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PARP Inhibitor Combination Therapy: Approved Treatments for Metastatic Castrate-Resistant Prostate Cancer Patients

Introduction

Given the promising results that Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors have demonstrated for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) patients who had progressed following prior androgen receptor pathway inhibitor (ARPI) and/or taxane-based chemotherapy, there has been increased interest in ‘moving up’ these agents along the disease spectrum, as well as combining them with other agents that may have a synergistic mechanism of action.

PARP Inhibitor Therapy for Prostate Cancer Patients: Emerging Combinations

Introduction

Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are drugs that prevent the repair of DNA single-stranded breaks and promote their conversion to double-stranded breaks resulting in a synthetic lethality.1 These drugs have demonstrated promising results for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) patients who experience disease progression following prior androgen receptor pathway inhibitor (ARPI) and/or taxane-based chemotherapy.

There is growing interest in combining these agents with other classes of drugs that may have synergistic mechanisms of action. A prime example of this is the use of combination PARP inhibitors and APRIs, with ARPIs inhibiting the transcription of specific homologous recombination repair (HRR) genes, inducing an HRR deficiency-like state, which potentiates PARP inhibitor activity, and, conversely, PARP inhibitors upregulating androgen receptor signaling, enhancing ARPI activity.2-4 This has culminated in the approval of three PARP inhibitor/ARPI combinations by the US Food and Drug Administration (FDA) for the treatment of mCRPC patients in the first line setting:
  • Olaparib plus abiraterone for BRCA1/2-mutated patients5
  • Niraparib plus abiraterone for BRCA1/2-mutated patients6
  • Talazoparib plus enzalutamide for HRR-mutated patients7
Numerous other PARP inhibitor combination strategies have since been evaluated, although, to date, none have resulted in regulatory approval for use in clinical practice. In this Center of Excellence article, we discuss emerging and potentially important PARP inhibitor combination strategies.

PARP Inhibitors + Radium-223

Olaparib + Radium-223

For patients with bone metastases, it has been theorized that the combination of a PARP inhibitor and radium-223 may have synergistic mechanisms of action. PARP inhibitors have shown efficacy as radiosensitizing agents which may promote the efficacy of radium-223, an α-emitting radioisotope that induces DNA double-strand breaks leading to cell death. This formed the foundation for the COMRADE trial, an open-label, multi-center, phase 1/2 study trial to test the safety and efficacy of radium-223 and olaparib. This trial included men with mCRPC who had ≥2 bone metastases without evidence of concurrent visceral metastases or lymphadenopathy > 4 cm.

The phase 1 portion of the study employed a 3+3 dose escalation design with fixed-dose radium-223 (55 kBq/kg IV every 4 weeks x 6) and escalating doses of olaparib. The dose level 1 (DL1) for was olaparib 200 mg PO BID while DL2 was 300 mg PO BID. In phase 1, the primary objective was to determine the recommended phase 2 dose (RP2D) for the randomized portion of the study, which was found to be 200 mg BID for olaparib. No dose limiting toxicities were observed at either DL1 or DL2. However, 5 of 6 patients enrolled at DL2 required dose reduction. Assessing secondary objectives, the authors found that the PSA response and alkaline phosphatase response rates were 16.7% (n=2) and 67% (n=8), respectively. At a median follow-up of 6.5 months, the 6 months rPFS was 58%, and the 12 months OS was 56%. Based on these results, the investigators concluded that olaparib can be safely combined with radium-223 at the RP2D of 200 mg orally twice daily with fixed dose radium-223.8

Niraparib + Radium-223

Utilizing a similar treatment strategy to that seen in the COMRADE trial, the combination of niraparib and radium-223 was evaluated in the phase 1b trial, NiraRad. This trial included 30 men with progressive mCRPC following ≥1 line of an ARPI and had evidence of bone metastases without bulky visceral disease and no documented BRCA1/2 alterations. The niraparib dose was escalated in combination with standard dosing of Radium-223 using a time-to-event continual reassessment method. The investigators determined that for patients with prior chemotherapy exposure, the maximum tolerated dose (MTD) for niraparib was 100 mg, whereas the MTD for chemotherapy-naïve patients was 200 mg. The median rPFS for all patients included in analysis was 7.1 months with an estimated 6-month rPFS of 51%.9

PARP Inhibitors + 177Lu-PSMA-617


177Lu-PSMA-617 delivers significant beta radiation to PSMA-expressing tumors causing single strand DNA breaks, which are typically repaired by PARP-dependent pathways. Blocking the PARP enzyme could have a synergistic mechanism of action by converting DNA single strand breaks to lethal double strand breaks via replication fork collapse. In the LuPARP trial presented at ASCO 2023, the investigators hypothesized that olaparib would promote the radiosensitization of 177Lu-PSMA-617, resulting in intensification of DNA damage and, thus, improved efficacy.

The LuPARP phase 1 trial schema was as follows:

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This trial included 48 patients with mCRPC, and all eligible patients had received a prior ARPI and docetaxel. All patients underwent a 68Ga-PSMA-11 plus an FDG-PET/CT with the following inclusion criteria:
  • PSMA SUVmax >15 at any site
  • SUVmax >10 at other sites
  • No FDG discordance
This study followed a 3+3 dose escalation design. In cohorts 1-6, the dose of olaparib was sequentially increased from 50 mg to 300 mg on days 2–15 (day 0: day of LuPSMA administration). In cohorts, 7 to 9, the timing of olaparib administration (days -4 to 14 and -4 to 18), along with the dose of olaparib, were sequentially varied. The investigators determined that the recommended phase 2 dose was 7.4 Gb of 177Lu-PSMA-617 in conjunction with olaparib 300 mg twice daily on days -4 to 18 of each 6-weekly cycle. 177Lu-PSMA-617 in combination with olaparib was well-tolerated, with no dose limiting toxicities. One treatment-related serious AE occurred (febrile neutropenia). Dose delay due to hematological toxicity occurred in 3 (9%) patients (cohorts 2, 5, and 6). Dose reduction was required in 4 patients (12%), including 3 due to hematological toxicity and 1 due to xerostomia.

From an efficacy standpoint, 177Lu-PSMA-617 in combination with olaparib demonstrated promising activity: in the overall cohort (i.e., Cohorts 1 to 9), the PSA50 and PSA90 response rates were 66% and 44%, respectively. The objective response rate (ORR) by RECIST v1.1 criteria was 78%.10 Compared to the results of the TheraP and VISION trials, the PSA50 responses were identical to those from TheraP (66%) and higher than those in VISION (46%).11,12 The PSA90 response of 44% in LuPARP was slightly higher than that in TheraP (38%).

Moreover, early results from Cohorts 7-9 were promising with PSA50 and PSA90 responses of 75% and 58%, respectively. However, results from this Phase 1 trial are not designed, nor powered, to assess efficacy outcomes.

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PARP Inhibitors + Immune Checkpoint Inhibitors

While immunotherapy has shown limited success in the mCRPC disease space, it is hypothesized that the increased cellular DNA damage induced by PARP inhibitors may lead to increased immune priming and subsequently promote immune cell infiltration. This has served as the rationale for emerging trials of combination PARP inhibitors and immune checkpoint inhibitors.

Rucaparib + Nivolumab

The CheckMate 9KD trial has evaluated the combination of rucaparib and nivolumab in two cohorts:
  • Cohort A1: Post-chemotherapy mCRPC (1–2 taxanes and ≤2 ARPIs)
  • Cohort A2: Chemotherapy-naïve mCRPC (Received prior ARPI)
In this phase II trial, patients received nivolumab 480 mg every 4 weeks plus rucaparib 600 mg two times per day until disease progression or unacceptable toxicity. The co-primary endpoints were ORR and PSA50 response rates in both all-treated patients and patients with homologous recombination deficiency (HRD)-positive tumors.

Among patients in Cohort A1 (n=58), the ORR was 10.3% in the overall cohort. Superior ORRs were observed in the HRD-positive (17.2%) and BRCA1/2-positive tumors (33.3%). PSA50 responses were observed in 12% of patients in the overall cohort, compared to 18% and 42% of HRD-positive and BRCA1/2-positive tumors, respectively. Median rPFS ranged between 4.9 and 5.8 months, whereas OS ranged between 13.9 and 15.4 months.

