial treatments.