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As expected, response rates and survival outcomes were superior in the less heavily pre-treated Cohort A2 (n=39). The ORR was 15.4% in the overall cohort, with ORRs of 25% and 33.3% in the HRD-positive and BRCA1/2-positive tumors, respectively. PSA50 responses were observed in 27.3% of patients in the overall cohort, compared to 42% and 85% of HRD-positive and BRCA1/2-positive tumors, respectively. Median rPFS ranged between 8.1 and 10.9 months, whereas OS ranged between 20.2 and 22.7 months.

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In cohorts A1 and A2, respectively, the most common any-grade and grade 3–4 treatment-related adverse events were nausea (41%) and anemia (14–21%). Approximately 25% of patients discontinued treatment secondary to adverse events.13

Olaparib + Pembrolizumab

Cohort A of the phase 1b/2 KEYNOTE-365 study enrolled patients with molecularly unselected, docetaxel-pretreated mCRPC whose disease progressed within 6 months of screening. In this trial, 102 patients received pembrolizumab 200 mg IV every 3 weeks + olaparib 400 mg capsule or 300 mg tablet orally twice daily. Patients could have received one chemotherapy agent other than docetaxel for mCRPC and ≤2 ARPIs. The primary endpoints were PSA50 response rates, ORR, and safety.

A PSA50 response was observed in 15% of patients. The confirmed ORR was 8.5% (5 partial responses) among patients with measurable disease.

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The median rPFS was 4.5 months, and the median OS was 14 months. Treatment-related adverse events were observed in 91% of patients. Grade 3–5 events occurred in 48% of patients (6% deaths), most commonly anemia (27%), fatigue (6%), and neutropenia (5%).14

This combination of olaparib + pembrolizumab was next assessed in the open-label, phase III KEYLYNK-010 trial that randomized mCRPC patients that had progressed on one prior ARPI and docetaxel in a 2:1 fashion to olaparib + pembrolizumab versus the alternate ARPI (i.e., if had received abiraterone, given enzalutamide and vice versa). The dual primary endpoints were rPFS and OS. This trial included 793 patients of whom 529 and 264 were randomized to olaparib + pembrolizumab and an alternate ARPI, respectively. There was no significant difference in rPFS (median: 4.4 versus 4.2 months; HR: 1.02, 95% CI: 0.82 – 1.25, p=0.55) or OS between the two treatment arms (median 15.8 versus 14.6 months; HR: 0.94, 95% CI: 0.77 – 1.14, p=0.26).

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Grade 3 treatment-related adverse events were more common with olaparib + pembrolizumab (35% versus 9%), with events leading to treatment discontinuation occurring in 11% and 1.6% of patients in the intervention and control arms, respectively. The most common grade ≥3 adverse events with olaparib + pembrolizumab were anemia (20%), fatigue (3%), and asthenia (2.3%).15

Olaparib + Durvalumab

In a single arm phase II trial, the combination of durvalumab 1,500 mg IV every 4 weeks and olaparib 300 mg twice daily was evaluated in 17 mCRPC patients with disease progression following prior ARPI. Overall, 9/17 (53%) patients had a PSA50 response, with 4 of these 9 patients having a radiographic response. The median rPFS of patients with DDR gene alteration was 16.1 months, with a 12-months PFS probability of 83.3%, compared to 36.4% in those without mutations (p=0.031). The most common treatment-related grade 3 or 4 adverse events were anemia (24%), lymphopenia (12%), infection (12%), and nausea (12%).16

figure-7-PARPi-emerging2x.jpg

Talazoparib + Avelumab

The JAVELIN PARP Medley trial is a phase 1b/2 basket trial evaluating the combination of talazoparib and avelumab in patients with advanced solid tumors, including mCRPC patients with and without HHR alterations (n=21). Patients received avelumab 800 mg every 2 weeks plus talazoparib 1mg once daily. In the overall cohort, PSA responses were observed in 2/21 patients, and in the HRR positive mCRPC cohort, the ORR was 11.1%.17

PARP Inhibitors + Bipolar Androgen Therapy

Prostate cancer cells can develop resistance to androgen ablation through an adaptive marked upregulation of androgen receptors over time in response to a low-androgen milieu. This upregulation can make these cells vulnerable to supraphysiologic testosterone exposure. Bipolar Androgen Therapy (BAT) has been proposed as a technique to overcome AR therapeutic resistance. Rapid cycling between polar extremes of supraphysiologic and near-castrate serum testosterone in asymptomatic men with mCRPC has proven to be safe and effective.18

Supraphysiologic androgen levels have been shown to induce double-strand DNA breaks and suppress the expression of genes involved in the DNA repair process.19,20 This has served as the rationale for evaluating the combination of olaparib and BAT in a single arm phase II trial. Thirty-six patients with mCRPC and disease progression following abiraterone and/or enzalutamide received olaparib 300 mg twice daily plus BAT (testosterone cypionate/enanthate 400 mg every 28 days with ongoing androgen deprivation). A PSA50 response was observed in 11/36 patients (31%) at 12 weeks, and the median rPFS in the intent-to-treat cohort was 13 months. The most frequently observed treatment-related adverse events were gastrointestinal related and fatigue. Five patients had grade ≥3 treatment-related adverse events, including one stroke (Grade 4) and one myocardial infarction (Grade 5).21

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PARP Inhibitors + Chemotherapy

The combination of the low dose oral PARP inhibitor veliparib (ABT-888) and temozolomide for docetaxel pre-treated mCRPC patients was evaluated in a single-arm, open-label, pilot study published by Hussain et al. in 2014. This trial included 26 patients with a median baseline PSA of 170 ng/ml. A PSA response was observed in 2 patients (8%), with a further 13 having stable PSA levels. The median PFS was 9 weeks, and the median OS was 40 weeks. Grade 3/4 adverse events occurred in >10 % of patients include thrombocytopenia (23 %) and anemia (15 %).22

PARP Inhibitors + Targeted Therapies

Olaparib + Cediranib

Cediranib is a pan-vascular endothelial growth factor receptor inhibitor that suppresses the expression of HRR genes and increases sensitivity to PARP inhibition in preclinical models.23 In an open-label phase II trial, patients with progressive mCRPC were randomly assigned to receive either cediranib 30 mg once daily plus olaparib 200 mg twice daily versus olaparib 300 mg twice daily alone. In the intention-to-treat cohort of 90 patients, the median rPFS was 8.5 months in the combination arm versus 4 months in the PARP inhibitor monotherapy arm (HR 0.62; 95% CI: 0.39–0.97, p=0.036). Among patients with HRR-deficient mCRPC, the median rPFS was 10.6 months with combination treatment versus 3.8 months with olaparib monotherapy. In the subset of patients with BRCA2-mutated mCRPC, median rPFS was 13.8 months in the combination arm versus 11.3 months in the olaparib only arm. Grade 3–4 adverse events occurred in 61% of patients in the combination arm, compared to 18% of patients in the monotherapy arm.24

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Olaparib + Ceralasterib

In an in vitro study, the combination of olaparib and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor, ceralasterib, was shown to selectively cause cell death in ATM-deficient cells.25 This served as the basis for the TRAP trial, a two-cohort study of mCRPC patients with HRR mutations (BRCA1/2 or ATM; n=35) and another without HRR mutations (n=12). All patients had progressed on ≥1 prior mCRPC therapy with no prior PARP inhibitors or platinum chemotherapy. In this study, olaparib was administered twice daily at a standard dose, and ceralasterib was administered daily on days 1¬–7 of a 28-day cycle. The primary endpoint was disease response (confirmed PSA50 or RECIST response). The response rate in the HRR cohort was 33%, compared to 11% in the HRR negative cohort, including 21% of patients experiencing a grade 3 treatment-related adverse event (no grade 4–5 events).26

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Conclusions and Future Trials


PARP inhibitors are an exciting class of drugs with a unique mechanism of action that lends itself to potential synergistic combinations with other classes of drugs. To date, the only combination to receive regulatory approval is that of PARP inhibitors + ARPIs; however, numerous exciting combinations continue to emerge. Additionally, given their success in the mCRPC disease space, there is increased interest in evaluating such combinations in earlier disease stages, including the high-risk localized and the metastatic hormone-sensitive settings. Summarized in the table below are select trials of PARP inhibitor combination therapy across the prostate cancer spectrum.

table-1-PARPi-emerging2x.jpg

Published March 2024

PARP Inhibitor Monotherapy for Prostate Cancer Patients

Introduction

Over the past decade, there have been significant advances in defining the genomic landscape of prostate cancer. The landmark study by Pritchard et al. published in The New England Journal of Medicine in 2016 demonstrated that germline DNA-repair gene mutations were present in approximately 12% of metastatic prostate cancer patients, most commonly BRCA2 (5.3%), CHEK2 (1.9%), and ATM (1.6%). Significantly, the frequency of such mutations increases across the prostate cancer spectrum – 2% in patients with NCCN localized low-to-intermediate risk tumors, 6% in those with localized high-risk tumors, and as high as 24% in patients with metastatic castrate-resistant prostate cancer (mCRPC).1 This is of utmost clinical importance as such mutations, both inherited and acquired (i.e., somatic), represent actionable clinical targets for drug therapy.

Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are drugs that prevent the repair of DNA single-stranded breaks and promote their conversion to double-stranded breaks leading to a synthetic lethality. These agents are most effective in homologous recombination repair (HRR)-deficient tumors (e.g., BRCA1/2), due to their compromised ability to repair DNA double strand breaks.2 In addition to breast and ovarian malignancies, PARP inhibitors have gained regulatory approval for the treatment of mCRPC patients:

  • Rucaparib for BRCA1/2-mutated patients (FDA approved in 2020)3
  • Olaparib for HRR-mutated patients (FDA approved in 2020)4
  • Olaparib plus abiraterone for BRCA1/2-mutated patients (FDA approved in 2023)5
  • Niraparib plus abiraterone for BRCA1/2-mutated patients (FDA approved in 2023)6
  • Talazoparib plus enzalutamide for HRR-mutated patients (FDA approved in 2023)7

In this Center of Excellence article, we will provide an in-depth overview of the current evidence for PARP inhibitor monotherapy in prostate cancer, summarizing efficacy results from major trials and discussing the adverse event profile of these agents.

Current Evidence for PARP Inhibitor Monotherapy

Olaparib

TOPARP-A was a pivotal phase II trial of olaparib in mCRPC in which 50 patients were treated with olaparib 400 mg twice daily until disease progression.8 The primary endpoint was the composite response rate defined either as an objective response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, or a ≥ 50% reduction in prostate-specific antigen (PSA50), or a reduction in the circulating tumor-cell count from ≥ 5 per 7.5 ml of blood to < 5 per 7.5 ml. All patients had prior treatment with docetaxel and 49 (98%) with abiraterone or enzalutamide. Sixteen of 49 (33%) evaluable patients had a response. Overall, 14 of the 16 responders had homozygous deletions, deleterious mutations, or both in DNA-repair genes — including BRCA1/2, ATM, Fanconi’s anemia genes, and CHEK2.

This was followed by TOPARP-B, an open-label, phase II trial in which men with HRR-mutated mCRPC that had progressed on ≥1 taxane therapy were treated with olaparib 400 mg or 300 mg twice daily in a randomized fashion.9 The primary endpoint was identical to the TOPARP-A trial. A targetable HRR gene aberration was found in 161 of 592 (27.2%) patients who underwent a targeted next-generation tumor sequencing. However, sequencing could not be performed on 119 (17%) of consented patients because of insufficient or poor-quality tissue. The confirmed composite response rate was 54.3% in the 400 mg cohort and 39.1% in the 300 mg cohort (p=0.14). Median radiographic progression-free survival (rPFS) was 5.5 months (95% CI: 4.4 – 8.3) in the 400 mg cohort and 5.6 months (3.7 – 7.7) in the 300 mg cohort. The predefined criteria for success were met for the 400 mg regimen but not for the 300 mg regimen.

These promising results served as the ‘precursor’ for PROfound, a randomized, open-label, phase III trial of olaparib 300 mg twice daily versus physician’s choice of standard of care therapy in men with HRR-mutated mCRPC who had disease progression while receiving a novel hormonal agent (e.g., enzalutamide or abiraterone). Patients were assigned to one of two cohorts based on their HRR gene alteration. Cohort A included patients with BRCA1, BRCA2, or ATM alterations, irrespective of co-occurring alterations in any other HRR genes. Cohort B had patients with alterations in any of the other 12 HRR genes (BRIP1, BARD1, CDK12, CHEK 1/2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L). Patients within each cohort were randomized in 2:1 fashion to olaparib versus standard of care . The primary endpoint was the rPFS in cohort A.

Of the 4,425 enrolled patients, 4,047 had tumor tissue available for testing and only 2,792 (69%) were successfully sequenced. A qualifying alteration in one or more of the 15 HRR genes was detected in 778 of 2,792 patients (28%). Median rPFS was significantly longer in the olaparib group than in the standard of care group (7.4 months versus 3.6 months; HR: 0.34; 95% CI: 0.25 – 0.47; p<0.001).

figure-1-PARPi-monotherapy2x.jpg

The confirmed objective response rate (ORR) was 33% in the olaparib group and 2% in the standard of care  group (odds ratio 20.9; 95% CI: 4.2 – 379.2; p<0.001). The median time to pain progression was also significantly longer in the olaparib group (HR: 0.44; 95% CI: 0.22 – 0.91; p=0.02). The final overall survival (OS) analysis demonstrated that olaparib improved OS in cohort A from a median of 14.7 to 19.1 months (HR: 0.69, 95% CI: 0.50 – 0.97). Notably, 84% of patients with imaging-based disease progression had crossed over from the standard of care  arm to olaparib at the time of analysis, which highlights the efficacy of earlier use of olaparib in this setting.10

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The data from PROfound formed the basis for the FDA-approval of olaparib 300 mg PO twice daily in men with HRR-mutated mCRPC after progression on enzalutamide or abiraterone.4

Rucaparib

The first PARP inhibitor to be approved by the FDA for the treatment of prostate cancer patients was rucaparib. On May 15, 2020, rucaparib was granted accelerated approval for patients with mCRPC and BRCA mutations (germline or somatic) who had progressed following treatment with androgen receptor-directed therapy and a taxane-based chemotherapy.3 This approval was based on the results of TRITON2, which was initially published in 202011 and most recently updated in 2023.12 TRITON2 is an international, open-label, phase II trial that evaluated the safety and efficacy of rucaparib 600 mg twice daily in mCRPC patients with DNA damage response (DDR) gene alterations who had progressed after 1–2 lines of an androgen receptor pathway inhibitor and one taxane-based chemotherapy. The efficacy cohort included 277 patients, of whom 172 (62.1%) had a deleterious germline or somatic BRCA alteration with 21.3%, 5.4%, 3.1%, 4%, and 4.7% having ATM, CDK12, CHEK2, PALB2, and other DDR gene mutations, respectively. A confirmed objective response was observed in 46% of BRCA patients with measurable disease (10% complete response). A superior response was observed among BRCA2 patients (48% versus 30% for BRCA1), which is potentially secondary to an increased frequency of biallelic mutations among BRCA2 patients and a greater coexistence of TP53 mutations among BRCA1-mutated men.13 The objective response was consistent irrespective of whether the BRCA mutation was somatic or germline and whether other DDR mutations were present or absent. All four patients with PALB2 mutations and measurable disease had an objective partial response, with none of the ATM-, CDK12-, CHEK2-mutated patients experiencing an objective response. A confirmed PSA50 response was observed in 53% and 55% of BRCA and PALB2-mutated patients, compared to 3.4–14% among patients with other DDR gene mutations. The median overall survival was 17.2 months for BRCA patients, compared to 11.1–14.6 months among ATM, CDK12, and CHEK2-mutated patients.

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Following the promising results of TRITON2, the phase 3 TRITON3 trial was published in 2023. This was a randomized phase 3 trial of mCRPC patients with a BRCA1, BRCA2, or ATM alterations who experienced disease progression following treatment with a second-generation androgen receptor pathway inhibitor. Patients underwent 2:1 randomization to receive oral rucaparib (600 mg twice daily) or a physician’s choice control (docetaxel or a second-generation ARPI [abiraterone acetate or enzalutamide]). The primary outcome was the median PFS according to independent review. There were 405 patients randomized to receive rucaparib (n=270) or the control group (n=135). At 62 months follow-up, imaging-based PFS was significantly prolonged in the rucaparib group compared to the control group, both in the BRCA subgroup (11.2 and 6.4 months, respectively; HR: 0.50; 95% CI: 0.36 – 0.69) and in the intention-to-treat population (10.2 and 6.4 months, respectively; HR: 0.61; 95% CI: 0.47 – 0.80; p<0.001 for both comparisons). No significant PFS benefit was observed in the ATM subgroup.

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In the BRCA subgroup, the median OS was 24.4 versus 20.8 months in favor of rucaparib (HR: 0.81, 95% CI: 0.58 – 1.12, p=0.21).14

Talazoparib

TALAPRO-1 was an open-label, phase II trial that evaluated talazoparib 1 mg/day in patients with evidence of progressive mCRPC who had measurable soft-tissue disease and evidence of one of 11 DDR mutations who had progressed following taxane-based chemotherapy (48% both docetaxel and cabazitaxel) and abiraterone and/or enzalutamide (98% of population). The primary endpoint was confirmed ORR. There were 128 patients enrolled, of whom 127 received at least one dose of talazoparib (safety population) and 104 had measurable soft-tissue disease (antitumor activity population). After a median follow-up of 16.4 months, the ORR was 30% (95% CI: 21.2 – 39.6%).15

Niraparib

GALAHAD was a multicenter, open-label, single arm phase II trial of 289 mCRPC patients with DNA repair gene defects and disease progression following a prior next-generation androgen signaling inhibitor and a taxane, who received niraparib 300 mg orally once daily. The primary endpoint was ORR in patients with BRCA alterations and measurable disease. At a median follow-up of 10 months, the ORR in the measurable BRCA cohort was 34.2%. The median duration of objective response was 5.6 months. Conversely, the ORR in the measurable non-BRCA cohort was 10.6%. Median rPFS (8.1 versus 3.7 months) and OS (13.0 and 9.6 months) were both longer in the BRCA cohort, compared to the non-BRCA cohort.16

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Management of Side Effects of PARP Inhibitors

The adverse event/safety profiles of all PARP inhibitors overlap considerably. The most common (any CTCAE grade) clinical side effects in phase III trials of rucaparib, olaparib and niraparib include:17

  • Nausea: ~75%
  • Fatigue: 60–70%
  • Vomiting: ~35%
  • Constipation: 20–40%
  • Dysgeusia: 10–40%
  • Anorexia: ~25%
  • Abdominal pain: 25–30%
  • Diarrhea: 20–30%
  • Headache: 20–25%
  • Cough: 10–15%

The most common (any CTCAE grade) lab abnormalities were:

  • Anemia: 40–50%
  • Thrombocytopenia: 15–60%
  • Neutropenia: 20–30%
  • Alanine aminotransferase (ALT) elevation: 5–36%
  • Aspartate aminotransferase (AST) elevation: 2–28%
  • Increased serum creatinine level: 10–15%

While nausea is the most common side effect of PARP inhibitor therapy, it tends to be mild in most cases. This side effect can be managed by taking the medication after a meal and an antiemetic (prochlorperazine or a 5-HT3 antagonist such as ondansetron) may be considered in patients who develop moderate or severe nausea and/or vomiting with PARP inhibitor therapy.

Close monitoring of patients following PARP inhibitor therapy initiation is required, particularly  in the first three months, as hematologic adverse effects usually occur early, but not invariably, and regular blood counts should continue while patients are on treatment. Anemia is the most common hematologic toxicity observed with PARP inhibitors, with grade 3–4 anemia observed in 22% of patients on olaparib, 27% of patients on rucaparib, and 31% of patients on niraparib first-line maintenance therapy ovarian cancer trials.18-21 The management of such events may include dose reductions and/or interruptions, with transfusions reserved for symptomatic anemic events or if the hemoglobin level falls to <7 g/dL. Thrombocytopenia appears to be more common with niraparib at 61%, as opposed to olaparib (14%) or rucaparib (28%). The niraparib FDA label thus recommends obtaining weekly platelet levels during the first month of therapy.

Elevated serum creatinine level occurs within the first few weeks of therapy and is thought to be an on-target effect due to the inhibition of renal transporter proteins. Thus, serum creatinine-based estimation of renal function may be inaccurate in patients receiving PARP inhibitor therapy. Alternative methods of glomerular filtration rate (GFR) estimation such as radionuclide scan or serum-cystatin C must be used in cases where a more accurate GFR estimate is necessary. Elevation of AST and ALT also tends to typically occur within the first two cycles and can be transient. Treatment interruption may not be required for mild AST/ALT elevations, but serum bilirubin levels must be checked in all patients to evaluate for drug-induced liver injury.

Owing to their mechanism of action, there was a concern regarding treatment-emergent myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with PARP inhibitor therapies. However, it appears that the risk of MDS/AML is <1.5%. Of the 2,351 patients treated in olaparib monotherapy trials, only 28 (<1.5%) developed MDS/AML. Of these, 25/28 patients had a BRCA mutation, two patients had a wild-type germline BRCA, and one patient had unknown BRCA mutation status. The duration of olaparib varied from < 6 months to > 2 years and all had received previous chemotherapy with platinum and/or other DNA damaging agents, or radiotherapy.17 If pancytopenia occurs at any point during PARP inhibitor therapy, treatment must be interrupted as per guidelines for the drug, and appropriate evaluation for MDS and AML must be undertaken. Therapy must be discontinued permanently if a diagnosis of MDS or AML is confirmed.

Another important consideration is the potential for clinically-significant drug-drug interactions (DDI) with all PARP inhibitors. Rucaparib and olaparib are primarily metabolized by different members of the cytochrome P450 enzyme family, resulting in only a partial overlap in DDIs. Niraparib is metabolized in the liver by carboxylesterase-catalyzed amide hydrolysis with cytochrome P450 playing only a negligible role.22 Many commonly used drugs (such as phenytoin, carbamazepine, ketoconazole, ciprofloxacin, digoxin) have uni- or bi-directional interactions with PARP inhibitors. Thus, careful attention must be paid to minimize DDI by avoiding, discontinuing, adjusting the dose, or clinical/lab monitoring of these medications before and during PARP therapy. Involving a dedicated oncology pharmacist, where available, may be a valuable aid in this treatment setting.

Conclusions and Future Directions

PARP inhibitor monotherapy has demonstrated promising outcomes for the treatment of HRR-mutated mCRPC patients with evidence of disease progression following treatment with an androgen receptor pathway inhibitor and/or taxane-based chemotherapy. As a result, there has been an increased interest in ‘moving up’ these agents along the disease spectrum, as well as combining PARP inhibitors with other agents that may have a synergistic mechanism of action.

Published March 2024

Novel Treatment Targets in the Metastatic Castrate-Resistant Prostate Cancer Disease Space

Introduction

Since the United States Food and Drug Administration (FDA) approval of mitoxantrone in 19961 and docetaxel in 20042 for the treatment of patients with metastatic castrate-resistant prostate cancer, we have witnessed the approval of numerous additional agents/combinations in this disease space:

The Current State of Treatment Implementation for mCRPC in North America

Introduction

There have been significant advances in the metastatic castrate-resistant prostate cancer (mCRPC) treatment landscape with the emergence and approval of numerous agents in this disease space.

PARP Inhibitor Plus Androgen Receptor Signaling Inhibitor Combinations: Will This Be The Future of mCRPC First-Line Therapy?

Introduction: Despite the approval of numerous agents in this setting, patients with metastatic castrate-resistant prostate cancer (mCRPC) have a poor prognosis, with an estimated median overall survival (OS) of approximately three years with currently approved first-line agents.1-3

Artificial Intelligence and Prostate Cancer: Risk Stratification After Primary Therapy, ADT Treatment Intensification, and Evaluation of Metastatic Disease

Artificial intelligence continues to transform the field of medicine, including the management of prostate cancer. In this Center of Excellence article, we discuss the contemporary literature evaluating artificial intelligence for risk stratification after primary therapy, ADT treatment intensification, and evaluation of metastatic disease.

Radiotherapy in Prostate Cancer: Utilization in the Metastatic Setting

While external beam radiotherapy is a standard treatment option as first-line therapy for men with localized prostate cancer, it has been more recently recognized as an important component in the care of men with metastatic prostate cancer. This Center of Excellence article will explore recent evidence for the utilization of radiotherapy in the metastatic setting.

The Current Landscape of PSMA PET Imaging in Prostate Cancer: Advanced Prostate Cancer

While PSMA PET/CT is currently FDA approved for the initial staging of patients with presumed localized, high-risk prostate cancer and for the diagnostic work up of patients with biochemical failure following primary treatment, the role of PSMA PET/CT in patients with known metastatic prostate cancer is not as well-defined.
  • Written by: Rashid Sayyid, MD MSc, & Zachary Klaassen, MD MSc
  • References:

     

    1. Deek MP, van der Eecken K, Sutera P, et al. Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE Trials. J Clin Oncol. 2022;JCO2200644.
    2. Philips R, Shi WY, Deek M, et al. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol. 2020;6(5):650-9.
    3. Kneebone A, Hruby G, Ainsworth H, et al. Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Detected via Prostate-specific Membrane Antigen Positron Emission Tomography. Eur Urol Oncol. 2018;1(6):531-7.
    4. Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide. N Engl J Med. 2020;383:1040–9.
    5. Smith MR, Saad F, Chowdhury S, et al. Apalutamide and Overall Survival in Prostate Cancer. Eur Urol. 2021;79:150–8.
    6. Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2020;382:2197–206.
    7. Fendler WP, Weber M, Iravani A, et al. Prostate-Specific Membrane Antigen Ligand Positron Emission Tomography in Men with Nonmetastatic Castration-Resistant Prostate Cancer. Clin Cancer Res. 2019;25(24):7448-54.
    8. Wang B, Liu C, Wei Y, et al. A Prospective Trial of 68Ga-PSMA and 18F-FDG PET/CT in Nonmetastatic Prostate Cancer Patients with an Early PSA Progression During Castration. Clin Cancer Res. 2020;26(17):4551-8.
    9. Fourquet A, Aveline C, Cussenot O, et al. 68 Ga-PSMA-11 PET/CT in restaging castration-resistant nonmetastatic prostate cancer: detection rate, impact on patients' disease management and adequacy of impact. Sci Rep. 2020;10(1):2104.
    10. Wright GL, Grob BM, Haley C, et al. Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy. Urology. 1996;48:326–34.
    11. Evans MJ, Smith-Jones PM, Wongvipat J, et al. Noninvasive measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that targets prostate-specific membrane antigen. Proc Natl Acad Sci USA. 2011;108:9578–82.
    12. Aggarwal R, Wei X, Kim W, et a. Heterogeneous Flare in Prostate-specific Membrane Antigen Positron Emission Tomography Tracer Uptake with Initiation of Androgen Pathway Blockade in Metastatic Prostate Cancer. Eur Urol Oncol. 2018;1(1):78-82.
    13. Emmett L, Yin C, Crumbaker M, et al. Rapid Modulation of PSMA Expression by Androgen Deprivation: Serial 68Ga-PSMA-11 PET in Men with Hormone-Sensitive and Castrate-Resistant Prostate Cancer Commencing Androgen Blockade. J Nucl Med. 2019;60:950-4.
    14. Ettala O, Malaspina S, Tuokkola T, et al. Prospective study on the effect of shortterm androgen deprivation therapy on PSMA uptake evaluated with 68Ga-PSMA-11 PET/MRI in men with treatment-naïve prostate cancer. Eur J Nucl Med Mol Imaging. 2020;47:665–673.
    15. Afshar-Oromieh A, Debus N, Uhrig M, et al. Impact of long-term androgen deprivation therapy on PSMA ligand PET/CT in patients with castration-sensitive prostate cancer. Eur J Nucl Med Mol Imaging. 2018;45:2045–2054.
    16. Seitz AK, Rauscher I, Haller B, et al. Preliminary results on response assessment using 68Ga-HBED-CC-PSMA PET/CT in patients with metastatic prostate cancer undergoing docetaxel chemotherapy. Eur J Nucl Med Mol Imaging 2018;45:602–12.
    17. Grubmüller B, Razul S, Baltzer P, et al. Response assessment using [68Ga]Ga-PSMA ligand PET in patients undergoing systemic therapy for metastatic castration-resistant prostate cancer. Prostate 2020;80:74–82.
    18. Kallur KG, Ramachandra PG, Rajkumar K, et al. Clinical utility of gallium-68 PSMA PET/CT scan for prostate cancer. Indian J Nucl Med 2017;32:110–7.
    19. Fanti S, Hadaschik B, Herrmann K. Proposal for Systemic-Therapy Response-Assessment Criteria at the Time of PSMA PET/CT Imaging: The PSMA PET Progression Criteria. J Nucl Med. 2020;61(5):678-82.

     

The Current Landscape of Metastatic Castration-Resistant Prostate Cancer: Radioligand Therapy

Radiopharmaceuticals are pharmaceutical agents which contain radioisotopes that emit radiation, which may be used for diagnostic or treatment purposes. Historically, beta-particle emitting agents including strontium-89 (Metastron), samarium-153 (Quadramet), phosphorus-32, and rhenium-186 were used as palliative therapies for patients with symptomatic bone disease.

The Current Landscape of Metastatic Castration-Resistant Prostate Cancer: Immunotherapy and Targeted Therapies

While there have been clear survival benefits for patients with metastatic castration resistant prostate cancer (mCRPC) with the use of taxane chemotherapy and novel androgen receptor targeting agents, most patients eventually progress following these treatments.

The Current Landscape of Metastatic Castration-Resistant Prostate Cancer: Novel Hormonal Therapies

While the emergence of castration resistant disease comes as a result of the disease progressing in spite of castrate levels of testosterone (at times called hormone refractory disease), prostate cancer (even in the castration resistance prostate cancer (CRPC) setting) remains heavily dependent on the androgen axis.

The Current Landscape of Metastatic Castration-Resistant Prostate Cancer: Nearly Two Decades of Treatment Options

Prostate cancer, while commonly diagnosed as localized disease, remains the second leading cause of cancer mortality in the United States and Europe.1 For patients who die of prostate cancer, some will be initially diagnosed and treated for metastatic hormone-sensitive disease (mHSPC).

  • Written by: Zachary Klaassen, MD MSc and Rashid Sayyid, MD MSc
  • References:
    1. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-1512.
    2. Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996:14(6):1756-1764.
    3. Osoba D, Tannock IF, Ernst DS, Neville AJ. Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. J Clin Oncol. 1999;17(6):1654-1663.
    4. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147-1154.
    5. de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med. 2019;381(26):2506-2518.
    6. Morgans AK, Hutson T, Guan AKD, et al. An economic evaluation of cabazitaxel versus a second androgen receptor-targeted agent (ARTA) for patients with metastatic castration-resistant prostate cancer previously treated with docetaxel and an ARTA: the United States payer perspective. BMC Health Serv Res. 2022;22(1):916.

The Role of Remote Interactions in Genitourinary Oncology: Implications for Practice Change in Light of the COVID-19 Pandemic

The rapid spread of Coronavirus Disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) has dramatically reshaped the structure of Western society, including on health care delivery.1 While care for patients with cancer has been prioritized in nearly every guideline and recommendation, data suggest that among patients with COVID-19, those with a history of cancer have significantly increased risk of severe outcomes.2 Further, patients most at risk of a severe SARS-CoV-2 phenotype are men and those of advanced age or comorbidity,1,3-6 demographics which mirror the patient population with genitourinary cancers.
  • Written by: Zachary Klaassen, MD, MSc
  • References:
    1. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. The New England journal of medicine. 2020.
    2. Dai M, Liu D, Liu M, et al. Patients with cancer appear more vulnerable to SARS-COV-2: a multi-center study during the COVID-19 outbreak. Cancer Discov. 2020.
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    4. Grasselli G, Zangrillo A, Zanella A, et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA : the journal of the American Medical Association. 2020.
    5. Myers LC, Parodi SM, Escobar GJ, Liu VX. Characteristics of Hospitalized Adults With COVID-19 in an Integrated Health Care System in California. JAMA : the journal of the American Medical Association. 2020.
    6. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA : the journal of the American Medical Association. 2020.
    7. Boehm K, Ziewers S, Brandt MP, et al. Telemedicine Online Visits in Urology During the COVID-19 Pandemic-Potential, Risk Factors, and Patients' Perspective. European urology. 2020;78(1):16-20.
    8. Castaneda P, Ellimoottil C. Current use of telehealth in urology: a review. World journal of urology. 2019.
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    10. Schaffert R, Dahinden U, Hess T, et al. [Evaluation of a prostate cancer Ehealth tutorial : Development and testing of the website prostata-information.ch]. Urologe A. 2018;57(2):164-171.
    11. Berry DL, Hong F, Blonquist TM, et al. Decision Support with the Personal Patient Profile-Prostate: A Multicenter Randomized Trial. The Journal of urology. 2018;199(1):89-97.
    12. Parsons JK, Zahrieh D, Mohler JL, et al. Effect of a Behavioral Intervention to Increase Vegetable Consumption on Cancer Progression Among Men With Early-Stage Prostate Cancer: The MEAL Randomized Clinical Trial. JAMA : the journal of the American Medical Association. 2020;323(2):140-148.
    13. Skolarus TA, Metreger T, Wittmann D, et al. Self-Management in Long-Term Prostate Cancer Survivors: A Randomized, Controlled Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2019;37(15):1326-1335.
    14. Viers BR, Lightner DJ, Rivera ME, et al. Efficiency, satisfaction, and costs for remote video visits following radical prostatectomy: a randomized controlled trial. European urology. 2015;68(4):729-735.
    15. Leahy M, Krishnasamy M, Herschtal A, et al. Satisfaction with nurse-led telephone follow up for low to intermediate risk prostate cancer patients treated with radical radiotherapy. A comparative study. Eur J Oncol Nurs. 2013;17(2):162-169.
    16. Belarmino A, Walsh R, Alshak M, Patel N, Wu R, Hu JC. Feasibility of a Mobile Health Application To Monitor Recovery and Patient-reported Outcomes after Robot-assisted Radical Prostatectomy. Eur Urol Oncol. 2019;2(4):425-428.
    17. Lange L, Fink J, Bleich C, Graefen M, Schulz H. Effectiveness, acceptance and satisfaction of guided chat groups in psychosocial aftercare for outpatients with prostate cancer after prostatectomy. Internet Interv. 2017;9:57-64.
    18. Trinh L, Arbour-Nicitopoulos KP, Sabiston CM, et al. RiseTx: testing the feasibility of a web application for reducing sedentary behavior among prostate cancer survivors receiving androgen deprivation therapy. Int J Behav Nutr Phys Act. 2018;15(1):49.
    19. Lee BJ, Park YH, Lee JY, Kim SJ, Jang Y, Lee JI. Smartphone Application Versus Pedometer to Promote Physical Activity in Prostate Cancer Patients. Telemed J E Health. 2019;25(12):1231-1236.
    20. Novara G, Checcucci E, Crestani A, et al. Telehealth in Urology: A Systematic Review of the Literature. How Much Can Telemedicine Be Useful During and After the COVID-19 Pandemic? European Urology (in press). 2020.
    21. Kontopantelis E, Roland M, Reeves D. Patient experience of access to primary care: identification of predictors in a national patient survey. BMC Fam Pract. 2010;11:61.
    22. Kane LT, Thakar O, Jamgochian G, et al. The role of telehealth as a platform for postoperative visits following rotator cuff repair: a prospective, randomized controlled trial. J Shoulder Elbow Surg. 2020;29(4):775-783.
    23. Wallis CJD, Morton G, Herschorn S, et al. The effect of selection and referral biases for the treatment of localised prostate cancer with surgery or radiation. British journal of cancer. 2018;118(10):1399-1405.
    24. Meti N, Rossos PG, Cheung MC, Singh S. Virtual Cancer Care During and Beyond the COVID-19 Pandemic: We Need to Get It Right. JCO Oncol Pract. 2020:OP2000281.
    25. Holstead RG, Robinson AG. Discussing Serious News Remotely: Navigating Difficult Conversations During a Pandemic. JCO Oncol Pract. 2020:OP2000269.
    26. Roberts ET, Mehrotra A. Assessment of Disparities in Digital Access Among Medicare Beneficiaries and Implications for Telemedicine. JAMA internal medicine. 2020.
    27. Lam K, Lu AD, Shi Y, Covinsky KE. Assessing Telemedicine Unreadiness Among Older Adults in the United States During the COVID-19 Pandemic. JAMA internal medicine. 2020.
    28. de la Torre-Diez I, Lopez-Coronado M, Vaca C, Aguado JS, de Castro C. Cost-utility and cost-effectiveness studies of telemedicine, electronic, and mobile health systems in the literature: a systematic review. Telemed J E Health. 2015;21(2):81-85.
    29. Jiang X, Ming WK, You JH. The Cost-Effectiveness of Digital Health Interventions on the Management of Cardiovascular Diseases: Systematic Review. J Med Internet Res. 2019;21(6):e13166.
    30. Shepperd S, Iliffe S. Hospital at home versus in-patient hospital care. Cochrane Database Syst Rev. 2001(3):CD000356.
    31. Qaddoura A, Yazdan-Ashoori P, Kabali C, et al. Efficacy of Hospital at Home in Patients with Heart Failure: A Systematic Review and Meta-Analysis. PloS one. 2015;10(6):e0129282.
    32. Caplan GA, Coconis J, Woods J. Effect of hospital in the home treatment on physical and cognitive function: a randomized controlled trial. The journals of gerontology Series A, Biological sciences and medical sciences. 2005;60(8):1035-1038.
    33. Raphael R, Yves D, Giselle C, Magali M, Odile CM. Cancer treatment at home or in the hospital: what are the costs for French public health insurance? Findings of a comprehensive-cancer centre. Health Policy. 2005;72(2):141-148.
    34. K. SR, Magee D, Hird AE, et al. Reoperation within 30 Days of Radical Cystectomy: Identifying High-Risk Patients and Complications Using ACS-NSQIP Database. Can Urol Assoc J (in press). 2020.
    35. Metcalf M, Glazyrine V, Glavin K, et al. The Feasibility of a Health Care Application in the Treatment of Patients Undergoing Radical Cystectomy. The Journal of urology. 2019;201(5):902-908.
    36. Catto JWF, Khetrapal P, Ambler G, et al. Multidomain Quantitative Recovery Following Radical Cystectomy for Patients Within the Robot-assisted Radical Cystectomy with Intracorporeal Urinary Diversion Versus Open Radical Cystectomy Randomised Controlled Trial: The First 30 Patients. European urology. 2018;74(4):531-534.
    37. van Hout L, Bokkerink WJV, Ibelings MS, Vriens P. Perioperative monitoring of inguinal hernia patients with a smartphone application. Hernia. 2020;24(1):179-185.
    38. Raja JM, Elsakr C, Roman S, et al. Apple Watch, Wearables, and Heart Rhythm: where do we stand? Ann Transl Med. 2019;7(17):417.
    39. Krishnan N, Li B, Jacobs BL, et al. The Fate of Radical Cystectomy Patients after Hospital Discharge: Understanding the Black Box of the Pre-readmission Interval. Eur Urol Focus. 2018;4(5):711-717.
    40. Krishnan N, Liu X, Lavieri MS, et al. A Model to Optimize Followup Care and Reduce Hospital Readmissions after Radical Cystectomy. The Journal of urology. 2016;195(5):1362-1367.
    41. Cai S, Grubbs A, Makineni R, Kinosian B, Phibbs CS, Intrator O. Evaluation of the Cincinnati Veterans Affairs Medical Center Hospital-in-Home Program. J Am Geriatr Soc. 2018;66(7):1392-1398.
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    43. Ramkumar PN, Haeberle HS, Ramanathan D, et al. Remote Patient Monitoring Using Mobile Health for Total Knee Arthroplasty: Validation of a Wearable and Machine Learning-Based Surveillance Platform. J Arthroplasty. 2019;34(10):2253-2259.
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PARP Inhibitors in Prostate Cancer

Prostate cancer is a clinically heterogeneous disease with many patients having an indolent course requiring no interventions and others who either present with or progress to metastasis. While underlying dominant driving mutations are not widespread, there have been a number of key genomic mutations that have been consistently identified in prostate cancer patients, across the disease spectrum including gene fusion/chromosomal rearrangements (TMPRSS2-ERG), androgen receptor (AR) amplification, inactivation of tumor suppressor genes (PTEN/PI3-K/AKT/mTOR, TP53, Rb1) and oncogene activation (c-MYC, RAS-RAF).1

The Impact of COVID-19 on Oncology Clinical Trials

Since the beginning of the COVID-19 pandemic in early 2020, the diagnosis, treatment and surveillance of cancer has been transformed globally. The heavy demand for resources, exacerbated by limited excess health system capacity, means that health care systems have become quickly overwhelmed and hospitals have become sources for virus transmission.

Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

While androgen deprivation therapy (ADT) is nearly ubiquitously successful in suppressing testosterone to castrate levels with resultant declines in prostate-specific antigen (PSA) levels, the development of resistance is nearly as inevitable. While the natural history is variable, evidence suggests that most patients with advanced or metastatic prostate cancer will have disease progression within two to three years after initiation of androgen deprivation therapy, resulting in so-called “castration-resistant prostate cancer.”

The Genetics of Prostate Cancer

Germline mutations in prostate cancer carcinogenesis

Some of the first data to delineate the value of assessment of inherited genetic changes in prostate cancer came from Pritchard and colleagues who assessed the prevalence of mutations in 20 DNA-repair genes among 692 patients with metastatic prostate cancer8. They identified such mutations in 82 men (11.8%).

Oligometastatic Prostate Cancer – Treatment of the Primary Tumor and Metastasis Directed Therapy

In 2018 1.3 million prostate cancer (PCa) cases were diagnosed worldwide, with approximately 20% having metastatic disease.1 Oligometastatic PCa is defined as a state of low-volume metastatic disease that appears to be prognostically different and likely amenable to different treatment options, which could potentially change the disease trajectory when compared with high-volume metastatic disease.2 

Prostate Cancer Survivorship

Physical Side Effects


Urinary Dysfunction

Urinary dysfunction is a side effect of both surgical and radiotherapy (RT) for local treatment of prostate cancer (PCa). Surgical side effects typically include a period of urinary incontinence for several months postoperatively followed by a degree of stress urinary incontinence that may persist for months or even years. RT-induced urinary dysfunction typically manifests as bladder irritability/overactivity either during treatment or shortly thereafter. Longer-term urinary dysfunction issues after RT may include urethral strictures necessitating periodic interventions and/or catheterization.

The ProtecT trial randomized 1,643 men from 1999 to 2009 to undergoing either active monitoring (n=545), surgery (n=553), or RT (n=545), finding that at a median 10 years of follow-up, PCa-specific mortality was low irrespective of treatment.2 As part of this trial, patient-reported outcomes were collected and have now become one of the benchmarks for counseling patients with regards to long-term side effects of treatment for localized PCa treatment.3 Questionnaires were completed at the time of diagnosis, at 6 and 12 months after randomization, and annually thereafter. Patients completed validated measures that assessed urinary, bowel, and sexual function and specific effects on quality of life, anxiety, and depression, and general health. The rate of questionnaire completion during follow-up was outstanding at >85% for most measures. Regarding urinary dysfunction, radical prostatectomy (RP) had the greatest negative effect on urinary continence, and although there was some recovery over time, these patients remained worse throughout follow-up compared to patients undergoing active monitoring or RT. Interestingly, RT had little effect on urinary incontinence, and there was a gradual decrease in urinary function over time for the men undergoing active monitoring. Urinary voiding and nocturia were worse in the radiotherapy group at 6 months but then mostly recovered and were similar to the other groups after 12 months. Urinary incontinence has been cited as being the most important factor for decision regret among receiving local therapy for PCa and may be incompletely explained/discussed with ~80% of patients prior to undergoing treatment.4

Sexual Dysfunction

Similar to urinary dysfunction, sexual dysfunction is a common side effect of localized therapy for PCa. Patients undergoing RP will suffer a degree of sexual dysfunction in the immediate postoperative period with a degree of recovering over 12-24 months after surgery. Many studies have been published assessing predictors of postoperative recovery of sexual function, commonly highlighting younger age and adequate function pre-operatively as predictors of post-operative recovery. Men undergoing RT, similar to urinary dysfunction, will not notice an immediate effect on sexual function during the treatment phase, but generally, suffer sexual dysfunction in the years post-radiation.

In the ProtecT trial, RP incurred the greatest degree of sexual dysfunction among all three treatment arms, with some recovery of function over time.3 The negative effect of RT on sexual function was greatest at 6 months, but sexual function then recovered somewhat and was stable thereafter. Sexual dysfunction also declined in the active monitoring group over time.

Primarily secondary to the sexual side effects of localized treatment for PCa, many cancer centers now have fellowship-trained experts that see these patients concomitantly with the oncologist. There are a variety of treatment options offered, including oral PDE-5 inhibitors (sildenafil, tadalafil, etc.), intracavernosal injection therapy, and penile prosthetics.

Bowel Dysfunction

Bowel dysfunction is typically low for patients undergoing RP or active surveillance (AS) but may be a detrimental side effect among men undergoing RT. In the ProtecT trial, bowel function was worse in the RT group at 6 months than in the other groups but then recovered somewhat, except for the increasing frequency of bloody stools; bowel function was unchanged in the active monitoring and RP groups.3

Bowel dysfunction and rectal toxicity has improved with the recent FDA approval of hydrogel rectal spacers. Prior to RT, patients may have a hydrogel rectal spacer (SpaceOAR®) placed in a transperineal fashion in the fat between the rectum and Denonvilliers' fascia. In the pivotal clinical trial assessing hydrogel spacers, 114 patients were enrolled between 2010 and 2011 with 54 patients selected for a hydrogel injection before the beginning of RT.5 Patients were surveyed at various time-points with the EPIC PCa questionnaire – among patients treated with a hydrogel spacer, mean bowel function and bother score changes of >5 points in comparison with baseline levels were found only at the end of RT (10-15 points; p < 0.01). Mean bowel bother score changes of 21 points at the end of RT, 8 points at 2 months, 7 points at 17 months, and 6 points at 63 months after RT were found for patients treated without a spacer. These bowel quality of life results have given hydrogel spacers an option among patients considering RT.

Other health-related effects

There is evidence that both RT and androgen deprivation therapy (ADT) may contribute to the development of coronary heart disease, sudden cardiac death, myocardial infarction, and skeletal-related events such as fracture.6

Psychological Side Effects

Depression and Anxiety

Depression is the most common psychiatric comorbidity among cancer patients, including patients with PCa. Ravi et al.7 previously utilized the SEER-Medicare database to assess the burden of mental health issues (anxiety, major depressive disorder, suicide) in patients with localized PCa. Among 50,586 men >65 years of age without a diagnosis of mental illness, 20.4% of men developed a mental illness with a median 55-month follow-up. Interestingly, patients undergoing WW (29.7%) and RT (29.0%) had a significantly increased incidence of mental illness compared to patients undergoing RP (22.6%; p<0.001). A systematic review of depression and anxiety in patients with PCa identified 27 articles comprising 4,494 patients.8 The meta-analysis of prevalence rates identified pretreatment prevalence of depression of 17.27% (95% confidence interval (CI) 15.06%-19.72%), on-treatment prevalence of 14.70% (95% CI 15.06%-19.72%) and post-treatment prevalence of 18.44% (95% CI 15.18%-22.22%). For anxiety, pretreatment prevalence was 27.04% (95% CI 24.26%-30.01%), on-treatment was 15.09% (95% CI 12.15%-18.60%) and post-treatment was 18.49% (95% CI 13.81%-24.31%). For patients undergoing AS, nearly one-third of patients (29%) report cancer-specific anxiety in the year following diagnosis.9 Interestingly, over time, this anxiety decreased significantly.

There is also increasing evidence that ADT for locally advanced and metastatic PCa is associated with depression. A study from 2016 using SEER-Medicare data found that men that received ADT, compared with patients who did not receive ADT, had higher 3-year cumulative incidences of depression (7.1% v 5.2), inpatient psychiatric treatment (2.8% v 1.9%), and outpatient psychiatric treatment (3.4% v 2.5%).10 Furthermore, the risk of depression increased with the duration of ADT, from 12% with ≤ 6 months of treatment, 26% with 7 to 11 months of treatment, to 37% with ≥ 12 months of treatment. A recent meta-analysis of 18 studies among 168,756 men found that ADT use conferred a 41% increased risk of depression (RR 1.41, 95%CI 1.18-1.70).11 These results were consistent when limiting the analysis to studies in localized disease (relative risk (RR) 1.85, 95%CI 1.20-2.85). Interestingly, this analysis did not find an association for continuous ADT with depression risk compared to intermittent ADT (RR 1.00, 95%CI 0.50-1.99).

Suicidal Risk

Patients with PCa have been shown to be at increased risk of suicide across several population-level studies. In a SEER analysis assessing suicide risk among patients with genitourinary malignancies from 1988-2010, Klaassen et al.12 found an age-adjusted standardized mortality ratio (SMR) of 1.37 for patients with PCa (95%CI, 0.99-1.86) Increasing age, metastatic disease and Caucasian race were risk factors for suicide among these patients. Interestingly, even patients >15 years after diagnosis were at increased risk of suicide compared to the general population (SMR 1.84, 95%CI 1.39-2.41). In an assessment of PCa suicidal risk compared to individuals with other malignancies, Dalela et al.13 found that risk of suicidal death was no different in men with PCa (1,165 [0.2%]) compared to men with other cancers (2,232 [0.2%]), However, within the first year of diagnosis, men with PCa had an increased risk of suicide (absolute risk reduction (ARR) 3.98, 95% CI 3.02-5.23 0-3 months after diagnosis). Furthermore, men with non-metastatic PCa who were Caucasian, uninsured, or recommended but did not receive treatment (hazard ratio (HR) vs treated 1.44, 95%CI 1.20-1.72) were at increased risk of suicidal death.

A meta-analysis of observational studies assessing incidence and risk factors of suicide after PCa diagnosis was recently published.14 This study included 8 observational studies involving 1,281,393 men diagnosed with PCa and 842,294 matched PCa-free men. Guo et al. found an overall increased relative risk of suicide of 2.01 (95% CI 1.52-2.64) among men diagnosed with PCa compared with those without PCa during the first year after diagnosis, particularly during the first 6 months after diagnosis (RR   2.24, 95%CI 1.77-2.85). Additionally, PCa patients were at an increased risk of suicide among men aged 75 years or older (RR  1.51, 95% CI 1.04-2.18) and for those treated with ADT (RR  1.80, 95% CI 1.54-2.12).

Until recently, all population-level studies assessing risk of suicide among PCa patients have not accounted for psychiatric comorbidities at the time of diagnosis. This is important, considering that being unable to adjust for psychiatric comorbidities makes it impossible to assess the true risk associated with a PCa diagnosis on suicidal risk. At the AUA 2019 annual meeting, Klaassen et al.15 presented data assessing all residents of Ontario, Canada diagnosed with either prostate, bladder or kidney cancer (1997-2014). Each patient was assigned a psychiatric utilization gradient (PUG) score in the five years prior to cancer diagnosis: 0 (none), 1 (outpatient), 2 (emergency department), 3 (hospital admission). Non-cancer controls were matched 4:1 to cancer patients based on sociodemographic variables and a marginal cause-specific hazard model was used to assess the effect of cancer on the risk of suicidal death. Among 191,068 patients included (137,699 PCa, 29,884 bladder cancer, 23,485 kidney cancer), 109,154 (57.1%) were PUG score 0, 79,553 (41.6%) PUG score 1, 1,596 (0.84%) PUG score 2, and 765 (0.40%) PUG score 3. Patients with genitourinary cancer had a higher risk of dying of suicide compared to controls (HR 1.16, 95%CI 1.00-1.36). Specifically, among individuals with PUG score 0, those with cancer were significantly more likely to die of suicide compared to patients without cancer (HR 1.39, 95%CI 1.12-1.74).

Guideline Recommendations

The Commission on Cancer requires cancer programs to develop and implement processes to monitor formation and dissemination of a survivorship care plan for all cancer patients with stage I-III disease treated with curative intent, and to have this plan in place within 1-year of diagnosis of cancer and no later than 6 months after completing adjuvant therapy.16 Guideline recommendations for PCa survivorship have primarily been driven by the American Cancer Society (ACS) and the American Society of Clinical Oncology (ASCO). The ACS noted in their 2014 guideline that survivorship should promote comprehensive follow-up care and optimal health and quality of life for the post-treatment PCa survivor.17 The guidelines also address health promotion, surveillance for PCa recurrence, screening for second primary cancers, long-term and late effects assessment and management, psychosocial issues, and care coordination among the oncology team, primary care clinicians, and non-oncology specialists. Subsequently, the ASCO Endorsement Panel reviewed the ACS guidelines, endorsing these guidelines with the following recommendations:18

• Measure PSA level every 6 to 12 months for the first 5 years and then annually, considering more frequent evaluation in men at high risk for recurrence and in candidates for salvage therapy. 

• Refer survivors with elevated or increasing PSA levels back to their primary treating physician for evaluation and management.

• Adhere to ACS guidelines for the early detection of cancer.

• Assess and manage physical and psychosocial effects of PCa and its treatment.

• Annually assess for the presence of long-term or late effects of PCa and its treatment.

Screening Measures

There are several screening tools to assess for quality of life, depression and suicidal risk. A study from 2017 assessed differences in the scores, relative severity and major depressive disorder from three standardized self-report scales for depression in PCa patients [The Hospital Anxiety and Depression Scale Depression subscale (HADS-D), the Self-rating Depression Scale (SDS) and the Patient Health Questionnaire (PHQ-9) for depression].19 Among 138 PCa patients, despite significant correlations between the total scores from the three scales, severity classification differed across the three scales. Furthermore, there was considerable underestimation of depression by the HADS-D compared to the PHQ-9 and a similar tendency for the SDS. This study highlights that scale construction and depression items included can produce different results across scales, making inter-study comparisons difficult. Despite these findings, we recommend that at minimum oncologists should be using at least one depression index to assess patient well-being at each clinic visit.

In addition to the aforementioned HADS-D, SDS, and PHQ-9 metrics, the National Comprehensive Cancer Network (NCCN) provides a guideline for identifying and explaining risk factors in patients with cancer, in addition to providing a “distress thermometer”. The NCCN defines distress, in the setting of cancer, as a multifactorial emotional experience of a psychological, social, and/or spiritual nature that may interfere with the ability to cope effectively with the diagnosis.20 Distress can range from sadness and fear to more disabling symptoms such as anxiety and depression. Furthermore, the time periods at which patients are at increased vulnerability begin with the realization of a suspicious symptom, all the way through to failure/disease recurrence and near the end of life. The NCCN recommends screening all patients for distress to recognize, monitor, and treat patients effectively.20

Previous work has also suggested that screening for depression and erectile dysfunction may be a way to decrease suicidal risk among PCa patients.21 A proposed algorithm allows for an initial evaluation with the EPIC-CP and PHQ-9 tools to assess for health-related quality of life and depression, respectively. If the EPIC-CP or PHQ-9 are negative for depression or erectile dysfunction, these tools should still be used at each visit to regularly evaluate patients. If EPIC-CP or PHQ-9 suggest problems with depression or erectile dysfunction, then an 8-question suicidal ideation questionnaire (adapted from Recklitis et al.22) should be completed. If the suicidal ideation questionnaire demonstrates any level of suicidal ideation, clinicians should make an urgent referral for psychiatric evaluation. This is particularly true when the patient has the concomitant high-risk suicidal risk profile of being elderly, white, single, or with high-risk or disease progression. Given that, at maximum, the patient must answer a 27-point composite questionnaire, this should be feasible in the busy clinical setting and can be provided to the patient at appointment check-in and completed in the waiting room before the physician-patient encounter. Regardless of the results from these screening tools, if any member of the healthcare team has an index of suspicion for suicidal ideation, the physician should immediately make a referral for psychiatric evaluation.

Conclusions

With nearly 3 million men in the United States living with PCa, survivorship programs are now mandated by the Commission on Cancer and play an integral role in health and well-being of men with PCa. In addition to the physical side effects of treatment that should be addressed at each clinic visit, there are crucial psychiatric side effects, including depression, anxiety, and suicidal ideation that should be screened for and recognized by all members of the healthcare team.

Published Date: December 2019
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